Autonomic Differential Diagnosis

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AUTONOMIC DISORDERS

Physiology & Pharmacology
Sympathetic & Parasympathetic

Diseases or syndromes
Acute
Amyloidosis
Catecholamines
Congenital
Diabetes Mellitus
Drugs & Toxins
Hereditary
Immune
Infections
Localized dysfunction
Paraneoplastic
Primary dysautonomia
System degenerations
Systemic diseases

System disorders
Cardiac
Gastrointestinal
Hypotension
Lacrimation
Ocular & Pupils
Pandysautonomia
Respiratory
Sexual
Sweating
Urinary

Other
Pavlov laboratory

From Horsley Gantt

From Horsley Gantt

AUTONOMIC DISEASE SYNDROMES

Systemic diseases
- Amyloidosis
- Diabetes Mellitus
- Porphyria
- Infections or related toxins
  - Botulism
  - Chagas'
  - Diphtheria: Systemic syndrome
  - HIV
  - Leprosy
  - Rabies
- Chronic renal or hepatic disease: Usually subclinical
Immune disorders
- Acute Dysautonomia
- Guillain-Barré Syndrome
- Paraneoplastic: Especially Small cell lung cancer
  - Sensory neuronopathy: anti-Hu
  - Dysautonomia: IgG vs α3 subunit of acetylcholine receptor
  - Enteric neuropathy: Hu; CV-2; DPPX
  - LEMS
- Sjögren's syndrome
- ? Collagen Vascular Disorders
System Degenerations
- Idiopathic Orthostatic Hypotension
- Shy-Drager (Multiple systems atrophy)
- Parkinsonism: DOPA responsive
- Mitochondrial - MNGIE
  (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy)
- Neuronal intranuclear inclusion disease (NIID)

Hereditary autonomic disorders

Congenital
Anhidrotic ectodermal dysplasia: Xq12
Aniridia: Paired box gene 6; 11p13
Biemond congenital anaesthesia
Dopamine β-Hydroxylase deficiency: 9q34
HSAN 2: HSN2; 12p13
HSAN 3: (Riley-Day): IKBKAP; 9q31
HSAN 4: TRKA/NGFR; 1q23
HSAN 6: DST; 6p12
Autonomic + Intellectual Δ: TECPR2; 14q32
Hirschsprung's congenital megacolon
Hypoventilation
Lacrimation: Absence
Visceral myopathy & PEO

Congenital dysautonomias, Other

Other hereditary autonomic disorders

Achalasia
AAA syndrome: AAAS; 12q13
Achalasia-Alacrimia-Intellectual Dysfunction: GMPPA; 2q35
APECED: Autoimmune regulator (AIRE); 21q22
Adult-onset Leukodystrophy: Lamin B1; 5q31
Ataxia + Thermoanalgesia
Blood pressure disorders
Epithelial Na⁺ channel Δ: SCNN1A; SCNN1B; SCN1G
Hypotension: Pseudohypoaldosteronism, Type 1
Hypertension: Liddle syndrome
Orthostatic Hypotension (Hyperbradykininism): 18q
Postural hypotension
Cold-Induced Sweating
Dementia with Lewy bodies
Dopamine receptor D4: 11p15

Fabry's: α-galactosidase; Xq22
HIDEA: P4HTM; 3p21
HSAN
+ Anosmia
Autonomic & Sensory: PRNP; 20p13
MNGIE
Multiple Endocrine Neoplasia 2b: RET oncogene; 10q11
Navajo
Pain with flushing
Parkinson disease
PCARP: FLVCR1; 1q32
Postural Orthostatic Tachycardia: SLC6A2; 16q12
Prion: 20p13
Rett syndrome: MECP2; Xq28
Tangier disease: ABC1; 9q31
Visceral neuropathy: Dominant; Recessive

Biemond congenital anaesthesia
Pain (submandibular, ocular & rectal) with flushing
Congenital dysautonomias, Other ¹
- Reduced sweating
- Syncope
- Vomiting
- Reduced salivation
- Feeding difficulties during infancy
- Growth retardation
- Reduced tears
- Abnormal temperature control

Drugs & Toxins
- Polyneuropathy
  - Drugs: Alcohol; Amiodarone; cis-Platinum; Cyclosporine A; Perhexiline;
    Taxol; Vacor; Vincristine
  - Heavy metals: Arsenic; Mercury; Thallium
  - Toxins: Acrylamide; Hexacarbons
  - Deficiency: Vitamin B12 (may present with postural hypotension)
- Cellular dysfunction: Pharmacologic
  - Reduce sympathetic activity
    - Sympathetic neuron: Guanethidine; Bethanidine
    - α-adrenoceptor blockade: Phenoxybenzamine; Prazosin
    - β-adrenoceptor blockade: Propranolol; Timolol
  - Increase sympathetic activity
    - Release noradrenaline: Tyramine
    - Monoamine oxidase inhibitors
    - β-adrenoceptor stimulants: Isoprenaline
  - Decrease parasympathetic activity
    - Botulinum toxin
    - Anticholinergic: Atropine; Probanthine
    - Anti-arrhythmics: Disopyramide
  - Increase parasympathetic activity
    - Cholinomimetics
      - Carbachol; Bethanicol; Pilocarpine
      - Mushrooms: Muscimol & Muscarine
    - Anticholinesterases
      - Reversible: Pyridostigmine; Neostigmine
      - Irreversible: Organophosphorus inhibitors
  - Autonomic overactivity
Primary Dysautonomia: Often monophasic + remission
- Acute
  - Pandysautonomia
  - Pure cholinergic dysfunction
    - Dysautonomia but no postural hypotension
    - Postural orthostatic tachycardia syndrome (POTS)
    - Gastrointestinal motility disorders
- Chronic autonomic failure
- Congenital: Nerve growth factor deficiency
Localized autonomic dysfunction
- Horner's syndrome: Ptosis; Miosis; Anhidrosis
- Reflex sympathetic dystrophy
- Crocodile tears (Bogorad's syndrome)
- Congenital respiratory failure
- Ross syndrome: Segmental anhidrosis; Hyporeflexia; Tonic pupils

AUTONOMIC SYNDROMES: System disorders

Acute
Cardiac
Gastrointestinal
Hypotension
Lacrimation
Ocular
Pandysautonomia
Respiratory
Sexual
Sweating
Urinary

Pandysautonomia: Autoimmune; Acute, Sub-Acute or Chronic ¹⁶

Onset
- Age: Adult or Child
- Signs
  - Most common: Postural hypotension (78%); GI dysfunction (70%); Anhidrosis
  - Other: Urinary; Impotence
- Females > Males 2:1
- Progression over 1 to 8 weeks
- "Viral prodrome" in 59%: Especially URI or Flu-like syndrome
- Previously healthy person
Anatomical features
- Distribution of autonomic dysfunction: Diffuse; Truncal; Scalp
- Autonomic systems involved: Sympathetic & Parasympathetic in 80%
Clinical features
- Orthostatic hypotension: Without compensatory tachycardia
- Gastrointestinal dysmotility (80%)
- Anhidrosis (60% to 74%)
  - Distribution: Diffuse or Distal predominant
  - Post-ganglionic
  - Heat intolerance
  - More with higher α3-AChR antibody titers
- Dry eyes & mouth (50%)
- Pupillary response reduced (30%)
- GU: Urinary or Erectile dysfunction (30%)
- Sensory (25%)
  - Reduced Small fiber modalities
  - Paresthesias in extremities
- Cough
- Cognitive impairment
- Course: Chronic persistent deficits or Monophasic
Laboratory
- CSF: Elevated protein in 60%; No cells
- Antibody: IgG vs α3 subunit of acetylcholine receptor ⁴ (30%)
  - Epidemiology
    - Frequency: 50% of acute onset pure autonomic syndromes
  - Systems involved: Sympathetic & Parasympathetic
  - Clinical
    - Initial features
      - Orthostatic: Blood pressure or pulse changes
      - GI: Motility disorders
    - Other features
      - Sudomotor: Postganglionic anhidrosis
      - Dry eyes & Mouth
      - Pupillary disorders
      - Urinary bladder dysfunction
    - Course: Monophasic
  - Antibody titers
    - Higher (≥ 1 nmol/L) correlate with
      - Autonomic features: Presence & More severe
      - Neoplasm
    - Low titers (0.03-0.09 nmol/L)
      - Autonomic syndromes: Limited
      - Not specific for autonomic disorders
    - Sero-negative
      - Persistent: Orthostatic hypotension; GI dysfunction
  - Neoplasms (30%): Breast; Lymphoma
  - Other disorders with anti-α3-AChR antibody: Especially intermediate titers
    - Isaacs syndrome: 50%
    - Lambert-Eaton syndrome: 10%
    - Myasthenia gravis: Some patients
    - Polyneuropathy
    - Encephalopathy
    - Lung cancer: 8%
  - Common associated antibodies
    - GAD-65
    - Muscle AChR
    - Voltage-gated cation channel
      - N-type Ca⁺⁺
      - P/Q type Ca⁺⁺
      - K⁺-associated
    - Striational
    - Hu
    - CRMP-5
  - Also see: AChR disorders
- Nerve pathology: Occasional perivascular inflammation
Disease associations
- Neoplasm: 20% to 30%; Especially with high titer IgG vs neuronal AChR
  - Adenocarcinoma (47%): Breast > Lung, Prostate, GI
  - Bladder
  - Rectal (6%)
  - Lymphoid (17%)
  - Small cell lung carcinoma: Cells may contain neuronal AChRs
- Diabetes: 10% of Diabetic autonomic neuropathy
Differential diagnosis
Recovery: Variable degrees
- Partial: Most common outcome
  - Slow over months to years;
  - Correlates with: Reduction in Antibody titer
  - Decreased Blocking of AChR function
- None: Some patients
- Complete recovery: Occasional
Treatment
- For any associated neoplasm
- Pharmacologic or Other: Anecdotal evidence
  - IV Ig; Especially in 1st 8 weeks of disease or progressing disability
  - Corticosteroids
  - Plasma Exchange
  - Other immumodulating medications
Animal model: Rabbits immunized vs recombinant α3 nAChR subunits ¹⁵
- Clinical features: GI hypomotility; Dilated pupils with impaired light response; Distended bladders
- Severity parallels serum levels of ganglionic nAChR autoantibody
- Post-synaptic defect
  - Failure of neurotransmission through abdominal sympathetic ganglia
  - Retention of neuronal viability

Dysautonomia + CNS syndrome ³³

Antibody & Target: IgG vs DPPX
- Tissue staining: Synaptic
- Antibody location: Serum & CSF
DPPX protein
- Dipeptidyl-peptidase-like protein-6 (DPPX)
- Regulatory subunit of neuronal Kv4.2 (KCND2) potassium channels
Clinical
- Onset
  - Age: Mean 53 years
  - Course: Insidious (75%), Sub-acute (25%)
- CNS (100%)
  - Cortical function: Amnesia, Delirium, Psychosis, Depression
  - Hyperexcitability: Myoclonus, Exaggerated startle, Rigidity, Hyperreflexia, Seizures
  - Brainstem: Eye movement disturbances, Ataxia, Dysphagia, Dysarthria, Respiratory failure
  - Sleep disorders: Insomnia, Periodic limb movements, Sleep apnea, Hypersomnia
- Autonomic (50%)
  - GI: Diarrhea, Gastroparesis, Constipation
  - Bladder
  - Cardiac conduction disorder
  - Occasional: Diaphoresis; Thermoregulation
- B-cell neoplasm (10%)
- Treatment: Immunotherapy effective in 60%

Gastrointestinal syndromes

Achalasia
Acquired
Amyloid
Chagas
CIPO (CIIP)
CIPO: FLNA
CIPO + Cardiac: SGOL1
RAD21
Congenital absence of pain
Hirschsprung's (HSCR)
Goldberg-Shprintzen: KIAA1279
Mowat-Wilson: SMADIP1
HSCR: RET

Multiple endocrine neoplasia 2B
Paraneoplastic
Post-surgical
Visceral
Myopathy
VSCM1: ACTG2
VSCM2: MYH11
+ Ophthalmoplegia
Multisystem (MSMDS): ACTA2
Neuropathy
VSCN1: ERBB3
VSCN2: ERBB2
VSCN3

Hirschsprung's congenital megacolon: General
- Epidemiology
  - Incidence: 1 in 5,000 newborns
  - Male predominance: 4 to 1
  - Sibling recurrence: Usually 3% to 4%; 200x higher than general population
- General features: Pathophysiology
  - Absent intrinsic ganglion cells in the submucosal & myenteric plexuses
    - Over variable lengths of the distal gut
  - Failure in time-specific migration of neural-crest derived ganglion cells into GI tract
  - Gene pathways involved
    - RET receptor tyrosine kinase: RET receptor; GDNF (RET receptor ligand)
    - Endothelin type B receptor: EDNR; Endothelin-3 (EDNR ligand)
    - SOX-10 mediated transcription
- Genetics
  - Susceptibility loci (HSCR)
    - 1: RET; 10q11
    - 2: EDNRB
    - 3: GDNF
    - 4: EDN3
    - 5: 9q31
    - 6: 3p21
    - 7: 19q12
    - 8: 16q23
    - 9: 4q31
    - 10: SOX10
    - PHOX2B
    - Visceral Neuropathy
      - 1: ERBB3, Recessive
      - 2: ERBB2, Recessive
      - 3: Dominant
    - Visceral Myopathy
      - 1: ACTG2
      - 2: MYH11
      - External Ophthalmoplegia
  - Inheritance patterns: Non-syndromic disease may be oligogenic
    - Aganglionosis only in sigmoid colon: Often sporadic; 60% to 85% of cases
    - Aganglionosis in long length of intestine: More likely familial occurrence
- Clinical features
  - General: Isolated HSCR 80%; Syndromic HSCR 20%
  - Onset: Congenital
  - Constipation
  - Vomiting
  - Abdominal distention
  - Intestinal obstruction
  - Associated congenital malformations (30%)
    - Cranial pigment formation
    - Sensory components of acoustic pathway
- Pathology
  - Absent enteric parasympathetic ganglia along a variable length of intestine
    - Incomplete migration of neurenteric ganglion cells from neural crest to gut
  - Acetylcholinesterase: Increased in submucosal & myenteric plexus of affected segment
  - Narrowed distal segment of bowel
  - Diagnosis: Absent or reduced ganglion cells in affected segment in rectal biopsy
Hirschsprung disease, susceptibility to, 2 (HSCR2)
● Endothelin receptor type B (EDNRB; HSCR2) ; Chromosome 13q22.3; Recessive
- Genetics
  - Penetrance: 30% to 85%
  - Allelic disorders
    - Waardenburg-Shah syndrome 4A (WS4A)
    - ABCD syndrome
- EDNRB protein
  - Role in: Schwann cell differentiation
  - Pain relations
    - Stimulus: Actions on endothelin-A receptors of local nociceptors
    - Analgesia: Endothelin-B receptors
- Clinical
  - GI (Hirschprung's): Short segment bowel disease in 95%
  - Deafness
  - Pigmentary anomalies
Hirschsprung disease, susceptibility to, 3 (HSCR3)
● Glial cell line-derived neurotrophic factor (GDNF) ; Chromosome 5p13.2; Dominant or Recessive
- Genetics
  - ? Some cases have digenic inheritance with RET
  - ? Penetrance
  - Allelic disorders
    - Central hypoventilation syndrome, Dominant
    - Pheochromocytoma, modifier of, Dominant
- Also see: Autonomic sleep ventilation failure
Congenital central hypoventilation with Hirschsprung disease (HSCR4)
● Endothelin-3 (EDN3) ; Chromosome 20q13.32; Recessive or Dominant with reduced penetrance
- Genetics: Allelic disorders
  - Waardenburg-Shah syndrome 4B (WS4B)
  - Hirschsprung disease, susceptibility to, 4
- Clinical
  - Autonomic sleep ventilation failure
  - GI: Megacolon (Often whole length aganglionosis); Esophageal motility reduced
  - Face: Antimongoloid eye slant; Triangular mouth
  - Low-set ears; Small nose
  - Heart rate control: Reduced
  - Differential diagnosis
    - Depression of ventilatory response to hypoxia and hypercapnia
    - Familial lethal sleep apnea
Hirschsprung disease, susceptibility
● Neurturin Chromosome 19p13.3; Sporadic
- ? Some cases have digenic inheritance with RET
Hirschsprung disease, cardiac defects, and autonomic dysfunction
● Endothelin-converting enzyme (ECE1) ; Chromosome 1p36.1; Dominant or Recessive
- Genetics
  - Mutation: Arg742Cys
  - Allelic with: Essential hypertension, susceptibility
- ECE1 protein
  - Involved in proteolytic processing of endothelin-1
- Clinical
  - Hirschsprung disease: Skip-lesions
  - Cardiac defects
  - Craniofacial abnormalities + Other dysmorphic features
  - Autonomic dysfunction: episodic
    - Agitation
    - Tachycardia
    - Fever
Hirschsprung disease, susceptibility to, 10 (HSCR10)
● SOX10 ; Chromosome 22q13.1; Dominant or Sporadic (Recessive)
- Genetics
  - Mutations: Upstream regulatory region; 38-kB Del, 38412781G-C, 38412215G-A
  - Allelic with
    - Waardenburg syndrome, type IIE (WS2E)
    - Waardenburg syndrome, type 4C (WS4C)
    - Yemenite deaf-blind hypopigmentation syndrome
    - Waardenburg-Shah syndrome, neurologic variant
- Clinical
  - Hypopigmentation
  - Deafness
  - Enteric aganglionosis
- Laboratory
  - Hypomyelination in CNS & PNS
Visceral Neuropathy 2 (VSCN2) (Hirschsprung disease (HSCR)) ⁴⁷
● ERB-B2 Receptor tyrosine kinase 2 (ERBB2; Herstatin; Neu; Her2) ; Chromosome 17q12; Recessive
- Epidemiology: 1 family, 2 patients
- Genetics
  - Mutation: Missense; c.2129C>T, Ala710Val; Homozygous
  - Allelic disorders: Somatic mutations in neoplasms
- ERBB2 protein
  - Present in enteric neurons
  - Locations: Nucleus & Endosome
  - IL6 signaling through MAP kinase pathway
  - ErbB receptor tyrosine kinase component
  - Over-expression in neoplastic transfoprmation of prostate cancer
  - Activated in nerve distal to transection
  - Schwann cell precursors
  - Breast cancer oncogene
  - M. leprae binds to extracellular domain of ERBB2
- Clinical
  - Arthrogryposis: Club feet
  - Polyneuropathy
  - Hearing loss
  - Ptosis
  - Hirschsprung disease: Short segment
- Laboratory
  - GI: Hypoganglionosis
Mowat-Wilson syndrome
● SMADIP1 (Zinc finger homeobox 1B; ZFHX1B; ZEB2) Chromosome 2q22.3; Dominant > Recessive
- Genetic: Mutations
  - Frameshift or Nonsense
  - Deletion syndrome: Occasional patient
- SMADIP1 protein (ZFHX1B; ZEB2)
  - 2-handed zinc finger/homeodomain proteins (Zinc finger homeo box 1B)
  - SMADIP1 interacts with receptor-mediated, activated full-length SMADs
  - Transcriptional repressor
  - Required for: Schwann cell differentiation & myelination
- Clinical
  - May appear in isolation (Non-syndromic) or with other systemic
  - Neonatal: Hypotonia; Hirschsprung megacolon
  - Facial phenotype: Broad nasal bridge (Hypertelorism); Open mouth; Triangular jaw
  - EENT: Large, deep-set eyes (Blue); Large uplifted earlobes
  - CNS
    - Mental retardation: Minimal speech; Delayed motor
    - Epilepsy
    - Learning problems
    - CNS Pathology: Microcephaly; Corpus callosum agenesis
  - Ocular: Iris coloboma; Ptosis; Bicolored irides
  - Heart disease: Congenital
  - Similar recessively inherited syndrome: Goldberg-Shprintzen
Goldberg-Shprintzen Megacolon syndrome (GOSHS) with Polymicrogyria ²²
● Kinesin family binding protein (KIFBP; KIF1BP; KIAA1279) ; Chromosome 10q22.1; Recessive
- Epidemiology: > 45 patients
- Genetics
  - Mutations: Loss of function; Stop, Deletion& Missense; Arg90X, Glu84X, Ser200X
- KIFBP protein ⁴⁹
  - Interacts with: Microtubules; Kinesins, SCG10
  - Tetratrico peptide repeat (TPR) family
  - Ubiquitous expression
  - Functions: Regulates
    - Axon microtubules: Organization & Dynamics
    - Kinesin attachment
    - Mitochondria: Biogenesis & Distribution
    - Mitosis: KIF15 & KIF18 interactions
    - Cytokinesis: Citron Kinase (CIT) interactor
  - Other TPR family disorders
    - Leber congenital amaurosis: AIPL1
    - Charcot-Marie-Tooth 4C: KIAA1985
- Clinical
  - CNS
    - Microcephaly
    - Mental retardation
  - GI: Hirschsprung disease (70%)
  - Face Dysmorphic: Broad nasal bridge, Hypertelorism, Synophrys, Large ears, Long nose
  - Peripheral neuropathy: Axon loss
  - Short stature
  - Other inconstant features
    - Eye: Megalocornea, Iris coloboma, Corneal ulcers; Ptosis, Arched eyebrows, Dense eyelashes
    - Urogenital anomalies
  - Similar Dominantly inherited syndrome: Mowat-Wilson
- Laboratory
  - Brain pathology: Micropolygyria; Corpus callosum hypoplasia
Hirschsprung susceptibility (HSCR1)
● RET oncogene (RET) ; Chromosome 10q11.21; Dominant or Sporadic
- Frequency: 50% of familial cases; 15% to 35% of sporadic cases
- Genetics
  - Gene mutations
    - Multigenerational families: Mutations occur throughout gene
    - Sporadic cases: Mutations in region encoding extracellular domain
  - Genetic mechanism ¹⁰
    - Loss of function
    - Association with other gene mutations
      - More severe, longer segment disease with additional Neurturin mutation
      - Other associated genetic loci (susceptibility)
        
        Locations
        
        HSCR6 ; Chromosome 3p21
        HSCR7 ; Chromosome 19q12
        
        Hirschsprung genetic modifier 8 (HSCR8) : Chromosome 16q23
        
        Hirschsprung genetic modifier 9 (HSCR9) : Chromosome 4q31.3-q32.3
        
        Transmission: Maternal > Paternal
        
        Magnitude of effects: Multiplicative among loci
  - Penetrance: 50% (Females) to 72% (Males)
  - Allelic disorders
    - Central hypoventilation syndrome, congenital
    - Medullary thyroid carcinoma
    - Multiple endocrine neoplasia IIA
    - Multiple endocrine neoplasia IIB
    - Pheochromocytoma
    - Renal agenesis
- Clinical
  - Often non-syndromic Hirschsprung's congenital megacolon
  - Short segment bowel disease in 25%
  - Autonomic sleep ventilation failure
Hirschsprung syndromes: Other
- Down syndrome-associated
  - ? Related to Hirschsprung genetic modifier (HSCR5)
  - On Chromosome 21q22.3
- Polydactyly, Renal agenesis, Deafness
- Hypoplastic nails or finger deformities
- Multiple endocrine neoplasia 2A ; 2B & Medullary thyroid carcinoma
- Heart defects, Laryngeal anomalies, Preaxial polydactyly
- Type D brachydactyly
- Pitt-Hopkins
Achalasia
- Definition
  - Absence of peristalsis in esophagus
  - Failure of relaxation of lower esophageal sphincter
- Etiology
  - Usually 1° disorder
    - Achalasia-Addisonianism-Alacrimia syndrome: AAAS
    - Achalasia-Alacrimia-Intellectual Dysfunction: GMPPA
    - Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED): AIRE
    - Achalsia, Early onset + Moya Moya: GUCY1A3
    - Achalasia-Microcephaly
    - Familial achalasia, esophageal
      ● Autosomal Recessive
  - Occasionally 2° to Chagas
- Pathology
  - Loss of ganglion cells & myenteric nerves
  - Reduced numbers of vasoactive intestinal peptide-containing myenteric plexus neurons
Multiple Endocrine Neoplasia 2b (or 3)
● Rearranged during transfection protooncogene (RET) ; Chromosome 10q11.21; Dominant
- Genetics
  - Common mutation: M918T
  - Allelic disorders
    - Central hypoventilation syndrome, congenital
    - Medullary thyroid carcinoma
    - Multiple endocrine neoplasia IIA
    - Pheochromocytoma
    - Renal agenesis
    - Hirschsprung disease, susceptibility
- Clinical
  - Morphology: "Marfanlike" body build (Long arms), Full & fleshy lips
  - GI dysmotility: Esophagus, Megacolon
  - Leg atrophy: Distal
  - Neuropathy
    - Autonomic; Some sensory & motor
    - Axon loss
  - Neoplasm associations
    - Medullary Thyroid
    - Pheochromocytoma
    - Ganglioneuromas: Tongue & Lips; GI tract; Corneal
Visceral myopathy with External Ophthalmoplegia, Familial
● Recessive
- Epidemiology: 3 German families
- Clinical
  - Eyes: Ptosis & ophthalmoplegia
  - GI: Intestinal pseudoobstruction; Ascites
  - Progression: Death often < 30 years
- Pathology
  - GI: Loss of smooth muscle in stomach & intestines
  - Peripheral neuropathy
Visceral Myopathy, Familial 1 (VSCM1)
● Actin, γ-2, Smooth muscle, enteric (ACTG2; ACTA3) ; Chromosome 2p13.1; Dominant, Recessive or Sporadic
- Nosology
  - Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)
  - Chronic Intestinal Pseudo-Obstruction (CIPO): Congenital or Late onset
- Epidemiology
  - > 25 families
  - 45% to 50% of CIPO
- Genetics
  - Mutations: Missense; Often de novo
  - Null alleles: Recessive
  - Severe: Arg178
  - Allelic disorders
    - Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome-5 (MMIHS5)
    - Possible variant: African Degenerative Visceral Leiomyopathy (ADL)
      - Mutations in ACTG2 & RET identified
- ACTG2 protein
  - Actin
  - Higher transcription levels in tissues with smooth muscle
  - Enteric muscle contraction
  - Mutations: Interfere with polymerization of ACTG2 into thin filaments
- Clinical
  - Onset age: Prenatal or Infancy
  - GI
    - Constipation
    - Intestinal dysmotility
    - Megacolon
    - Intestinal malrotation
  - Urinary
    - Megacystis
    - Hydronephrosis
  - Course: Persistent into adulthood
  - Treatment: Surgical; Transplantation
- Laboratory
  - Jejunum: Outer muscular layer thin
  - GI ganglion cells: Present
CIPO type: Chronic Atrial & Intestinal Dysrhythmia
● Shugoshin-like 1 (SGOL1) : Chromosome 3p24.3; Recessive
- Epidemiology: 17 patients, 14 families
- Genetics
  - Mutation: Missense; Lys23Glu
- SGOL1 protein
  - Location: Nucleus
  - Mitotic progression
  - Chromosome cohesion & segregation during mitosis
  - Prevents premature dissociation of cohesin complex from centromeres after prophase
- Clinical
  - Onset age: Usually 1st or 2nd decade
  - Cardiac: Dysregulation of cardiac sinus node; Sinus bradycardia
  - GI: Chronic intestinal pseudoobstruction (CIPO)
- Laboratory
  - GI pathology: Ganglia mislocalized & hypoplastic
Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (CIPO; CIIPX)
● Filamin A (FLNA) : Chromosome Xq28; Recessive
- Epidemiology: > 30 patients
- Genetics
  - Mutations: Duplications of Xq28 including FLNA; Stop; Missense
  - Allelic disorders
    - ?FG syndrome 2
    - Cardiac valvular dysplasia, X-linked
    - Congenital short bowel syndrome, Recessive
    - Frontometaphyseal dysplasia 1, Recessive
    - Heterotopia, periventricular, Dominant
    - Intestinal pseudoobstruction, neuronal, Recessive
    - Melnick-Needles syndrome, Dominant
    - Otopalatodigital syndrome, type I, Dominant
    - Otopalatodigital syndrome, type II, Dominant
    - Terminal osseous dysplasia, Dominant
- FLNA protein
  - Down-regulates: Androgen receptor function
  - Location: Cytoplasmic or Nuclear
  - Transcription regulation
  - Interacts with: FLNC; FILIP1
- Clinical
  - Onset: Early childhood
  - Bowel malrotation
  - CNS: Developmental delay; Spasticity
Visceral neuropathy, Familial (VSCN1)
● ERBB3; Recessive
Visceral neuropathy 3, Familial (VSCN3)
● Dominant
- Epidemiology: 4 families
- Clinical
  - Onset age: 1st to 7th decades
  - Eyes: Ptosis; Pupils unresponsive
  - GI
    - Intestinal pseudo-obstruction
    - Esophageal achalasia
    - Abdominal distention
  - Polyneuropathy
    - Sensory loss
    - NCV: Axon loss
- Pathology: Myenteric plexus
  - Neurons: Abnormal morphology; Increased number
  - Nerve trunks & Myenteric ganglia: Hyperplastic
Cartilage-hair hypoplasia (CHH)
● Mitochondrial RNA-processing endoribonuclease, RNA component (RMRP) ; Chromosome 9p13.3; Recessive
- Epidemiology: Old Order Amish (US); Finland
- Genetics
  - Mutations
    - Insertions & Deletions; In & out of frame
    - Finnish & Old Order Amish: A70G
  - Allelic with
    - Metaphyseal dysplasia without hypotrichosis
    - Anauxetic dysplasia
- RMRP
  - RMRP gene: Untranslated, encodes RNA, not protein
  - Ribonucleoprotein: Contains protein & RNA components
  - RNA encoded by single-copy gene in nucleus: Imported into mitochondria
  - Enzyme activity
    - Endoribonuclease
    - Cleaves mitochondrial RNA complementary to light chain of displacement loop
- Clinical
  - Skeletal
    - Short stature: Disproportionate
    - Joint hyperextensibility: Hands, wrist, & feet
    - Metaphyseal dysplasia: May be only manifestation
  - Hair: Hypoplastic; Fine, sparse & light-colored
  - Autonomic
    - Intestine: Neuronal dysplasia; Megacolon; Malabsorption
  - Malignancy: Increased risk of lymphoma & skin neoplasm
- Laboratory
  - Defective immunity: Susceptibility to chickenpox; Lymphopenia; Neutropenia
  - Anemia: Hypoplastic macrocytic
Acquired GI disorders
- Chagas' disease (Trypanosomiasis cruzii)
- Gustatory sweating (Frey's syndrome)
- Paraneoplastic
- Post-surgical
  - Regional sympathectomy
  - Dumping syndrome: Post-vagotomy & gastric drainage
  - Heart transplantation

Heart rate: Parasympathetic control

Tachycardia
- Fixed: Diabetes mellitus; Amyloidosis
  - Cardiac parasympathetic failure
- Guillain-Barré
- Flavin-containing monooxygenase 3
  - Fish odor syndrome
    - Tachycardia & hypertension after eating cheese containing tyramine
    - Trimethylaminuria produces fish odor
- Postural Orthostatic Tachycardia Syndrome (POTS)
- Cardiomyopathy: Dystrophinopathy
- Normal
  - Inspiration
  - Magnitude of changes with inspiration & expiration decreases with age
Bradycardia
- Resting: Dopamine β-hydroxylase deficiency
  - Parasympathetic sparing
- Response to stimuli
  - Carotid sinus hypersensitivity
  - Swallow & vasovagal syncope
  - Expiration (Vagal; Cholinregic)
- Cardiomyopathy: Emery-Dreifuss

Postural hypotension (Blood pressure: Sympathetic, noradrenergic control)

Causes
- 1° Autonomic dysfunction
  - Hereditary
    - Hereditary Orthostatic Hypotension
      - Streeten: Hyperbradykininism
      - ORTHYP1: DBH
      - ORTHYP2: CTB561
    - Amyloidosis
    - Epithelial sodium channel genes: Pseudohypoaldosteronism
    - Mitochondrial disorder: Maternal inheritance
    - Postural Orthostatic Tachycardia Syndrome (POTS): SLC6A2
    - Spastic-Ataxia with Lipodystrophy: CAV1
    - Mast cells: TPSAB1
  - Sporadic
- Hypotension
  - Corticosteroid-binding globulin deficiency : Fatigue; Hypotension
- Low intravascular volume
- Vasodilation
- Reduced cardiac output
- Drugs: Amphetamines; Vinca alkaloids
Exacerbation
- Rapid positional change
- Morning
- Large meals
- Prolonged recumbency
- Warm environment
- Increased intrathoracic pressure: cough; micturition; defecation; exertion
- Vasoactive drugs
Treatment ³⁹
- Avoid exacerbating factors
  - Avoid: Alcohol; Sugary beverages
  - Correct anemia
- Physical: Compression Stockings; Abdominal binder
- Reduce salt loss: Mineralocorticoids
  - Fludrocortisone 0.1 mg qd to qid
- Vasoconstriction
  - Resistance vessels
    - Midodrine (α-adrenergic agonist) 10 mg bid or tid
    - Phenylephrine
    - Phenylpropanolamine 25 mg tid
  - Capacitance vessels: Dihydroergotamine
  - Indirect: Ephedrine; MAO inhibitors; Yohimbine
- Prevent vasodilation
  - Prostaglandin synthetase inhibitors: Indomethacin; Flurbiprofen
  - Dopamine receptor blockade: Metoclopramide; Domperidone
  - β-2 adrenoceptor blockade: Propranolol
- Prevent postprandial hypotension
  - Avoid gastric filling: Smaller more frequent meals
  - Adenosine receptor blockade: Caffeine 250 mg
    - Strong coffee or tea before arising from bed & with meals
  - Water drinking ⁹
    - Acts rapidly (Minutes)
    - Before meal: 120 to 480 ml over 5 minutes
    - Total daily intake: 2 to 3 liters
    - Mediated through sympathetic activation: Increased plasma norepinephrine
  - Peptide release inhibitors: Somatostatin analogue; Octreotide
  - Other medications: Ibuprofen 400 mg; Phenylpropanolamine 25 mg; Ergotamine Intranasal: 1 or 2 puffs
- Increase cardiac output: Pindolol; Xamoterol
- Increase red cell mass: Erythropoietin
- Reduce nocturnal polyuria: Desmopressin
- Reduce fall in diastolic pressure: Pyridostigmine (60 mg) ²⁴
- Avoid supine hypertension:
  - Treatment: ACE inhibitor with maximal dose at bedtime
    - Pyridostigmine bromide
    - Enalapril
  - Reduce excessive fludrocortisone
  - No vasoconstrictors after 6 pm
  - Sleep with head of bed elevated

Other blood pressure disorders

Epithelial sodium channel genes SCNN1A ; SCNN1B ; SCN1G
- Hypotension: Pseudohypoaldosteronism, Type 1
- Hypertension: Liddle syndrome

Sweating ⁴⁰

General
Hyperhidrosis
Acquired
Hereditary
CNS
Anhidrosis
Differential diagnosis
Drugs
Hereditary

General
- Mechanism of evaporative heat loss
- From: Eccrine glands
- Control
  - Afferent
    - Peripheral: Thermoreceptors in skin & viscera
    - CNS: Spinothalamic tract to reticular formation; Medial preoptic area of the hypothalamus
  - Efferent
    - CNS: Rostral ventromedial medulla; Spinal cord intermediolateral column
    - Peripheral
      - Autonomic type: Sympathetic
      - Transmitters: Muscarinic cholinergic (ACh); Cholinergic M3-type receptors
      - Anatomy: Face (T1-T4; Arms (T2-T8; Trunk (T4-T12; Legs (T10-T12)
      - Pathway: White rami communicantes to paravertebral sympathetic
- Sweating Types
  - Thermoregulation: Most eccrine sweat glands on forehead & arms
  - Emotional: Palms & Soles

Hyperhidrosis

Hyperhidrosis Definiton: Sweating above necessary to maintain core temperature
Mechanisms
- Aquaporin-5 (AQP5) in sweat gland plasma membranes necessary for secretion of sweat
General disorders
- Essential generalized
- Compensatory for loss of sweating elsewhere
- May be initial symptom with progression to anhydrosis

Gustatory sweating (Frey's syndrome; Baillarger�s syndrome) ⁵⁰

Pathologies
- Aberrant parasympathetic, cholinergic axons supply (facial) sweat glands & vessels
- Auriculotemporal nerve: Aberrant regeneration by parasympathetic axons
- Damaged sympathetic nerve fibers → ↑ Sweat gland sensitivity
  - Sweat glands stimulated by Ach released from adjacent parasympathetic fibers
Etiologies
- Hereditary, Dominant: 1 family
- Acquired
  - Parotid lesions: Especially neoplasms & parotidectomy
  - Diabetes
  - Age: > 45 years
Clinical
- Onset ages: Child & Adult
- Stimuli: Spicy foods; Independent of food type; Smell
- Sweating distribution
  - Face ± Head or Upper body
  - Superior cervical ganglion area
- Onset: End of, or After, meal
- Duration: 10 to 30 minutes
- Other features: Face warmth; Flushing; Pruritis
- Treatment: Botulinum toxin
- Course: Stable or Regression (Especially children)

Lucja Frey 1918

Toxic
Other acquired
- POEMS syndrome
- Neuromyotonia
- Holmes-Adie
- Harlequin syndrome
- Stiff-person syndromes (PERM)
- Axillary sweating
- Segmental hyperhidrosis
  - Causes: Syringomyelia; Vascular disorders; Neoplasms
  - Possible treatments: Botulinum toxin; Mexiletine
- Hirayama
- Endocrine
  - Acromegaly
  - Hyperthyroid
  - Menopause
  - Hypoglycemia
  - Diabetes
- Neoplasm
  - Carcinoid
  - Pheochromocytoma
  - Hematologic: Lymphoma; Leukemia; Castleman
  - Renal cell
- Medications
  - Direct: Propranolol, Physostigmine, Pilocarpine, Bethanechol,
    Tricyclic antidepressants, Serotonin reuptake inhibitors, Proton pumpo inhibitors
  - Drug withdrawal: Opiates; Alcohol
  - Neuroleptic malignant syndrome
- Nocturnal
  - Infection: Tuberculosis; Endocarditis
  - Neoplasm: Lymphoma
  - Endocrine: Diabetes mellitus; Acromegaly; Menopause
  - Other: Obstructive sleep apnea; Prinzmetal angina
- Focal
  - Essential focal: Palmoplantar; Axillary; Craniofacial
  - CNS-related: Infarction; Spinal cord; CISS; Olfactory; Chiari I
  - PNS: Autonomic PN; Dermatomal
  - Craniofacial: Gustatory; Lacrimal; Harlequin; Ross
- Dermatologic
  - Pretibial myxedema
  - POEMS
Hereditary
- HSAN IIB
- Riley-Day syndrome (HSAN 3)
- Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation
- Congenital absence of pain
- SPOAN
- HUMOP2
- Cold-Induced Sweating syndromes (CISS)
  - CISS1 (Crisponi): CRLF1
  - CISS2: CLCF1
  - CISS3: KLHL7
- Hyperhidrosis, Palmoplantar
  ● Chromosome 14q11.2-q13; Dominant
  - Epidemiology: Common in Japanese in Hawaii & Chinese
  - Nosology: Primary focal hyperhidrosis (PFH)
  - Genetics: Linkage in 3 of 11 families
  - Clinical
    - Onset age: Childhood
    - Distribution
      - Linked families: Mainly palmar
    - Exacerbated by: Emotion
    - Not present at night
- Primary focal hyperhidrosis ²⁹
  ● Autosomal Dominant
  - Epidemiology: Northern Italian family
  - Genetics: Not linked to 14q
  - Clinical
    - Onset age: 4 to 12 years
    - Distribution: Palms; Axilla; Soles
    - Other autonomic
      - Intermittent toe blanching & coldness
      - Orthostatic symptoms
    - Exacerbation: Warm environment; Stress
    - No sweating during sleep
    - Course: Progression over decades
  - Laboratory
    - Sympathetic & Parasympathetic dysfunction
    - Skin: Reduced innervation, proximal & distal
- Hypertrophic Osteoarthropathy, primary, autosomal recessive, 1 (PHOAR1)
  ● 15-Hydroxyprostaglandin dehydrogenase (HPGD; PDGH1) ; Chromosome 4q34.1; Recessive
  - Epidemiology: Male > Famale
  - Genetics: Allelic with Cranioosteoarthropathy & Digital clubbing
  - Clinical
    - Onset: Birth
    - Skin
      - Hyperhidrosis
      - Oily
      - Thickened
      - Flushing
      - Hyperkeratosis
    - Head & Neck
      - Face: Coarse; Ptosis; Prominent folds
      - Palate: High arched
    - Skeletal
      - Fingers: Clubbing
      - Bones: Multiple disorders
      - Joints: Arthralgias; Reduced mobility
  - Laboratory
    - Prostaglandin E2: Increased in urine
- Mal de Meleda
  ● Secreted LY6/Plaur domain-containing protein (SLURP1) ; Chromosome 8q24.3; Recessive
  - Epidemiology: High frequency in Island of Meleda, Dalmatia, Yugoslavia
  - SLURP1 protein
    - May interact with neuronal acetylcholine receptors (CHRNA7 )
    - Secreted
  - Clinical
    - Onset age: Early infancy
    - Mouth: Perioral erythema
    - Hands: Brachydactyly
    - Skin
      - Congenital symmetrical palmoplantar keratosis
      - Ichthyosis
      - Hyperhidrosis
      - Lichenoid plaques
    - Nails: Fragile, Lusterless
- Odontoonychodermal dysplasia (OODD)
  ● Wingless-type mmtv integration site family, member 10A (WNT10A) ; Chromosome 2q35; Recessive
  - Clinical
    - Tongue: Smooth; Reduced papillae
    - Hypodontia
    - Hyperhidrosis: Palms & Soles
    - Hyperkeratosis
    - Nails: Dystrophic; Absent
    - Hair: Absent at birth
- Nail disorder, nonsyndromic congenital, 5 (NDNC5)
  ● Autosomal Dominant
  - Nosology: Hereditary distal onycholysis
  - Clinical
    - Nails
      - Growth: Decreased rate
      - Scleronychia
      - Detachment: Straight or concave proximal edge
    - Hyperhidrosis: Palmoplantar
    - Cold Sensitivity: Fingers
- Book syndrome
  ● Autosomal Dominant
  - Premolar aplasia
  - Hyperhidrosis
  - Canities prematura
- Gamstorp-Wohlfart Syndrome
  ● Autosomal Dominant
  - Myokymia
  - Myotonia
  - Muscle wasting
  - Hyperhidrosis
CNS Related
- Shapiro syndrome: Essential Hypothermia with Hyperhidrosis
- Acquired: Post-traumatic or Post-Hemorhagic
- Fatal familial insomnia
- Parkinson disease

Anhidrosis

General: Due to damage to
- Preganglionic sympathetic efferent axons
- Unmyelinated, postganglionic, cholinergic axons in peripheral nerves
- Sweat glands in skin

Differential diagnosis

Distribution	Etiology of Anhidrosis	Pathology
Distal	Polyneuropathies	Postganglionic
Proximal	Shy-Drager	Central Preganglionic
Diffuse	Amyloidosis Chronic idiopathic dysautonomia Congenital sensory neuropathy Cystinosis Diabetes insipidus Ectodermal dysplasia Fabry's Familial (Normal sweat glands) Harlequin syndrome Helix syndrome: CLDN10 HSN: IV; VI Idiopathic orthostatic hypotension LEMS Neuronal intranuclear inclusion disease Pandysautonomia Sjögren Tangier disease Tellurium	Pre- or Post- ganglionic
Ectodermal dysplasia	Anhidrotic Recessive ED + Immunodeficiency: IKBKG ED: EDARADD ED: EDAR Dominant ED + T-cell deficiency: NFKBIA X-linked ED1: EDA ED: Other Hidrotic ED2: GJB6; 13q12; Dominant	Preganglionic
Focal	Diabetic radiculo-neuropathy Leprosy Local neuropathy (ulnar) Horner's: + Ptosis; Miosis Ross: + Hyporeflexia; Tonic pupils Sympathectomy	Post-ganglionic
Hemianhidrosis	Cerebral infarction Spinal cord tumor	Sympathetic outflow Central
Skin disease	Dermatophytosis Limb-Mammary syndrome	Sweat ducts plugged & Other

Drugs
- Ach release inhibition: Presynaptic
  - NMJ blocking agents: Botulinum toxin
- Anti-cholinergic: M3 receptor antagonism
  - Anti-cholinergics: Atropine, Cyproheptadine, Doxepin, Glycopurrolate, Hyoscyamine
  - Tricyclic antidepressant: Amitriptyline
  - Anti-histamine: Diphenhydramine
  - Anti-spasmodic, bladder: Oxybutinin, Toloterodine
  - Anti-psychotics: Chlorpromazine, Clozapine, Quetiapine
- Carbonic anhydrase inhibition
  - Anti-seizure: Topiramate, Zonisamide
- Central adrenergic
  - Anti-hypertensive: Clonidine
- Hypothalamic μ-Opioid receptor antagonist
  - Opioid: Fentanyl, Hydrocodone, Morphine, Oxycodone
Hereditary
- Anhidrotic ectodermal dysplasia (ED1)
  ● Ectodysplasin-A (EDA) ; Chromosome Xq13.1 Recessive
  - Protein: Small, 135 AA, transmembrane
  - Clinical
    - Hair: Sparse
    - Teeth: Abnormal or missing
    - Anhidrosis: Due to lack of sweat glands
    - Hyperthermia: Life threatening or brain damage
    - Carrier females: Abnormal teeth
- Hypohidrotic ectodermal dysplasia with immunodeficiency
  ● IKK-γ (IKBKG; NEMO) ; Chromosome Xq28; Recessive
  - Genetics
    - Mutations produce partial loss of IKK-γ function
    - Allelic with incontinentia pigmenti : Complete loss of IKK-γ function
  - IKK-γ protein
    - Required for activation of nuclear factor κ B transcription factor
    - Role in T & B cell function
  - Clinical
- Anhidrotic ectodermal dysplasia 11
  ECTD11A: Dominant
  ECTD11B: Recessive
  ● EDAR-associated death domain (EDARADD) ; Chromosome 1q42-q43
  - EDARADD protein
    - Expressed in epithelial cells during the formation of hair follicles and teeth
    - EDARADD self-associates
    - Death domain protein
      - Interacts with death domain of EDAR
      - Links the receptor to downstream signaling pathways
  - Clinical: Similar to X-linked AED
  - Mouse: 'Crinkled' phenotype
- Anhidrotic ectodermal dysplasia 10
  ECT10A: Dominant
  ECT10B: Recessive
  ● Ectodysplasin 1, anhidrotic receptor (EDAR) ; Chromosome 2q12.3
  - EDAR protein
    - Structural similarity to TNF
    - Triggers NF-kappa-B (see 164011) through the NEMO protein
  - Clinical
    - Similar to X-linked AED
    - Abnormal morphogenesis of teeth, hair & eccrine sweat glands
- Anhidrotic ectodermal dysplasia + T-cell immunodificiency
  ● Nuclear factor of kappa light chain gene enhancer in B-cells inhibitor-α; (NFKBIA) ; Chromosome 14q13.2; Dominant
  - Mutations
    - Heterozygous or Stop
  - NFKBIA protein
    - Inhibits NFKB complex
    - Inactivate NF-kappa-B by trapping it in cytoplasm
  - Clinical
    - Multiple infections
    - Conical teeth
    - Skin: Dry; Rough
  - Laboratory
    - Skin biopsy: Absent sweat glands
- Anhidrotic ectodermal dysplasia: Other
  ● with Deafness
  ● with Retardation
- Hidrotic ectodermal dysplasia (ED2)
  ● Gap junction protein β-6 (GJB6, Connexin-30, CX30) ; Chromosome 13q12.11; Dominant
- Anhidrosis, isolated, with normal sweat glands (ANHD)
  ● Inositol 1,4,5-triphosphate receptor, type 2 (ITPR2; InsP₃R2) ; Chromosome 12p12.1-p11.2; Recessive
  - Nosology: Dann-Epstein-Sohar syndrome
  - Epidemiology: Pakistani family
  - Genetics
    - Mutation: Homozygous; Gly2498Ser
    - Also: ALS modifier locus
  - ITPR2 protein
    - Calcium ion transmembrane transporter activity
    - Inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity
    - Phosphatidylinositol binding
    - Membrane: Endoplasmic reticulum
  - Clinical
    - Heat intolerance
    - Anhidrosis: Generalized
  - Laboratory
    - Pathology: Sweat glands: Normal
    - Eccrine sweating: Reduced
- HELIX Syndrome
  ● Claudin 10 (CLDN10) ; Chromosome 13q32.1; Recessive
  - Nosology
    Hypohidrosis
    Electrolyte imbalance
    Lacrimal gland dysfunction
    Ichthyosis
    Xerostomia
  - Epidemiology: 4 families; 19 patients
  - Genetics
    - Mutations: Missense; Met1Thr, Asn48Lys, Ser131Leu
  - CLDN10 protein
    - Expressed in: Dermis & Sweat glands: Renal
    - Localize to: Tight junctions between epithelial cells
    - Regulate: Transepithelial ion exchange; Electrical resistance
  - Clinical
    - Onset: Congenital
    - Heat intolerance
    - Anhidrosis
    - Alacrima
    - Xerostomia
    - Nephrolithiasis: Onset in adolescence
    - Pain: Recurrent bouts
    - Dental: Enamel wear
  - Laboratory
    - Parathyroid hormone: High levels
    - 25-Hydroxy vitamin D: Low
    - Mg⁺⁺ & Ca⁺⁺: Low in urine
    - Mg⁺⁺: High in serum
    - Plasma renin: High
    - Sweat gland morphology: Normal

Urinary

Nocturia: Postural hypotension
- Relocation of fluid from periphery
- Treatment: Desmopressin
Nocturia: Cholinergic dysautonomia
- Bladder atony
- Common in Shy-Drager (Multiple System Atrophy): Lesion in sacral Onuf's nucleus
- Treatment
  - Scheduled voiding with double voiding techniques
  - Clean, intermittent self-catheterization
  - Infection prevention
Hereditary

Sexual dysfunction

Erection: Dependent on parasympathetic supply & Nitric oxide
- Treatment
  - Intracavernous injections of
    - Prostaglandin E, or Papaverine ± Phentolamine
  - Topical nitroglycerin paste
  - Physical: Surgery
Ejaculation: Dependent on sympathetic system

Ocular

Adie
Horner's
Ross
Muscarinic AChR disorders
Actin smooth muscle disorders
Other pupil disorders
Congenital MG
Acetylcholinesterase (AChE) deficiency
Hereditary neuropathy
2J (P₀ mutations)
HSAN 2B
Miosis
Tubular aggregate myopathy (Stormorken)
TAM1: STIM1
TAM2: ORAI1

From: Monique Ryan

Congenital Horner's: Iris heterochromia

Horner's syndrome

From: P Bailey
- Clinical features
  - Ptosis
    - Partial: Never covers visual field
    - May affect upper (Müller's muscle) & lower lid (elevated)
  - Pupil
    - Miosis
      - More evident in dark
      - Never severe
      - Dilation: Slow; Poor in dark
    - Differential diagnosis of very small pupil
      - Miotic drops
      - CNS disorder
      - Adie
      - Argyll Robertson
  - Hypohidrosis
    - Preganglionic lesion proximal to carotid bifurcation
    - Distribution: Face & Head
  - Hyperemia: Conjunctival & lid; With acute lesion
  - Facial vasodilation: Variable
  - Enophthalmos: Appearance but rarely true
- Lesions & Anatomy
  - General anatomy: Ipsilateral sympathetic pathways
  - CNS locations: "First order neurons"
    - Anatomy
      - Origin: Posterolateral hypothalamus
      - Descending Pathway: Brainstem; Intermediolateral column of spinal cord
      - Termination: Ciliospinal center (of Budge) in spinal cord at C-8 to T-2 levels
    - Disorders
      - Brainstem: Lateral medullary syndrome
      - Cervical spinal cord: Disc; Osteophyte; Mass
      - Child: Arnold-Chiari; Syringomyelia
  - Preganglionic: "Second order neurons"
    - Anatomy
      - Origin: Ciliospinal center (of Budge) of thoracic spinal cord
      - Pathway: Mediastinum; Pulmonary apex; Supraclavicular space
      - Ascends through: Stellate & Middle cervical ganglia
      - Termination: Superior cervical ganglion at level of carotid bifurcation & angle of jaw
    - Lesions
      - Often neoplasm
        
        Usually with brachial plexus involvement
      - Early lesion → Hyperfunction with mydriasis & hyperhidrosis
  - Postganglionic: "Third order neurons"
    - Anatomy
      - Origin: Superior cervical ganglion
      - Ascending pathways
        
        Internal carotid artery (Adventitia): Into skull & Cavernous sinus
        
        Sympathetic fibers
        
        Enter orbit through suprior orbital fissure
        
        Nerves: Long ciliary nerves
        
        Nasociliary branch of ophthalmic division of trigeminal nerve
        
        2nd branch
        
        Passes through ciliary ganglion
        
        Joins postganglionic ciliary nerves (Short ciliary nerves)
        
        Termination
        
        Penetration of sclera
        
        Travel in suprachoroidal space
        
        Innervate: Dilator pupillae muscle; Inferior & Auperior (Müller) tarsal muscles
        
        External carotid artery
        
        Vasomotor & Sudomotor innervation of hemiface
    - Clinical Features
      - Ptosis
      - Miosis
      - Pain
      - ± Hypohidrosis
    - Lesions
      - Carotid artery dissection
      - Intracranial (Cavernous sinus) or Internal carotid thrombosis
        
        Horner syndrome + VI nerve paresis: Ipsilateral posterior cavernous sinus
      - Paratrigeminal syndrome: Pain in face & Horner's
  - Congenital Horner's
    - Iris heterochromia: Blue iris on side of lesion
  - Hereditary polyneuropathy
    - Amyloid: Bilateral (50%)
    - HSAN-I: Occasional; Unilateral or Bilateral
- Diagnostic testing
  - Pharmacologic testing for localization: Compare responses in 2 eyes
    - No pupil dilation by: Cocaine (10%) or Apraclonidine (0.5%)
    - Postganglionic: No dilation with Hydroxyamphetamine (1%)
  - Anatomic evaluation
    - MRI with angiography; Brain & Cervical spine
Holmes-Adie syndrome
- Hereditary
  - Autosomal dominant
  - HMSN: P₀ mutations with axonal neuropathy
- Acquired
  - Most common in young women
  - Children: Often with history of chickenpox
  - Specific causes
    - Sjögren's
    - Autonomic neuropathy
    - Guillain-Barré: Occasional
- Pathology
  - Parasympathetic, post-ganglionic, denervation
  - Lesion: Ciliary ganglion; Posterior ciliary nerves
- Clinical features
  - Pupil: "Tonic"
    - Dilated
    - Myotonic
      - Light: Slowly or not reactive
      - Near effort
        
        Strong & slow reaction
        Often tonic: Differs from Argyll Robertson
      - Refixation at distance: Slow dilation
      - Pathology: Reduced cells in parasympathetic ciliary ganglia
    - Sectors of residual light reaction when viewed by slit lamp
    - Unilateral or Bilateral
  - Tendon reflexes: Areflexia ³⁷
    - H-reflexes may be preserved
    - ? Due to pathology in dorsal root ganglia or posterior columns
  - Other associated features
    - Orthostatic hypotension
    - Reduced Cardivascular reflexes; Syncope
    - Hypo- or Hyper-hidrosis
    - Carotid gustatory syndrome
    - Diarrhea
    - Chronic cough: Increased with deep breathing or hyperventilation
Ross syndrome ¹³
- Epidemiology: Males & Females
- Clinical features
  - Onset age: 1st to 5th decade
  - Anhidrosis
    - Segmental or Generalized
    - Residual sweating: Most common on trunk; Hyperhidrosis (compensatory) in these areas
    - Course: Progressive loss; Areas may be hyperhidrotic before sweating loss
    - Heat intolerance
  - Hyporeflexia: Especially at ankles
  - Tonic pupils
    - Slow reaction to light
    - Normal constriction to a near target
    - Dilute pilocarpine (0.062%) & adrenalin (0.1%): Postganglionic parasympathetic & sympathetic denervation of pupils
  - Other autonomic dysfunction in some patients
    - Cardiac
    - Orthostatic hypotension
  - Sensory
    - Subclinical changes
    - Reduced temperature, pain & tactile sensation in some patients
- Electrophysiology
  - H-reflex: Absent; Disorder of monosynaptic connection to motor neuron
  - Nerve conduction: Normal
  - Sympathetic
    - Skin responses: Absent
    - Peripheral outflow abnormalities
    - Muscle sympathetic activity (MSNA): Spared
  - Cardiovascular reflexes: Normal
- Pathology: Skin
  - Post-ganglionic parasympathetic denervation: Sudomotor; Severe
  - Sensory epidermal axon loss: Less severe
    - Loss of unmyelinated & myelinated fibers
    - Reduced innervation of sweat glands, blood vessels & erector pilorum muscles
  - Adrenergic axon loss: Less severe
- Acquired disoders with similar features
  - Sjögren syndrome
  - Cholinergic urticaria
  - ANA positivity
  - Cytomegalovirus
  - Hepatitis C, chronic
Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS)
● Actin-α2, Smooth muscle, aorta (ACTA2) ; Chromosome 10q23.31; Dominant or Sporadic
- Epidemiology: 7 patients
- Genetics
  - Mutations: Arg179His; Missense
  - All de novo mutations
- Clinical
  - Eye
    - Mydriasis, Congenital
    - Retina: Small vessel infarcts & aneurysms
  - Cardiac & Vascular
    - Patent ductus arteriosus
    - Aortic aneurysm, thoracic (AAT6)
    - Vasculopathy (Moya-Moya 5)
  - Intestine
    - Malrotation
    - Hyperperistalsis
  - Genitourinary
    - Bladder: Hypotonic
    - Cryptorchidism
  - CNS
    - Periventricular: White matter hyperintensities
    - Small brain vessels: Brain infarcts & Aneurysms

Multisystem syndromes with congenital ptosis
- Baraitser-Winter syndrome 1 (BRWS1) : Actin-β (ACTB)
- Baraitser-Winter syndrome 2 (BRWS2) : Actin-γ1 (ACTG1)

Absence of lacrimation (Alacrima)

Sjögren's
Congenital absence
- Achalasia-Addisonianism-Alacrimia syndrome
- Achalasia-Alacrimia-Intellectual Dysfunction
- Alacrima congenita
  ● Autosomal Dominant
  ● Autosomal Recessive
- Riley-Day (HSAN 3)
- Congenital absence of lacrimal & salivary glands (ALSG)
  ● FGF10 ; Chromosome 5p12; Dominant
  - Allelic with: Lacrimoauriculodentodigital syndrome (LADD)
- CDG1V

Respiratory disorders, Autonomic

Congenital Central Hypoventilation Syndromes (CCHS) \

General
CCHS
1: PHOX2B
2: MYO1H
3: LBX1
Other
- General
  - Often associated with other autonomic disorders
  - Hirschsprung: 30%
  - Nosology: Ondine's curse
  - Clinical criteria
    - Hypoventilation, hypoxemia & hypercarbia during quiet sleep
    - No cardiac, pulmonary, neuromuscular, EEG or cerebral MRI abnormality
- CCHS1
  ● Paired mesoderm homeo box 2B (PHOX2B; PMX2B) ; Chromosome 4p13; Dominant
  - Most common gene mutated in congenital hypoventilation syndromes: 60% to 80%
  - De novo mutations in 1st generation
  - May be associated with Hirschsprung & Neoplasms
  - Mutations ²¹
    - Some patients with polyalanine expansion mutations
      - Most common mutation type
      - Usually in-frame duplication
      - Add 5 to 13 alanines to normal 20-residue polyalanine tract
      - Somatic mosaicism
      - Mutation size same in different generations
      - Late onset disease: 5 alanine insertion size
    - Frameshift or Missense mutations: Many present with
      - Hirschsprung disease
      - Tumors of the sympathetic nervous system
        
        Types: Neuroblastoma, Ganglioneuroblastoma, Ganglioneuroma
        
        Location: Tumors often multifocal
  - Disease mechanisms
    - "Gain-of-function" alanine mutations: Cytoplasmic aggregation of normal & mutant proteins
    - Haploinsufficiency mutations: Cause dilated pupils & ciliary ganglion atrophy
- CCHS2 & Autonomic dysfunction
  ● Myosin 1H (MYO1H) ; Chromosome 12q24.11; Recessive
  - Epidemiology: 1 family, 3 patients
  - Genetics
    - Mutation: 1-bp Del, 2524A
  - Myosin 1H protein
    - Unconventional (Non-muscle) myosin
    - Expression: Central nervous system
  - Clinical
    - Neonatal: Apneic spells; shallow breathing
    - GI: Dysmotility; Poor swallowing
    - Cardiac: Sinus bradycardia
    - Temperature: Dysregulation
    - Developmental delay: Global; Hypotonia
- Genetic associations: Other
  ● Endothelin-3 ; Chromosome 20q13.2; Recessive or Dominant with reduced penetrance
  - Also see: Hirschsprung
  ● RET oncogene ; Chromosome 10q11.21; Dominant or Sporadic
  - Also see: Hirschsprung
  - Malformation of enteric nervous system
  ● GDNF ; Chromosome 5p13.2; Dominant (HSCR1) or Recessive
  - Also see: Hirschsprung
  ● BDNF ; Chromosome 11p14.1; Dominant
  - Isolated CHS
  - Father with postural hypotension & vasovagal syncope
  ● Human achaete-scute homolog-1 (HASH-1; ASCL1) ; Chromosome 12q23.2; Dominant, Incomplete penetrance
  - Mutations: Some are loss of alanines in polyalanine tract ¹⁸
    - Normal: 13 Alanines
    - Mutations: 5 or 8 Alanines
  - HASH-1 protein expression
    - CNS
    - PNS
    - Development: Enteric nervous system, Esophagus to rectum; Adrenal medulla
    - Neuroblastoma
  - HASH-1 Function
    - Development of olfactory & most peripheral autonomic neurons
    - Formation of neuronal circuits within CNS
    - Mutations produce impaired noradrenergic neuronal development
    - Interacts with E2-2 protein
  - Clinical syndromes
    - Central hypoventilation
    - Haddad syndrome
Mental retardation + Intermittent hyperventilation (Pitt-Hopkins syndrome) ²⁶
● TCF-4 ; Chromosome 18q21.2; Dominant or Sporadic
- Genetics: Mutations
  - Heterozygous
  - Types: Microdeletion; Missense; Stop; Splice site
- TCF-4 protein
  - E-protein: Class I basic helix-loop-helix transcription factor
  - Subcellular location: Nuclear
  - Expressed in fetal & adult brain
  - Disease mechanism
    - Haploinsufficiency
    - ? Impaired noradrenergic & other neuronal development
  - Complexes with ASCL1
- Clinical
  - Onset: Infancy
  - CNS
    - Psychomotor delay: Severe
    - Epilepsy
    - Hyperventilation: Daily episodes; Diurnal
  - Hypotonia
  - Morphology
    - Growth retardation: Mild
    - Microcephaly: Postnatal
    - Face
      - Nose: Large; High bridge; Flared nostril
      - Mouth: Wide; Fleshy lips; Broad palate; Wide spaced teeth; M-shaped cupid�s bow
      - Ears: Helices dysplastic & thick
    - Eyes
      - Enophthalmia
      - Strabismus
      - Eyebrows: Thin in midline portion
  - GI: Some patients
    - Hirschsprung disease
    - Constipation
  - ? Malignancy: Lymphoma in oldest patient
- CNS pathology
  - Cerebellum: Hypoplasia of hemispheres & vermis
  - Corpus callosum: Hypoplasia
  - Hippocampus: Small
  - Caudate nuclei: Bulging
Joubert syndromes

Multiple Systems Atrophy (Shy-Drager)

● Sporadic or Autosomal Dominant

Nosology: Other similar or overlapping disorders
- Striatonigral degeneration
- Adult-onset sporadic olivopontocerebellar atrophy (OPCA)
- Shy-Drager syndrome
Genetic susceptibility
- COQ2
- RFC1
Clinical features
- Onset
  - Age: Adult
  - Parkinsonism: Early
  - Bladder dysfunction
  - Orthostatic hypotension ³⁶
    - May initially present as: Pure autonomic failure
    - Predictors of progression to MSA
      - Cardiovagal impairment: Mild
      - Sweat loss: Preganglionic pattern of sweat loss
      - Bladder dysfunction: Severe
      - Supine norepinephrine > 100 pg/mL
      - Motor signs: Mild
- Autonomic
  - Orthostatic hypotension
  - Bladder incontinence
  - Anhidrosis
  - Ptosis
  - Bowel dysfunction
- Extrapyramidal
  - Parkinsonism (87%): Especially Rigidity, Postural instability & Bradykinesia
  - Dystonic response to L-DOPA
- Upper motor neuron signs (50%): Spasticity; Brisk tendon reflexes
- Bulbar
  - Scanning speech
  - Stridor: Laryngeal abductor paralysis (also see Recessive ataxia)
- Cerebellar disorders (Especially OPCA variant): 50%
- Myoclonus: Stimulus-�sensitive; Limbs & Face
- Peripheral nervous system
  - Lower motor neuron signs (20%)
  - Polyneuropathy: Sensory-Motor (20%)
- Skin: Dusky discoloration of the extremities
- Course
  - Variably progressive
  - Median survival: 6 to 10 years
Laboratory
- Bladder dysfunction (> 90%)
- EMG: Denervation (20%)
Pathology
- Neuronal loss & Gliosis
  - Extrapyramidal: Putamen; Substantia nigra; Locus ceruleus
  - Other brainstem: Inferior olive; Pontine nuclei
  - Purkinje cells
  - Spinal cord: Intermediolateral cell column (Thoracic); Onuf's nucleus
- Glial cytoplasmic inclusions (Argyrophilic): Suprasegmental motor systems; Supraspinal autonomic system
- Autonomic pathology
  - Spinal cord: Reduced sympathetic preganglionic neurons in intermediolateral cell column
  - Medulla
    - Reduced Catecholaminergic neurons (A1/C1) in ventrolateral intermediate reticular formation
    - Normal projections
      - Descending: Intermediolateral cell column in spinal cord
      - Ascending: Vasopressin neurons in hypothalamus
External link: eNeurology

Riley-Day (HSAN 3) ¹⁹

● Inhibitor of κ light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP; ELP1)

; Chromosome 9q31.3; Recessive

Epidemiology: Most patients Ashkenazi-Jewish
Genetics: IKBKAP mutations
- T to C transition in base pair 6 in donor splice site of intron 20 (2507+6T-C)
  - Major haplotype: Present in 99.5% of disease alleles
  - Common ancestral haplotype: Founder effect
  - Carrier frequency in Ashkenazi-Jewish population: 1/36
  - Mutation effect
    - Variable skipping of exon 20
    - Wild type message expressed in tissue-specific manner
      - Lymphocytes: Mostly wild type protein
      - Brain: Primarily mutant protein
- Arg696Pro: Missense mutation
  - Rare
  - All patients heterozygous for major haplotype
  - Mutation predicted to disrupt potential threonine phosphorylation site
  - Associated with mild phenotype
- Pro914Leu ¹⁴
  - Found in non-Jewish patient
  - Otherwise typical clinical syndrome
  - Mutation disrupts protein phosphorylation
- Allelic disorder
  - Medulloblastoma

IKBKAP protein

Member of complex containing other unidentified proteins
Location: Highest levels of IKBKAP protein in cerebellum, thalamus, pituitary, testes
Function: ? Role in gene-activation mechanisms
- Regulation & Activation of stress response through c-Jun N-terminal kinase (JNK) signaling path
- Mutant: May alter interaction of IKAP with JNK
  - Misregulation of JNK
  - Inadequate development & differentiation
Mutant gene variably expressed
- Most of mRNA in brain is missing exon 20
- Wild type mRNA more abundant in fibroblasts
Complete absence of expression in all tissues may be lethal

Clinical features

Onset: Congenital
Early in disease course
- Newborn: Hypothermia; Vomiting crises; Hypotonia
- Eye
  - Lacrimal Flow (Overflow tears): Reduced or Absent (99%)
  - Cornea: Hypesthesia & Erosions
- Fungiform Tongue Papillae: Absent
- Sensory loss
  - Modalities
    - Pain Insensitivity
    - Temperature: Abnormal Warm & Cold threshholds
    - Functional muscle spindle afferents: Absent
    - Large fiber modalities: Relatively spared
    - Visceral sensation: Preserved
  - Distribution: Trunk & Lower extremities most affected
- Deep tendon reflexes: Absent
- Autonomic crises
  - General: Irritability, Fever, fainting
  - Postural hypotension: No compensatory tachycardia
  - Crises
    - Triggers: Emotional or pysical stress
    - Hypertension
    - Tachycardia
    - Hyperhidrosis
    - Behavioral changes
    - Treatments
      - Vomiting: Diazepam
      - Hypertension: Clonidine
  - Skin blotching (99%)
  - Hyperhidrosis (99%)
  - Normal sympathetic skin responses
  - GI disorders
- GI dysfunction: Dysmotility
  - Esophageal & Gastric
  - Dysphagia
  - Gastroesophageal reflux
  - Vomiting crises
- Skeletal
  - Scoliosis
    - Juvenile
    - Left curves more common than idiopathic scoliosis
  - Trauma: Repeated
    - Fractures & Aseptic necrosis
    - Neurogenic (Charcot) joints
- Respiratory
  - Abnormal responses to hypoxic & hypercarbic states
  - Aspiration: Recurrent pneumonias
  - Restrictive lung disease
  - Sleep: Central apnea & hypopnea
  - Breath holding
- Cardiovascular: Postural hypotension
- Renal: Ischemia; Pre-renal azotemia
- Muscle: Possible increased frequency of rhabdomyolysis ³⁵
  - Frequency: 7.5 per 10,000 person-years
  - Control: 0.44 per 10,000 person-years (Statin using patients)
- CNS: Normal intellect
Course
- Older patients
  - Finger nail dystrophy
  - Taste: Reduced, especially sweet
  - Vibration loss: With increasing age (> 13 years)
  - Ataxia: Gait disorder; Poor balance
  - Psychiatric syndromes
- Usually fatal: Death in 50% < 30 to 40 years
- Causes of death: Pulmonary; Renal; Sudden death
Other
- Features specific to RD syndrome
  - Lack of overflow tears
  - Early onset postural hypotension
- Other Ashkenazi Jewish disorders
  - Cystic fibrosis
  - Tay-Sachs
  - Canavan disease

HSAN 3: Clinical Diagnosis

Overflow emotional tears	Absent
Lingual fungiform papillae	Absent
Patellar tendon reflexes	Absent
Axon flare after intradermal histamine	Absent
Ashkenazi Jewish heritage	Present

Laboratory
- Hyponatremia: During crises
- Intradermal histamine: Absent flare
- Catecholamines
  - HVA/VMA ratios: High
  - DOPA/DHPG ratios: High in plasma
  - Standing: Low increase in plasma levels of NE and dopamine β-hydroxylase
  - Emotional crises: Very high plasma NE and DA levels
Pathology
- Unmyelinated axons
  - Number: Marked reduction
    - 5% to 15% of normal
    - Course: Progresasive loss
- Dorsal root ganglia cell bodies: Reduced number
- Autonomic neurons: Loss
  - Small superior cervical sympathetic ganglia
  - Parasympathetic ganglia: Generally normal; Exception is sphenopalatine ganglion
- Large axons: Relatively spared: 65% to 100% of normal
- Spinal cord
  - Reduced primary substance P axons in substantia gelatinosa
  - Intermediolateral gray columns: Reduced neurons

Congenital sensory neuropathy with anhidrosis (HSAN 4; CIPA)

● TRKA/ NGF receptor (NTRK1)

; Chromosome 1q23.1; Recessive

Nosology: Congenital insensitivity to pain with anhidrosis (CIPA)
Epidemiology: 1:25,000 incidence
Gene mutations
- Types: Deletions, splice-site, frame shift, & missense
- > 52 identified: Most are private
- Domains: Signal peptide, extracellular & intracellular
- High prevalence of disease in Israeli-Bedouin Arabs: Due to 1926-ins-T mutation
- Mutations in same gene associated with: Medullary thyroid carcinoma, familial
- Functional consequenses of mutations
  - Extracellular domain: May prevent nerve growth factor binding to TRKA receptor
  - Intracellular domain: Can interfere with signal transduction
Protein
- Single extracellular, transmembrane & intracellular domains
- Extracellular domain: NGF binding; Signal peptide
- Intracellular domain: Tyrosine kinase
Clinical features: Homogeneous
- Onset
  - Congenital: Hypotonia
  - Childhood: Delayed motor milestones; Hypohidrosis; Painless fractures
- Sensation
  - Congenital insensitivity to pain
    - Eye
      - Decreased corneal sensitivity & reflexes
      - Emotional tearing: Present
    - Sensation: Reduced pain, temperature & visceral
    - Some regional partial sparing of pain sensation
      - Nose bridge
      - Ears: Behind ears; External auditory meatus
      - Posterior cervical skin area: Some patients
  - Temperature sensation: Absent or Reduced
  - Normal: Touch, Vibration, Joint position
- Tendon reflexes: Normal, Increased or Decreased
- Autonomic
  - Skin: Absent sweating (Anhidrosis); Blotching
  - Normal: Blood pressure control; GI motility; Overflow tears
- CNS
  - Mental retardation
- Self mutilation (Acromutilation)
  - Joint deformities: Knees & Ankles
  - Mouth: Tip of tongue; Lips
  - Skin: Scarring & Burns
- Systemic
  - Fever
    - Idiopathic
    - Episodic & Recurrent
    - Early disease manifestation: 3 months
  - Episodic hyperpnea
- Finger nail dystrophy
- Wound healing: Slow
- Course
  - Early death from hyperpyrexia: Up to 20%
  - Septicemia
Laboratory
- Provocative tests ⁸
  - Histamine: Wheal evoked; No axon flare response (100%)
  - Mecholyl: No tearing
  - Pilocarpine: No sweating
  - Sympathetic skin responses: Absent (100%)
- Plasma norepinephrine levels: Low or absent, Supine & Upright
- Nerve conduction velocities: Normal
- Anemia (79%)
Pathology
- Peripheral nerve
  - Small myelinated & Unmyelinated axons: Absent; 0% to 5% of noraml
  - Large myelinated axons: Mildly reduced; 45% to 65% of normal
- Dorsal root ganglia
  - Small sensory neurons absent: Associated with insensitivity to pain
- Sweat glands: Absence of innervation of eccrine glands
  - Hypotrophic or absent in dermis
  - Associated with anhidrosis & hyperthermia
- Autonomic ³⁴
  - Postganglionic sympathetic neurons: Probably severely depleted
  - Chromaffin cells of adrenal medulla: Spared
- Skin: Reduced innervation; Remaining axons stain for GAP-43
Variant syndrome: Milder phenotype ³¹
- NTRK1 Genetics
  - Inheritance: Recessive
  - Mutations
    - c.851-33T>A: Splice site; Common in Korean patients
    - Pro768Leu: May be associated with milder phenotype
- Clinical
  - Skeletal: Recurrent bone fractures; Painless joint destruction
  - Intelligence: Normal
  - Motor: Strength normal
  - Sensory exam: Vibration & Pin normal
- Laboratory
  - EMG & NCV: Normal
  - Sympathetic skin responses: Reduced
  - Heart rate variance: Normal

HSAN 6: Autonomic Sensory Neuropathy ²⁸

● Dystonin (DST)

; Chromosome 6p12.1; Recessive

Epidemiology: > 15 families; Ashkenazi Jewish
Genetics
- Mutations
  - Stop: c.14,865 delA (Ashkenazi)
  - Missense
- Allelic disorders
  - Epidermolysis bullosa simplex, Autosomal recessive 2 (EBSB2)
  - Axonal Neuropathy, Recessive
  - HSAN 6
Dystonin protein
- Cytoskeleton linker: Actin filaments to Intermediate filaments & Microtubules
- Plakin family
- Size: Very large
- Alternatively spliced
  - Creates many plakin family linker proteins
  - Bullous pemphigoid antigen 1 (BPAG1) proteins
  - Different isoforms in: CNS; Muscle; Skin
Clinical
- Onset
  - Age: Birth to 4th decade
  - Hypotonia
  - Respiratory failure
- Dysautonomia
  - Absent tears
  - Skin blotching
  - GI dysmotility
    - Feeding difficulties
    - Diarrhea, chronic
  - Hypohidrosis
  - Episodic
    - Hyperpyrexia
    - Desaturation
    - Bradycardia despite
    - Blood pressure lability
  - Tongue: Fungiform papilla Reduced
- Sensory loss
  - Severe
  - Distal
  - Arms & Legs
  - Panmodal
- Deep tendon reflexes: Absent
- Weakness: Intrinsic foot muscles
- Contractures: Distal arthrogryposis; Club feet; Hips; Knees; Fingers
- Osteomyelitis/Amputation: Distal; Hands or Feet
- Cranial
  - Face: Motionless; Open-mouthed; Chin small
  - Ears: Low set
  - Palate: High arched
- Retardation (Ashkenazi family): Psycho-motor; Severe
- Course
  - Ashkenazi: Early death (< 2 years)
  - Italian family: Survival to adulthood
Laboratory
- Histamine test: Abnormal; No axon flare
- Skin biopsy: Reduced axon numbers
- Brain MRI: Normal
DST variant: Axonal Neuropathy, Recessive ⁴⁴
- Epidemiology: 1 family; 2 siblings
- Genetics
  - Mutations
    - Nonsense: p.R84X
      - Affects 2 isoform variants with N-terminal transmembrane domain
    - Splice donor: c.8283+1G>A; 22 amino acid in-frame deletion
      - Location: Spectrin repeat domain of BPAG1a & BPAG1b isoforms
  - Loss of BPAG1 a2 & b2 isoforms: Correlates with axonal neuropathy
  - Allelic disorders
- BPAG1: Protein mutations
  - Loss may disrupt axonal transport
  - Actions via: Dynactin^{p150Glued 19}; Retrolinkin; Microtubule-associated protein 1B
- Clinical
  - Onset age: 2nd decade
  - Weakness
    - Distal
    - Legs > Arms
  - Sensory loss: Distal; Panmodal
  - Tendon reflexes: Absent at ankles
  - Progression: Gait disorder; Falling
  - Ataxia
    - Features: Dysmetria; Nystagmus; Scanning speech
    - Onset: With disease progression
- Laboratory
  - NCV: Axon loss, Motor & Sensory
  - Brain MRI: Normal

Parkinson disease, juvenile onset

● Parkin

; Chromosome 6q26; Recessive

Genetics: Mutations
- Location: Exons 2 to 9; Most frequent in exon 7
- Missense & small deletions
- Patients often compound heterozygotes
Onset: Several syndromes ¹⁷
- Age
  - Range: 7 to 64 years
  - Usually: < 40 years
  - Late: 1 patient with consanguinous parents
- Clinical syndromes at onset
  - Parkinson syndrome: Tremor
  - Dystonia: Exercise induced or Cervical
  - Peripheral
    - Autonomic dysfunction: may be present alone in 60%
    - Peripheral neuropathy: Axonal
Clinical
- Parkinson's: Bradykinesia; Rigidity; Akinesia
- Tremor: Leg & Hand
- Dystonia: Especially feet
- Dyskinesias: With treatment; 100%
- Tendon reflexes: Usually normal; Occasionally brisk
- Autonomic (60%)
  - Urgency, urinary: 45%
  - Impotence: 28% of males
  - Othostatic symptoms: 13%
- Cortical
  - Psychosis
  - Cognitive function: Normal
- Course: Slow progression
Treatment response: L-DOPA; Anticholinergics

Dopamine β-Hydroxylase deficiency (ORTHYP1) ⁴¹

● Dopamine β-hydroxylase, plasma (DBH)

; Chromosome 9q34.2; Recessive

Epidemiology: 21 patients
Genetics
- Mutations: Missense & Splice
DBH protein
- Function: Catalyzes oxidative hydroxylation of dopamine to norepinephrine
- Location: Adrenal medulla; Synaptic vesicles of postganglionic sympathetic neurons
- DBH axons ⁴³
  - Abundant around arterioles & arrector pili muscles
  - Associated with: NPY
Clinical
- Neonatal
  - Eyes: Ptosis & Delayed opening
  - Hypotension
  - Hypoglycemia
  - Hypothermia
- Childhood & Adult
  - Postural hypotension
    - Lightheadedness & Dizziness
    - Syncope
    - Progressive with exertion
  - Nasal stuffiness
  - Ejaculation: Prolonged or retrograde (normal erection)
  - Exercise tolerance: Reduced
  - Eyes
    - Ptosis
    - Intraocular pressure: Reduced with standing
    - Pupils
      - Size: Mildly small
      - Respond to: Light & Accommodation; Parasympatholytics (Dilation)
      - No response: Hydroxyamphetamine
  - Sleep: Disordered
  - Sweating: Normal
- Exacerbation
  - Heat
  - Heavy meals
  - Alcohol
- Skeletal
  - Palate: High Arched
  - Joints: Hyperextensible
- Cognition: Normal
- Treatment: L-threo-3,4-dihydroxyphenylserine (DOPS) - Elevates noradrenaline levels
  - Dose: 100-600 mg (Droxidopa) po, 2x or 3x per day
Laboratory
- Dopamine beta-hydroxylase deficiency
- Noradrenaline & Adrenaline: Low in plasma, urine & CSF
- Dopamine: High in plasma, urine & CSF
- Autonomic function testing
  - Systems
    - Sympathetic: Failure
    - Parasympathetic: Preserved
  - Supine
    - Blood pressure: Low to Normal
    - Heart rate: Low to Normal
  - Upright position assumed (or Valsalva maneuver)
    - Systolic blood pressure: Falls < 80 mm Hg
    - Compensatory rise in heart rate
    - Inability to stand motionless for > Few minutes
  - Hyperventilation: Blood pressue falls
- Anemia (60%)
- BUN: Increased (67%)
- Glucose: Hypoglycemic episodes
- Skin biopsy: DβH axons lost; PGP 9.5 axons preserved ⁴²

Orthostatic Hypotension 2 (ORTHYP2)

● Cytochrome b561 (CYB561)

; Chromosome 17q23.3; Recessive

Epidemiology: 2 families, 4 patients
Genetics
- Mutations: Homozygous; Gly88Arg; Trp44X
CTB561 protein
- Transmembrane protein
- Catecholamine & Neuropeptide secretory vesicles: Adrenal medulla, Pituitary, Neuroendocrine tissues
- Supplies reducing equivalents to
  - DBH in chromaffin granules
  - Peptidylglycine alpha-amidating monooxygenase (PAM) in neurosecretory vesicles
- Expression in brain
Clinical
- Onset age: Infant or Early childhood
- Orthostatic hypotension, severe
- Dizziness & occasional fainting on standing.
- No compensatory tachycardia
Laboratory
- Sympathetic dysfunction
- Norepinephrine & Epinephrine & downstream metabolites: Decreased in plasma & urine
- Hypoglycemia: 1 family
- Anemia: 1 family

Dopamine receptor D4

● Chromosome 11p15.5; Recessive

Clinical features in 1 patient
- Autonomic hyperactivity
  - Dermatographism
  - Excess sweating
  - Reduced body temperature
  - Intermittent sinus tachycardia
- Acoustic neuromas
- Obesity
Novelty seeking personality trait

Orthostatic Hypotension, Streeten, Hereditary

● Chromosome 18q; Dominant

Nosology: Hyperbradykininism; Streeten type
Genetics: Occasional non-penetrant patient
Clinical
- Onset: Light-headedness on standing
- Ankle discoloration: Blue-purple
- Blood pressure
  - Systolic: Reduced; Orthostatic drop in Systolic BP (>18 mm/Hg)
  - Diastolic: Increased
- Tachycardia
- Signs & Symptoms resolve when patient is supine
- Progresses to syncope & palpitations
- Treatments: Propranolol, Fluorocortisone or Cyproheptadine
Laboratory
- Plasma bradykinin: High

Aniridia, Type 2

● Paired box gene 6 (PAX6)

; Chromosome 11p13; Dominant

Allelic disorders
Pax6
- Paired box gene family
- Transcriptional regulator involved in oculogenesis
- Governs cellular proliferation and migration of 'later-born' neurons
- Other tissues: Pancreas; Anterior pituitary
Clinical
- Eye
  - Cataract
  - Nystagmus
  - Visual acuity: Reduced; Foveal hypoplasia; Glaucoma
- Blood pressure control: Abnormal
- Thermoregulation disorders
- Olfaction: Reduced
Other PAX6 syndromes
- Peters anomaly
- Ectopia pupillae
- Foveal hypoplasia
- Optic nerve hypoplasia or aplasia
- Keratitis
PAX6: 2 mutations
- Onset: Infancy
- Craniofacial: No eyes; Head small; Large ears; Nose flattened bridge, choanal atresia & pinpoint nares
- CNS: Absent optic nerves & chiasm; Brain small; Absent corpus callosum
- Death: Less than 1 month of age
Other aniridia: Gillespie syndrome
Animal model: Small eye mouse (Sey)

Achalasia-Addisonianism-Alacrimia (AAA) syndrome (Allgrove) ¹¹

● AAAS (Aladin)

; Chromosome 12q13.13; Recessive

Epidemiology
- 7 families: North American, North African & European
- Family history: Consanguinous families or Sporadic
AAAS Gene mutations
- Location: All parts of gene
- Truncation & Missense
- Compound heterozygotes
  - One mutation is frameshift
  - Second mutation
    - Missense: Milder disease
    - Stop or mutation in important protein region: More severe disease
- Associated with families having full AAA phenotype
- AAA syndrome has genetic heterogeneity
Aladin protein
- Type: WD-repeat family of regulatory proteins
- Gene expression
  - Cerebral: ? Role in development of PNS & CNS
  - Neuroendocrine: Adrenal gland
  - Gastrointestinal tract
- Subcellular location: Nuclear
  - Targeted to nuclear pore complexes (NPCs; Sites of nucleocytoplasmic transport)
- Mutated protein
  - Common: Fails to localize to NPCs
  - Other: ? Abnormal nuclear pore function
Clinical

From M Al-Lozi
- Onset: Usually childhood
- GI
  - Achalasia: Dysphagia; Vomiting
  - Gastric atonia
  - Feeding difficulties
  - Xerostomia; Angular cheilitis
  - Tongue: Glossitis; Fissured
- Endocrine
  - Adrenal insufficiency: Some patients
- Skin
  - Hyperpigmentation
  - Excessive creases on plams & soles
  - Hyperkeratosis
- Face: Long thin; Long philtrum; Narrow upper lip
- Skeletal: Short stature; Osteoporosis; Microcephaly
- Eyes
  - Alacrimia: Most consistent clinical feature
  - Optic atrophy
  - Pupillary disorders: Pupillotonia; Anisocoria; Miosis
  - Photophobia
- Peripheral neuropathy
  - Modalities: Motor-Sensory or Motor
  - Weakness: Distal; Legs & Hands
  - Sensation: Often normal
  - Pathology: Axon loss
- CNS
  - Spasticity
  - Spinocerebellar syndrome
  - Optic atrophy
  - Mental disability
- Autonomic dysfunction: General
  - Parasympatheic & Sympathetic
  - Cardiovascular
  - Sudomotor
Laboratory
- Hypoglycemic episodes
- NCV
  - Predominantly motor involvement
  - Axonal loss (Small CMAPs); Mild slowing
  - Sural: Reduced SNAP amplitudes with age
- ACTH: High
- Pathology
  - Adrenal: Absent adrenal zona fasciculata; Almost normal zona glomerulosa
  - Lower oesophagus: Absence of ganglion cells and axons
  - Muscle: Denervation; Grouped atrophy
  - Nuclear morphology: Normal
Variant syndrome: Adult onset, ALS-like disorder ²⁷
- Onset age: Teens or Adults
- Bulbar
  - Dysarthria
  - Dysphagia
  - Spastic tongue
- Weakness
  - Onset: Legs
  - Proximal & Distal
  - Symmetric
  - Motor neuropathy
    - Distribution: Legs; Arms (Ulnar)
    - Wasting: Hypothenar & other hand muscles; Calves
- Fasciculations: Limbs & Tongue
- Upper motor neuron
  - Spasticity: All limbs
  - Tendon reflexes: Brisk, except at ankles
- Autonomic
  - Achalasia
  - Dysautonomia
    - Alacrimia
    - Orthostatic hypotension
    - Impotence
    - Hyperhidrosis
- Endocrine: Adrenal insuficiency, later onset
- Other
  - Lingua plicata
  - Plantar hyperkeratosis
  - Alacrimia
  - Face: Hypertrophic nasal roots; Anterior cowlick
- Progression: Slow
- Laboratory
  - NCV
    - CMAP amplitudes: Small
    - Normal velocity
    - SNAPs: Normal
  - EMG: Chronic denervation
  - Brain MRI: Cerebral atrophy, moderate

Achalasia-Alacrimia-Intellectual Dysfunction (AAMR) ³²

● Guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA)

; Chromosome 2q35; Recessive

Epidemiology: 14 families, 21 patients
Genetics
- Mutations: Missense; Frameshift; Nonsense; Splice site
GMPPA protein
- GMPPB regulatory subunit
  - Allosteric feedback inhibitor of GMPPB
- GDP-mannose: Component of N-glucan &, via dolichol-P-mannose, O-glycan chains in glycoproteins
- Mutation effects on α-Dystroglycan ⁴⁸
  - Enhanced mannose incorporation into glycoproteins
  - Increased turnover of α-Dystroglycan
  - Effect may be reversed by: Mannose restriction in diet
- Other CDGs in GDP-mannose pathway
  - Ia (PMM2-CDG )
  - Ib (MPI-CDG )
Clinical
- Onset age: Birth
- Achalasia: Birth to 7 years
- Alacrimia: Birth
- Intellectual disability
  - Delayed milestones
  - Speech delay
- Other autonomic
  - Sweating reduction: 20%
  - Postural hypotension: 30%
- Gait disorder: Some patients
- Hypotonia: Few patients
- Hyperkeratosis: 1 family
- Tendon reflexes: Usually normal
- Ocular
  - Visual problems: Occasional
  - Anisocoria: Some patients
- Hypotonia
- Skeletal
  - Short stature
  - Thumb anomalies: Hypoplasia
  - Face dysmorphic: Columella Overhanging, Alae nasae hypoplastic, Mouth downturned, Philtrum short, Prognathia
- Adrenal: Normal
Laboratory
- GDP-mannose levels (Lymphocytes): High
- Serum proteins: Normal N-glycosylation
- Muscle α-Dystroglycan
  - Core protein: Reduced
  - Glycosylation-specific epitopes: Increased

Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED)

● Autoimmune regulator (AIRE)

; Chromosome 21q22.3; Recessive or Dominant

Nosology: Autoimmune polyendocrine syndrome, Type I (APS1)
Epidemiology: Mostly in Finns, Sardinians & Iranian Jews
Genetics
- Mutations: > 60 described
- Allelic disorder: Myasthenia gravis susceptibility in Chinese
AIRE protein
- Promotes T cell tolerance to self-antigens
- Upregulates ectopic expression of tissue specific self-antigens in medullary thymic epithelial cells (mTECs) in thymus
- Promotes deletion of T cells that recognize self-antigens with high affinity
- Mutation: Defective negative selection of self-reactive effector T cells
Clinical
- Onset age: 1st decade
- Candidiasis: Chronic mucocutaneous
- Endocrine
  - 1° Hypoparathyroidism
  - 1° Hypogonadism
  - Adrenal insufficiency
  - Diabetes mellitus: Insulin-dependent; GAD antibodies
  - Hypothyroidism: Latent
  - Hypoaldosteronism: Transient, Isolated
  - Gonadal failure: Primary sertoli cell insufficiency
- Autoimmune disorders, Multiple
- Myopathy ³⁰
  - Frequency: Few patients
  - Clinical
    - Onset age: 14 to 45 years
    - Most patients female
    - Weakness
      - Proximal > Distal
      - Arms & Legs
      - Symmetric
      - Head drop
      - Respiratory: Some patients
    - Atrophy: Proximal & Trunk
    - Course: Slowly progressive to disability & respiratory failure
  - Muscle pathology
    - Myopathy: Varied muscle fiber size
    - Internal architecture: Irregular
    - Type 1 muscle fiber atrophy
    - Inflammation: None
    - MHC-1: Normal
  - Laboratory
    - Serum CK: Normal
- Neuropathy
  - 2 adolescent males
  - Clinical: Weakness; Sensory loss
  - NCV: May have demyelination
- Hair: Alopecia totalis
- Nails: Dystrophy
- Teeth: Dental enamel hypoplasia
- Eyes: Keratopathy; Keratoconjunctivitis
- GI: Malabsorption; Diarrhea; Chronic active hepatitis; Achalasia
Laboratory
- Pernicious anemia: Juvenile-onset
- Humoral immunity
  - Hypogammaglobulinemia
  - Antibodies: Antiadrenal, Antithyroid & Antinuclear
- Cellular immunity: Low T4/T8 cell ratio
Mouse model: AIRE G228W mutation on autoimmuneprone non-obese diabetic (NOD) background
- Develop
  - Spontaneous autoimmune polyneuropathy with demyelinating features
  - P0 (MPZ) antibodies

Postural Orthostatic Tachycardia Syndrome (POTS) ²

General
Genetics
Clinical
Laboratory
Treatment

Nosology: Postural Tachycardia syndrome (PoTS)
Definition
- Symptomatic orthostatic intolerance
- Associated with: Heart rate increment
  - ≥ 30 beats/minute
  - Within 10 minutes of Δ from supine to upright
Epidemiology: 0.2% to 1% of US population
Genetics: Family history in some patients
- Orthostatic intolerance
  ● SLC6A2 ; Chromosome 16q12.2; Dominant
  - Epidemiology: 1 family; 2 identical twins
  - Genetics
    - Mutation: Missense Ala457Pro
    - Variable penetrance
  - SLC6A2 protein
    - Norepinephrine transporter
    - Mutated norepinephrine transporter protein: Non-functional
  - Clincal features
    - Onset age: 2nd decade
    - Fatigue
    - Orthostatic intolerance
    - Altered heart-rate regulation
      - Upright posture: Heart rate increases by ≥ 30 beats per minute; No orthostatic hypotension
    - Syncope
  - Laboratory: Altered norepinephrine metabolism
- Ehlers-Danlos, Type III (Hypermobility)
Clinical
- Patient characteristics
  - Young: Mean 14 to 29 years; Range 12 to 50 years
  - Female to Male: 4:1
- Onset
  - Course: Acute, Subacute, or Insidious
  - Prodromes
    - Viral illness & other infections: 50% of patients
    - Other: Trauma, Surgery Stress, Pregnancy
- Symptoms
  - General: Associated with vaso-dilation in vascular beds
  - Develop on standing
  - Resolve with recumbency
  - 3 or more symptoms present for > 3 months
    - Weakness: Lower extremity or Diffuse
    - Light-headedness or Dizziness
    - Vision: Blurred
    - Palpitations
    - Dyspnea: Breathing difficulty
    - Nausea
    - Headache: Increased with standing
  - Other symptoms
    - Tremor
    - Prodrome: Infectious (50%)
    - Exercise intolerance: Fatigue
    - Syncope
    - Pain: Chest or Abdomen
    - Dry eyes or mouth
    - GI: Bloating; Early satiety; Diarrhea & Constipation
  - Symptoms aggravated
    - Heat
    - Meals: Food or Alcohol
    - Dehydration
    - Exertion
    - Time of day: Early
    - Menstrual
    - Speed of postural change
- Signs
  - Heart rate
    - Increase of > 30 bpm: Within 10 minutes of standing
    - Increase usually to ≥ 120 bpm
  - No orthostatic hypotension
  - Venous pooling in legs with standing
  - Sweating in legs: Reduced
  - Joint hypermobility
  - Mitral valve prolapse
- Prognosis
  - Improvement in majority (80%): 60% may become normal
  - Better with history of infectious prodrome
- Treatment
  - Volume expansion
    - Diet: High salt (In patients without hypertension)
    - High fluid intake
      - Rapid water drinking, 120 to 480 ml over 5 minutes
      - Especially in morning
  - Meals: Small; Frequent
  - Head-up tilt: At night
  - Physical countermaneuvers
  - Elastic stockings & Abdominal binders
  - Pharmacologic
    - Fludrocortisone
      - < 300 µg daily
      - Not with: Fluid retention; Hypertension
    - β-adrenergic antagonists
      - Bisoprolol or Propranolol (20 mg)
      - Low doses
      - Contraindicated with asthma
    - Midodrine: Sympathetic denervation
      - 2.5 mg 3 times daily before meals
      - Increase after few weeks if necessary
      - Maximum dose: 30 mg daily
      - Not used with hypertension
    - Pyridostigmine: GI side effects common
    - Octreotide
      - For: Post-prandial symptoms
      - Subcutaneous: 25 to 50 µg before food ingestion
    - Ivabradine: Sinus node blockade; For more severe tachycardia
    - Clonidine
Laboratory: Partial sympathetic denervation, especially in legs ⁵
- Tilt testing: Excessive heart rate increment
  - Test: Tilt-up 60° for 10 to 60 minutes
  - Outcome
    - Tachycardia: 120 to 170 bpm on tilt-up
    - Reach levels by by 2 min
    - May increase progressively over time
    - Blood pressure: No change
- Adrenergic testing
  - Stimuli (Cold pressor; Na nitroprusside; Tyramine): Reduced increase of norepinephrine levels in legs
  - Plasma norepinephrine levels
    - Supine: Normal or Low (60% of normal)
    - Standing: Rise to > 600 pg/ml
  - Valsalva maneuver
    - Moderately forceful attempted exhalation against a closed airway
    - Impaired baroreflex-mediated peripheral vasoconstrictor function
  - Cardiovagal tests: Normal
- Sweating: Distal hypohidrosis, postganglionic

Hypotension in the elderly ⁶

Associated factors
- Standing: Hypotension increases With length of time standing
- Post-prandial
  - High carbohydrate content of meal
  - Warm temperatures
- Anti-hypertensive medications
Clincial: May be associated with syncope

Adult-onset Leukodystrophy (ADLD) ³

● Lamin B1

; Chromosome 5q23.2; Dominant

Epidemiology: European, North & South American families
Genetics ²⁵
- Mutation: Lamin B1 gene duplication
- Allelic disorder: Microcephaly 26, primary, autosomal dominant (MCPH26); de novo Missense mutations
Lamin B1 protein
- Widely expressed
- Component of nuclear lamina (envelope)
- Mutation: Over-expression in brain
- Over-expression causes abnormal nuclear morphology: Blebbing & folding of membrane
Clinical
- Onset
  - Adult: 30's to 50's; Mean 41 years
  - Autonomic features first
- Autonomic
- Pyramidal
  - Loss of fine motor skills
  - Spastic paraparesis or tetraparesis ~90%
  - Pseudobulbar palsy
- Posterior column dysfunction
- Cerebellar
- Course
Differential diagnosis
- Progressive multiple sclerosis
- Toxic demyelination: Hexachlorophene; Cuprizone
Laboratory
- CNS MRI
- Neuropathology
  - Locations: White matter of centrum semiovali & cerebellar peduncles
  - Myelin loss in isolated and confluent patches
  - Microscopic
    - Vacuolation of white matter
    - Oligodendrocytes abundant within lesions
    - Astrocytes sparse: Processes abnormally beaded & foreshortened
    - No inflammation or clear neuronal pathology

Cold-Induced Sweating Syndrome ¹²

● Cytokine receptor�like factor 1 (CRLF1)

; Chromosome 19p13.11; Recessive

Epidemiology: Israeli & Norwegian families

Norwegian family: Neonatal; Feeding & Respiratory disorders

Gene mutations
- Norwegian family: More severe; 844_845delGT
- Israeli family: 2 missense mutations; R81H & L374R
- Also occur in: Crisponi syndrome
CRLF1 protein
- Expressed in skeletal muscle & other tissues
- Soluble cytokine receptor: Homology to type 1 receptors
- Associates with cardiotrophin-like cytokine
- Competes with CNTF for binding to CNTF receptor
- Syndromes involving related proteins
Clinical
- Onset age: Variable
- Sweating
  - Onset: 1st or 2nd decade
  - Induced at temperatures of 7°C to 18°C
  - Anatomical distribution
    - Sweating begins in localized region: Presternal; Hand
    - Becomes profuse on large segments: Above waist; Patches on back and chest
  - No sweating in affected areas with heat or fever
  - Course: Non-progressive
- Sensory loss: Small fiber modalities
  - In more severely affected patients
  - Reduced heat & surgical induced pain
  - Reduced sensation of heat in hot environments
- Feeding: Reduced interest in food
- Skeletal
  - High-arched palate: Nasal voice
  - Face
    - Reduced facial expression
    - Depressed nasal bridge
    - Limited opening of mouth
  - Elbow contractures
  - Clinodactyly
  - Kyphoscoliosis: Thoracolumbar

Cold-Induced Sweating Syndrome 2

● Cardiotrophin-like cytokine factor 1 (CLCF1)

; Chromosome 11q13.2; Recessive

Epidemiology: Single Australian patient
Genetics: Heterozygous mutations; Tyr107Ter & Arg197Leu
CLCF1 protein
- Family: Interleukin-6 cytokines
- Syndromes involving related proteins
Clinical
- Onset: Infancy; Feeding difficulties; Sweating
- Sweating
  - Induced by cold
  - Inability to sweat in hot weather
  - Location: Especially face, trunk & upper limbs
- Face
  - Weakness: Mild
  - Ears: Set at right angles to skull
- Polyneuropathy
  - Predominantly sensory
  - Axon loss
- Skeletal & Morphological
  - Palate: High-arched palate
  - Elbows: Valgus deformity; Inability to extend fully
  - Clinodactyly: Fingers & Toes, syndactyly of second and third toes of both feet
  - Thoracolumbar scoliosis
  - Lmbar lordosis
  - Degenerative disease of the cervical & lumbar spine
- Course: Non-progressive

Cold-Induced Sweating Syndrome 3/Crisopni-like) (CISS3)

● Kelch-like 7 (KLHL7)

; Chromosome 7p15.3; Recessive

Epidemiology: 4 Turkish families, 5 patients
Genetics
- Mutations
  - Homozygous
  - Missense & Truncation: Arg420Cys, Cys421Ser, Arg372Gln, 1-BP del, 1022T
  - In or near Kelch domain
- Allelic disorder: Retinitis pigmentosa 42
KLHL7 protein
- Substrate recognition subunits for cullin-3 -containing E3 ubiquitin ligase complexes
- Polyubiquitinate target proteins for proteasome-mediated degradation
Clinical: Crisponi-like
- Onset age: Infancy
- Hyperthermia
- Paroxysmal contractions of oropharyngeal muscles: Feeding & swallowing difficulties.
- Skeletal: Camptodactyly, Joint contractures, Full cheeks, High-arched palate, Depressed nasal bridge
- Cold induced sweating: 1 patient at 4 years
- Retinitis pigmentosa: After 2 years
- Course: Death at 7 to 24 months in 3 patients

Harlequin Syndrome

Definition
- Dysautonomic (Sympathetic) syndrome
- Lesion side: Anhidrosis
- Contralateral side: Sweating with flush
Epidemiology: More common in females
Clinical
- Onset: May be sudden
- Hypohidrosis
  - Unilateral
  - Face ± Upper trunk
  - Lesion side
- Normal side
  - Hyperhidrosis
  - Flushing
- Induced by: Heat or Exercise
- Course: Benign; Often stable
- Occasional
  - Arms: Ipsilateral or Contralateral
  - Overlap with: Pupil Δ (70%)
    - Tonic
      - Ross syndrome
      - Holmes-Adie syndrome
    - Horner syndrome
      - Small
      - Ipsilateral
  - Parasomnia overlap syndrome
Causes
- Idiopathic
- Brainstem infarction
- Pancoast lesion
- Neurinoma: Superior mediastinal
- Internal jugular vein catheterization
Pathology
- Sympathetic axons: Postganglionic (Most) cervical
- Parasympathetic neurons: Ciliary ganglion
- Superior cervical ganglion

From: M Al-Lozi

From: R Bucelli

Neuronal Intranuclear (Hyaline) Inclusion Disease (NIID) ³⁸

● Notch2 N-terminal-like C (NOTCH2NLC)

; Chromosome 1q21.2; Dominant or Sporadic

Epidemiology
- > 140 patients
- Asians: Most common cause of NIID
- Europeans: GGC repeat expansions unusual
Genetics
- Mutations
  - CGG (GGC) repeat expansions (66 to 517)
  - Location: 5' untranslated region of gene
- Allelic disorders
  - Neuromuscular
    - Oculopharyngodistal Myopathy + Neurological features (OPDM3)
    - Polyneuropathy, Axonal (Motor CMT)
    - ALS ⁴⁵
      - CGG mutations present in 0.7%
      - Severe & Rapid disease
  - Neurodegenerative
    - Multiple system atrophy (MSA)
    - Leukoencephalopathy
    - Alzheimer�s disease + Frontotemporal dementia (AD/FTD)
    - Tremor, essential 6
    - Retinal dystrophy
    - Parkinsonism: Intermediate length GGC expansion
- Other 5' CGG expansion disorders; OPML1; FXTAS
NOTCH2NLC protein
- Brain: Expression increases with age
- Interacts with Notch receptors & enhanced Notch signaling
Clinical
- Onset
  - Age: Usually childhood
  - Autonomic disorders
- Autonomic failure
  - Incontinence: Fecal; Urinary
  - Postural: Hypotension; Light-headedness; Syncope
  - Erectile dysfunction
  - Hypohidrosis
  - GI: Pseudo-obstruction
  - Course: May be progressive or episodic
- Cerebellar dysfunction
  - Ataxia: Gait
  - Dysarthria
  - Ocular dysmetria
  - Tremor
- Peripheral neuropathy: Some families ²³
  - Motor: Weakness of face & limbs; Nasal voice; Dysphagia
  - Sensory loss: Pan-modal; Distal
  - Electrophysiology: Axonal loss
  - Nerve pathology
    - Axon loss: Small > Large
    - Schwann cell inclusions: Stain with ubiquitin
- Motor
  - Weakness: Legs or Diffuse
  - Hypotonia
- Tendon reflexes: Increased or Reduced (with neuropathy)
Laboratory
- MRI
  - Cerebellar ± Cortical atrophy
  - DWI signal intensity in corticomedullary junction of cerebral white matter
- EMG: Distal denervation; Sphincter abnormalities
- Muscle biopsy: Normal
- Serum CK: High in some patients
Pathology
- Neuronal & glial nuclear inclusions
  - Eosinophilic
  - Ubiquitinated
  - Neuronal nuclear
  - Locations
    - Widespread in CNS & PNS
    - Neuronal, Rectal or Skin biopsy (Ubiquitin staining)
    - Peripheral nerve with sensory involvement
- Neuronal loss & gliosis
  - Sympathetic & Sensory ganglion neurons
  - Spinal & Brainstem motor neurons
NOTCH2NLC variant: Oculopharyngodistal Myopathy + Neurological features (OPDM3) ⁴⁶
- Epidemiology: 7 Japanese & 5 Chinese patients
- Genetics
  - Inheritance: de novo individuals or single generation
  - Mutations: NOTCH2NLC CGG expansions, 116 to 674 repeats
- Clinical
  - Onset age: Infancy to 67 years
  - Eye: Ptosis, Ophthalmoplegia
  - Weakness
    - Bulbar: Dysarthria, Dysphagia
    - Face
    - Limbs: Often predominantly distal
  - Deep tendon reflexes: Reduced
  - Neural: Varied
    - Leukoencephalopathy
    - Retinal pigmentary degeneration
    - Ataxia
    - Tremor
    - Deafness
    - Peripheral neuropathy
- Laboratory
  - Muscle pathology
    - Fiber sizes: Varied
    - Vacuoles, rimmed
    - Immature muscle fibers: Myofibers with neonatal myosin heavy chain
    - Intra-myonuclear inclusions: Poly-ubiquitinated proteins, SUMO1, Phospho-p62/SQSTM1
    - Ultrastructure: Nuclear tubulofilamentous inclusions without limiting membrane
  - Skin: p62-positive intranuclear inclusions
  - Muscle imaging
    - Asymmetric
    - Muscles involved: Gluteus maximus, Vastus lateralis, Adductor magnus, Rectus femoris
  - Brain MRI
    - FLAIR: Middle cerebellar peduncles; Paravermal
    - DWI: Corticomedullary junction
  - Serum CK: 436 to 1886
  - CSF protein: High
NOTCH2NLC variant: Polyneuropathy, Axonal or Intermediate ⁵⁴
- Epidemiology
  - 39 patients
  - Geographic: 6% of Taiwan & 1.2% of Japan CMT
- Genetics
  - Mutations: GGC repeats
    - Number: 71 to 222 (Controls 4 to 39)
    - Repeat size relations
      - Generally fewer than NIID or OPDM
      - No clear association with onset age or symptoms
  - Inheritance
    - Dominant or de novo
    - Family history of Polyneuropathy: 45%
    - 2 family members with NIID
- Clinical
  - Onset
    - Age: Mean 34 to 37 years; Range 7 to 61 years
    - Tingling: Feet or Hands
  - Polyneuropathy
    - General
      - Often motor predominant
      - Sensory only: Few patients
      - Mild severity
    - Sensory
      - Paresthesias (72%): Legs, Arms, Tongue
      - Pin or Vibration loss (57%)
    - Cramps (43%)
    - Weakness (43%)
      - Distal > Diffuse
      - Legs > Arms
      - Pure motor PN: 1 patient
    - Tendon reflexes: Reduced or Absent
  - Autonomic
    - Abnormal (44%): Especially in more severe disease
    - Anhidrosis
    - Constipation
    - Orthostatic hypotension
  - CNS
    - Involuntary movements (29%): Most Postural tremor
  - Course: Slow progression
- Laboratory
  - NCV
    - General: Intermediate range (69%); Axonal (31%)
    - Mild slowing (Arms > 38 m/s)
    - CMAP & SNAP amplitudes: Often normal
  - Skin biopsy
    - Inclusions: p62 & Ubiquitin
    - Eosinophilic
    - Location: Sweat gland cells; Dermal fibroblasts
  - Serum CK: High in 75%; Mean 559
  - Nerve biopsy
    - Axon loss
    - Thinly myelinated axons
    - Ultrastructure: Intranuclear inclusions
      - Filamentous aggregates
      - In Schwann & perineurial cells
  - Brain MRI: Atrophy or Luecoaraiosis

Hypotonia, Hyperventilation, impaired Intellectual development, Dysautonomia, Epilepsy & Eye Abnormalities (HIDEA)

● Prolyl 4-Hydroxylase, Transmembrane (P4HTM)

; Chromosome 3p21.31; Recessive

Epidemiology: 5 families, 13 patients
Genetics
- Mutations: Loss of function
P4HTM protein
- Expression highest: Brain & Eye
- Oxygen-dependent regulation of hypoxia-inducible factor (HIF)
- Mutations: Insoluble proteins
Clinical
- Onset age: 1 top 5 years
- Hypotonia
- Intellectual disability
- Eye: Strabismus
- Epilepsy
- Respiratory: Pneumonia, recurrent; Sleep apnea
- Autonomic: Constipation; Hypo- or Hyperthermia; Hypohidrosis
- BMI: High (50%)
Laboratory
- Brain MRI: Normal
- Muscle biopsy
  - Mitochondria: Complex activities reduced; Abnormal morpohology; COX- fibers
  - Fiber sizes: Varied

Dementia with Lewy bodies ²⁰

Genetics: Mutations in
- SNCA
- SNCB
Clinical
- Onset age: 65 years
- Cognitive
  - Decline: Progressive
  - Fluctuating: Cognition or Arousal
  - Visual hallucinations: Recurrent, Formed
- Parkinsonism: Spontaneous
- Falls
- Syncopal episodes
- Sensitivity to neuroleptic medication
- Autonomic dysfunction
  - Anhidrosis: Distal
  - Hypotension, Orthostatic
  - Urinary symptoms (35%)
Brain pathology: Lewy bodies, widespread

Mast Cells

Mast Cells: General ⁵¹

Development & Migration
- Lineage: Myeloid, Hematopoietic
- Progenitors: Small intestine; Express CXCR2
- α4β7 Integrins: Bind to VCAM1 on endothelium
- Other associated molecules: CCR-2; CCL-2
Phenotypes
- Mucosal: Produce tryptase
- Connective tissue: Produce tryptase, chymase, carboxypeptidases
Locations: Connective tissue
- Mucosal & Epithelial
- Muscle: Perimysium
- Junction points of host & external environment
  - Places of entry of antigen
  - Gastrointestinal tract, Skin, Respiratory epithelium
Granules
- Number: 50-200
- Contents: Histamine, Heparin, Cytokines, Chondroitin sulfate, Neutral proteases
Express
- TLRs 1 to 7 & 9
- NOD-like receptors
- Retinoic-acid-inducible gene
Activation
- IgE binding to FcεRI
- Hypoxia; Ischemia/Reperfusion
Functions
- Vascular: Dilation & Homeostasis
- Immune responses
- Angiogenesis
- Venom detoxification

Mast Cells: Disorders

Immune: Allergy, Asthma, Anaphylaxis
Gastrointestinal disorders
Malignancies
Cardiovascular diseases
Neuroinflammation
Idiopathic mast cell activation syndrome (MCAS)
- Small fiber neuropathy (80%)
- Dysautonomia
- Serum tryptase: Baseline < 8 ng/ml
Hereditary α-tryptasemia (HαT) ⁵²
● Tryptase α/β-1 (TPSAB1; MCP7) ; Chromosome 16p13.3; Dominant
- Epidemiology
  - 5% to 7% of Western populations
  - Greater in patients with known severe anaphylaxis
- Genetics
  - TPSAB1: Gene copy number increased
- Clinical
  - Cutaneous: Flushing & Pruritus
  - Gastrointestinal: Lower GI symptoms
  - Neurological ⁵³
    - Pain: Chronic
    - Small fiber neuropathy (80%)
    - Dysautonomia (100%)
      - Sympathetic, Parasympathetic or Sudomotor
      - Orthostatic intolerance
      - Sweating disorders
    - Cerebral blood flow
      - Orthostatic: Reduced
      - "Brain fog"
  - Connective tissue: Primary dentition retained
  - Anaphylaxis: Severe
  - Asymptomatic: Many carriers
- Laboratory
  - Serum tryptase: Baseline (BST) high
    - > 8 ng/ml
    - Additional TPSAB1 copy encoding α-tryptase: BST increased by 9 to 10 ng/mL
  - Mast cells, Bone marrow: Increased, Atypical

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References

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