Autonomic Differential Diagnosis

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AUTONOMIC DISORDERS

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
Physiology & Pharmacology
Pavlov laboratory
External links
Canine dysautonomia
Pupil disorders

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: anti-Hu; CV-2
  - 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
Hirschsprung's congenital megacolon
Hypoventilation
Lacrimation: Absence
Visceral myopathy & PEO

Other congenital dysautonomias

Other hereditary autonomic disorders
Achalasia
Achalasia-Addisonianism-Alacrimia syndrome: 12q13
APECED: Autoimmune regulator (AIRE); 21q22
Adult-onset Leukodystrophy: Lamin B1; 5q31
Ataxia with 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
CISS1: CRLF1; 19p12
CISS2: CLCF1; 11q13
Dementia with Lewy bodies
Dopamine receptor D4: 11p15
Fabry's: α-galactosidase; Xq22
HSAN + Anosmia
Multiple Endocrine Neoplasia 2b: RET oncogene; 10q11
Navajo
Pain with flushing
Parkinson disease
Postural Orthostatic Tachycardia: SLC6A2; 16q12
Rett syndrome: MECP2; Xq28
Tangier disease: ABC1; 9q31
Visceral neuropathy: Dominant; Recessive

Biemond congenital anaesthesia
Pain (submandibular, ocular & rectal) with flushing
Other congenital dysautonomias¹
- 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 receptor⁴ (30%)
  - Higher antibody titers (≥ 1 nmol/L) correlate with
    - Autonomic features: Presence & More severe
    - Neoplasm
  - 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%
  - Low titers (0.03-0.09 nmol/L): Non-specific
  - Sero-negative
    - Persistent: Orthostatic hypotension; GI dysfunction
  - Common associated antibodies
    - GAD-65
    - Muscle AChR
    - Voltage-gated cation channel: N-type Ca⁺⁺; K⁺-associated; P/Q type Ca⁺⁺
    - 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 subunits¹⁵
- 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

Gastrointestinal syndromes

Achalasia
Acquired
Chagas
Familial visceral myopathy
Hirschsprung's
Goldberg-Shprintzen
Mowat-Wilson
Multiple endocrine neoplasia 2B
Paraneoplastic
Post-surgical

Hirschsprung's congenital megacolon
- General features
  - Pathophysiology
    - 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
  - Onset: Congenital
  - 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
  - Epidemiology
    - Incidence: 1 in 5,000 newborns
    - Male predominance: 4 to 1
    - Sibling recurrence: Usually 3% to 4%; 200x higher than general population
- Clinical features
  - 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
l RET oncogene (HSCR1) ; Chromosome 10q11.21; Dominant or Sporadic
- Frequency: 50% of familial cases; 15% to 35% of sporadic cases
- Gene mutations
  - Multigenerational families: Mutations occur throughout gene
  - Sporadic cases: Mutations in region encoding extracellular domain
- Genetic mechanism¹⁰
  - 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
      - Transmission: Maternal > Paternal
      - Magnitude of effects: Multiplicative among loci
- Penetrance: 50% (Females) to 72% (Males)
- Clinical
  - Often non-syndromic Hirschsprung's congenital megacolon
  - Short segment bowel disease in 25%
  - Autonomic sleep ventilation failure
l Endothelin receptor type B (EDNRB; HSCR2) ; Chromosome 13q22.3; Recessive
- Genetics
  - Penetrance: 30% to 85%
  - Allelic with: Waardenburg-Shah syndrome (WS4)
- Clinical
  - GI (Hirschprung's): Short segment bowel disease in 95%
  - Deafness
  - Pigmentary anomalies
l GDNF (HSCR3) ; Chromosome 5p13.2; Dominant or Recessive
- ? Some cases have digenic inheritance with RET
- ? Penetrance
- Also see: Autonomic sleep ventilation failure
l Endothelin-3 (EDN3; HSCR4)) ; Chromosome 20q13.32; Recessive or Dominant with reduced penetrance
- Genetics: Allelic with: Waardenburg-Shah syndrome (WS4)
- Congenital central hypoventilation with Hirschsprung disease
  - 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
l Neurturin Chromosome 19p13.3; Sporadic
- ? Some cases have digenic inheritance with RET
l 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
l SOX10 ; Chromosome 22q13.1; Dominant or Sporadic (Recessive)
- Hypomyelination in CNS & PNS
- Hypopigmentation
- Deafness
- Enteric aganglionosis
- Allelic with
  - Waardenburg syndrome, type IIE (WS2E)
  - Yemenite deaf-blind hypopigmentation syndrome
  - Waardenburg-Shah syndrome, neurologic variant
l SMADIP1 (Zinc finger homeobox 1B; ZFHX1B; ZEB2) Chromosome 2q22.3; Dominant or Recessive
- Nosology
  - Mowat-Wilson syndrome : Usually Dominant
  - Similar recessively inherited syndrome: Goldberg-Shprintzen
- Genetic: Mutations
  - Frameshift or Nonsense
  - Deletion syndrome: Occasional patient
- SMADIP1 protein (ZFHX1B)
  - 2-handed zinc finger/homeodomain proteins (Zinc finger homeo box 1B)
  - SMADIP1 interacts with receptor-mediated, activated full-length SMADs
- 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
l KIAA1279 ; Chromosome 10q22.1; Recessive
- Nosology
  - Goldberg-Shprintzen syndrome (GOSHS) with polymicrogyria²²
  - Similar Dominantly inherited syndrome: Mowat-Wilson
- Epidemiology: Moroccan family
- Genetics
  - Homozygous stop mutations: Arg90X; Glu84X
- KIAA1279
  - Tetratrico peptide repeat (TPR) family
  - Ubiquitous expression
  - Other TPR family disorders
    - Leber congenital amaurosis: AIPL1
    - Charcot-Marie-Tooth 4C: KIAA1985
- Clinical
  - CNS
    - Microcephaly
    - Mental retardation
    - Micropolygyria
  - Hirschsprung disease
l Down syndrome-associated
- ? Related to Hirschsprung genetic modifier (HSCR5)
- On Chromosome 21q22.3
l Hirschsprung genetic modifier 8 (HSCR8) : Chromosome 16q23

l Hirschsprung genetic modifier 9 (HSCR9) : Chromosome 4q31.3-q32.3

l Other Hirschsprung syndromes
- 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
    - Familial achalasia
      l Autosomal Recessive
    - Achalasia-Microcephaly
    - Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED)
  - 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)
l RET oncogene ; Chromosome 10q11.21; Dominant
- Ganglioneuromas: Tongue & Lips
- GI dysmotility: esophagus, megacolon
- Neoplasms: Medullary Thyroid; Pheochromocytoma
Familial visceral myopathy with external ophthalmoplegia
- Clinical
  - Eyes: Ptosis & ophthalmoplegia
  - GI: Intestinal pseudoobstruction; Ascites
  - Progression: Death often < 30 years
- Pathology
  - Loss of smooth muscle in stomach & intestines
  - Peripheral neuropathy
Familial visceral neuropathy
l Recessive
- Onset: 1st 2 decades
- Clinical
  - Intestinal pseudo-obstruction
  - Other: Some patients with PNS or CNS features
    - Ataxia
    - Pupils: Poorly reactive
    - Tendon reflexes reduced
    - Sensory loss: Vibration & Position sense
Familial visceral neuropathy
l Dominant
- Clinical
  - GI
    - Intestinal pseudo-obstruction
    - Esophageal achalasia
  - Neurologic exan: Often normal
- Pathology: Myenteric plexus
  - Neurons: Abnormal morphology; Increased number
  - Nerve trunks: Hyperplastic
Cartilage-hair hypoplasia (CHH)
l Mitochondrial RNA-processing endoribonuclease, RNA component (RMRP) ; Chromosome 9p13.3; Recessive
- 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
- Epidemiology: Old Order Amish (US); Finland
- Clinical
  - Skeletal
    - Short stature: Disproportionate
    - Joint hyperextensibility: Hands, wrist, & feet
    - Metaphyseal dysplasia: May be only manifestation
  - Hair: Hypoplastic; Fine, sparse & light-colored
  - 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
    - Amyloidosis
    - Hereditary Orthostatic Hypotension: Hyperbradykininism
    - Epithelial sodium channel genes: Pseudohypoaldosteronism
    - Mitochondrial disorder: Maternal inheritance
    - Postural Orthostatic Tachycardia Syndrome (POTS)
    - Spastic-Ataxia with Lipodystrophy
  - 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
- Avoid exacerbating factors
- Stockings
- Reduce salt loss: Mineralocorticoids
  - Fludrocortisone 0.1 mg qd to qid
- Vasoconstriction
  - Resistance vessels
    - Midodrine 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 drinking⁹
    - 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:
  - Reduce excessive fludrocortisone
  - No vasoconstrictors after 6 pm
  - Sleep with head of bed elevated
  - Treatment: Enalapril (ACE inhibitor) with maximal dose at bedtime

Other blood pressure disorders

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

Sweating: Sympathetic; Muscarinic cholinergic control

Hyperhidrosis
Anhidrosis

Hyperhidrosis
- Mechanisms
  - Aquaporin-5 (AQP5) in sweat gland plasma membranes necessary for secretion of sweat
- General disorders
  - Compensatory for loss of sweating elsewhere
  - May be initial symptom with progression to anhydrosis
- Toxic
- Other acquired
  - POEMS syndrome
  - Neuromyotonia
  - Holmes-Adie
  - Harlequin syndrome
  - Gustatory sweating (Frey's syndrome)
    - Aberrant sympathetic, cholinergic axons supply facial sweat glands
  - Axillary sweating
  - Segmental hyperhidrosis
    - Causes: Syringomyelia; Vascular disorders; Neoplasms
    - Possible treatments: Botulinum toxin; Mexiletine
  - Hirayama
  - Endocrine
    - Acromegaly
    - Carcinoid
    - Pheochromocytoma
    - Hyperthyroid
    - Menopause
    - Hypoglycemia
  - Medications: Propranolol, Physostigmine, Pilocarpine, Tricyclic antidepressants, Serotonin reuptake inhibitors
- Hereditary
  - HSAN IIB
  - Riley-Day syndrome (HSAN 3)
  - Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation
  - Hyperhidrosis, Palmoplantar
    l 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
    l 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)
    l 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
    l 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)
    l 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)
    l 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
    l Autosomal Dominant
    - Premolar aplasia
    - Hyperhidrosis
    - Canities prematura
  - Gamstorp-Wohlfart Syndrome
    l Autosomal Dominant
    - Myokymia
    - Myotonia
    - Muscle wasting
    - Hyperhidrosis
  - Cold Sweating syndromes
    - CISS1
    - CISS21

Anhidrosis

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

Differential diagnosis

Distribution	Etiology of Anhidrosis	Pathology
Distal	Polyneuropathies	Postganglionic
Proximal	Shy-Drager syndrome	Central Preganglionic
Diffuse	Amyloidosis Chronic idiopathic dysautonomia Congenital sensory neuropathy Diabetes insipidus Ectodermal dysplasia Fabry's Familial anhidrosis (normal sweat glands) Harlequin syndrome Idiopathic orthostatic hypotension Neuronal intranuclear inclusion disease (NIID) Pandysautonomia Sjögren Tangier disease Tellurium	Pre- or Post-ganglionic
Ectodermal dysplasia	Anhidrotic ED1: EDA; Xq12; Recessive ED + Immunodeficiency: IKBKG; Xq28; Recessive ED: EDARADD; 1q42; Recessive ED: EDAR; 2q11; Recessive ED + T-cell deficiency: NFKBIA; 14q13; Dominant ED: Other Hidrotic ED2: GJB6; 13q12; Dominant	Preganglionic
Focal	Diabetic radiculo-neuropathy Leprosy Local neuropathy (ulnar) Horner's (Ptosis; Miosis; Anhidrosis) Ross: Anhidrosis; Hyporeflexia; Tonic pupils Sympathectomy	Post-ganglionic
Hemianhidrosis	Cerebral infarction Spinal cord tumor	Central sympathetic outflow
Skin disease	Dermatophytosis Limb-Mammary syndrome	Plugging of sweat ducts & Other

Anhidrotic ectodermal dysplasia (ED1)
l 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
l 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
l EDAR-associated death domain (EDARADD) ; Chromosome 1q42-q43; Recessive or Dominant
- 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
l Ectodysplasin 1, anhidrotic receptor (EDAR) ; Chromosome 2q12.3; Recessive or Dominant
- 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
l 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
l with Deafness
l with Retardation
Hidrotic ectodermal dysplasia (ED2)
l Gap junction protein β-6 (GJB6, Connexin-30, CX30) ; Chromosome 13q12.11; Dominant

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
Other pupil disorders
Hereditary neuropathy
2J (P₀ mutations)
HSAN 2B

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
  - Congenital Horner's
    - Heterochromia: Blue iris on side of lesion
  - Associations: Hereditary polyneuropathy
    - Amyloid: Bilateral (50%)
    - HSAN-I: Occasional; Unilateral or Bilateral
- Lesions
  - Ipsilateral sympathetic pathways
  - CNS
    - Lateral medullary syndrome
    - Cervical spinal cord: Occasional
      - Child: Arnold-Chiari; Syringomyelia
  - Preganglionic
    - Location: Mediastinum; Pulmonary apex; Supraclavicular space
    - Lesion
      - Often neoplasm
      - Usually with brachial plexus involvement
      - Early lesion ® hyperfunction with mydriasis & hyperhidrosis
  - Postganglionic: Ptosis, Miosis, Pain & preserved ipsilateral facial sweating
    - Location: Carotid plexus along internal carotid artery; Carotid artery dissection
    - Intracranial (Cavernous sinus) or Internal carotid thrombosis
    - Paratrigeminal syndrome: Pain in face & Horner's
- Pharmacologic testing: Compare responses in 2 eyes
  - No pupil dilation by cocaine
  - Postganglionic: No dilation with 1% hydroxyamphetamine
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
  - Areflexia: ? 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 syndrome¹³
- Epidemiology: Males & Females
- Onset: 1st to 5th decade
- Clinical features
  - 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

Absence of lacrimation

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

Respiratory disorders, Autonomic

Congenital central hypoventilation syndrome (CCHS)
- 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
- Genetic associations
  l Endothelin-3 ; Chromosome 20q13.2; Recessive or Dominant with reduced penetrance
  - Also see: Hirschsprung
  l RET oncogene ; Chromosome 10q11.21; Dominant or Sporadic
  - Also see: Hirschsprung
  - Malformation of enteric nervous system
  l GDNF ; Chromosome 5p13.2; Dominant (HSCR1) or Recessive
  - Also see: Hirschsprung
  l BDNF ; Chromosome 11p14.1; Dominant
  - Isolated CHS
  - Father with postural hypotension & vasovagal syncope
  l 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
  - Mutations²¹
    - 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
Mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome) ²⁶
l 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)

l Sporadic or Autosomal Dominant

Nosology: Other similar or overlapping disorders
- Striatonigral degeneration
- Adult-onset sporadic olivopontocerebellar atrophy (OPCA)
- Shy-Drager syndrome
Clinical features
- Onset: Adult; Early Parkinsonism & Bladder dysfunction
- Autonomic
  - Orthostatic hypotension
  - Bladder incontinence
  - Anhydrosis; 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

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

; Chromosome 9q31.3; Recessive

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
- Pro914Leu¹⁴
  - Found in non-Jewish patient
  - Otherwise typical clinical syndrome
  - Mutation disrupts protein phosphorylation
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
Epidemiology: Most patients Ashkenazi-Jewish

Clinical features

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

Onset: Congenital
Early in disease course
- Newborn: Hypothermia; Vomiting crises; Hypotonia
- Eye
  - Lacrimal Flow (Overflow tears): Reduced or Absent (99%)
  - Corneal 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
    - Hypertension
    - Tachycardia
    - Hyperhidrosis
    - Behavioral changes
    - Treatments: Diazepam (Vomiting); Clonidine (Hypertension)
  - Skin blotching (99%)
  - Sweating: Increased (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: Fractures & Aseptic necrosis
- 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
Older patients
- Finger nail dystrophy
- Taste: Reduced, especially sweet
- Vibration loss: With increasing age (> 13 years)
- Ataxia: Gait disorder
- Psychiatric syndromes
Course
- 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

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 b-hydroxylase
  - Emotional crises: Very high plasma NE and DA levels
Pathology
- Unmyelinated axons
  - Marked progressive reduction: 5% to 15% of normal
  - Reduced number of cell bodies in dorsal root ganglia
- Loss of autonomic neurons
  - Small superior cervical sympathetic ganglia
  - Parasympathetic ganglia: Generally normal; Exception is sphenopalatine ganglion
- Large axons relatively spared: 65% to 100%
- Spinal cord
  - Reduced primary substance P axons in substantia gelatinosa
  - Intermediolateral gray columns: Reduced neurons

Congenital sensory neuropathy with anhidrosis (HSAN 4)

l TRKA/ NGF receptor (NTRK1)

; Chromosome 1q23.1; Recessive

Nosology: Congenital insensitivity to pain with anhidrosis (CIPA)
Gene mutations
- Types: Deletions, splice-site, frame shift, & missense
- > 40 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
- 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
- Tendon reflexes: Normal, increased or decreased
- Autonomic
  - Absent sweating
  - Skin blotching
  - Normal: Blood pressure control; GI motility; Overflow tears
- CNS
  - Mental retardation
- Self mutilation
  - 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 tests⁸
  - Histamine: Wheal evoked; No axon flare response (100%)
  - Mecholyl: No tearing
  - Pilocarpine: No sweating
  - Sympathetic skin responses: Absent (100%)
- 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
- Skin: Reduced innervation; Remaining axons stain for GAP-43

Lethal autonomic sensory neuropathy (HSAN 6) ²⁸

l Dystonin (DST)

; Chromosome 6p12.1; Recessive

Epidemiology: Ashkenazi Jewish
Genetics
- Mutation: c.14,865 delA
Dystonin protein
- Cytoskeleton linker: Actin filaments to Microtubules
- Plakin family
- Size: Very large
- Different isoforms in: CNS; Muscle; Skin
Clinical
- Onset
  - Age: Birth
  - Hypotonia
  - Respiratory failure
- Dysautonomia
  - Absent tearing,
  - Skin blotching
  - Feeding difficulties
  - Episodic
    - Hyperpyrexia
    - Desaturation
    - Bradycardia despite
    - Blood pressure lability
  - Fungiform papilla: Reduced on tongue
- Deep tendon reflexes: Absent
- Contractures: Distal arthrogryposis; Club feet; Hips; Fingers
- Face: Motionless; Open-mouthed; Low set ears; High arched palate; Small chin
- Retardation: Psycho-motor; Severe
- Course: Early death (< 2 years)
Laboratory
- Histamine test: Abnormal; No axon flare
- Brain MRI: Normal

Parkinson disease, juvenile onset

l 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 syndromes¹⁷
- Age: 7 to 64 years; Usually < 40 years; Later in 1 patient with consanguinous parents
- 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 45%; Impotence 28% of males; Othostatic faintness 13%
- Cortical
  - Psychosis
  - Cognitive function: Normal
- Course: Slow progression
Treatment response: L-DOPA; Anticholinergics

Dopamine β-Hydroxylase deficiency

l Chromosome 9q34.2; Recessive

Clinical features
- Neonatal
  - Ptosis & delayed eye-opening
  - Hypotension, hypoglycemia, and hypothermia
- Childhood & adult
  - Progressive postural hypotension with exertion
  - Nasal stuffiness
  - Prolonged or retrograde ejaculation (normal erection)
  - Reduced exercise tolerance
  - Ptosis
Laboratory
- Dopamine beta-hydroxylase deficiency
- Low plasma, urine, and CSF noradrenaline and adrenaline
- Increased plasma, urine, and CSF dopamine
Treatment: L-dops - Elevates noradrenaline levels

Dopamine receptor D4

l 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

Hereditary Orthostatic Hypotension

l Chromosome 18q; Dominant

Nosology: Hyperbradykininism; Streeten type
Genetics: Occasional non-penetrant patient
Onset: Light-headedness on standing
Clinical
- 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

l 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

l 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 disorder²⁷
- 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

Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED)

l Autoimmune regulator (AIRE)

; Chromosome 21q22.3; Recessive

Nosology: Autoimmune polyendocrine syndrome, Type I (APS1)
Epidemiology: Mostly in Finns, Sardinians & Iranian Jews
Genetics: > 60 mutations
Clinical
- Onset: 1st decade
- Endocrine
  - 1° Hypoparathyroidism
  - 1° Hypogonadism
  - Adrenal insufficiency
  - Diabetes mellitus: Insulin-dependent; GAD antibodies
  - Hypothyroidism: Latent
  - Hypoaldosteronism: Transient, Isolated
  - Gonadal failure: Primary sertoli cell insufficiency
- 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
- Hair: Alopecia totalis
- Teeth: Dental enamel hypoplasia
- Eyes: Keratopathy; Keratoconjunctivitis
- GI: Malabsorption; Diarrhea; Chronic active hepatitis; Achalasia
- Moniliasis
Laboratory
- Pernicious anemia: Juvenile-onset
- Humoral immunity
  - Hypogammaglobulinemia
  - Antibodies: Antiadrenal, Antithyroid & Antinuclear
- Cellular immunity: Low T4/T8 cell ratio

Postural Orthostatic Tachycardia Syndrome (POTS) ²

Nosology: Postural Tachycardia syndrome (PoTS)
Definition
- Symptomatic orthostatic intolerance
- Associated with heart rate increment of at least 30 beats/minute
Patient characteristics
- Young: Mean 29 years; Range 15 to 50 years
- Female to Male: 4:1
Onset
- Course: Acute or Subacute
- Prodromes
  - Viral illness: 50% of patients
  - Other: Trauma, Surgery Stress
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
Laboratory: Partial sympathetic denervation, especially in legs⁵
- 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: Impairmed baroreflex-mediated peripheral vasoconstrictor function
  - Cardiovagal tests: Normal
- Sweating: Distal hypohidrosis, postganglionic
Family history
- Orthostatic intolerance : 27%
  l SLC6A2 (Norepinephrine transporter) ; Chromosome 16q12.2; Dominant
  - Mutation: Missense Ala457Pro
  - Mutated norepinephrine transporter protein: Non-functional
  - Clincal features
    - Altered heart-rate regulation
    - Laboratory: Altered norepinephrine metabolism
    - Variable penetrance
- Ehlers-Danlos, Type III (Hypermobility)
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
    - 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 symptioons
    - Subcutaneous: 25 to 50 µg before food ingestion
  - Ivabradine: Sinus node blockade; For more severe tachycardia
  - Clonidine
Prognosis
- Improvement in majority (80%): 60% may become normal
- Better with history of infectious prodrome

Hypotension in the elderly⁶

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

l Lamin B1

; Chromosome 5q23.2; Dominant

Epidemiology: Irish-American families
Genetics²⁵
- Mutation: Duplication of Lamin B1 gene
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
Onset
- Adult: 30's to 50's; Mean 41 years
- Autonomic features first
Clinical

Autonomic

Bowel/bladder dysfunction
Impotence (in males)
Orthostatic hypotension
Hypohidrosis

Pyramidal
- Loss of fine motor skills
- Spastic paraparesis ~90%
- Posterior column dysfunction
Cerebellar

Nystagmus 69%
Ataxia 100%

Course

Slowly progressive over 20 years
Loss of voluntary movement
Fatal

Differential diagnosis
- Progressive multiple sclerosis
- Toxic demyelination: Hexachlorophene; Cuprizone
MRI of CNS: Symmetrical widespread myelin loss

Begins in frontal lobes of the brain
Extends to cerebellum

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 Syndrome¹²

l Cytokine receptor�like factor 1 (CRLF1)

; Chromosome 19p13.11; Recessive

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
Epidemiology: Israeli & Norwegian families
Onset: Variable
- Norwegian family: Neonatal; Feeding & Respiratory disorders
Clinical
- 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

l 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

From: M Al-Lozi

Harlequin Syndrome

Clinical
- Hypohidrosis: Unilateral
- Hyperhidrosis: Normal side
- Flushing: Normal side
- Induced by: Heat or Exercise
- Onset: May be sudden
- Course: Benign
- Occasional
  - Arm involvement, ipsilateral or contralateral
  - May overlap with: Ross syndrome; Horner syndrome
  - Parasomina overlap syndrome
Causes
- Idiopathic
- Brainstem infarction
- Neurinoma: Superior mediastinal
- Internal jugular vein catheterization
Possible pathology
- Pre- or postganglionic cervical sympathetic axons
- Parasympathetic neurons: Ciliary ganglion

Neuronal Intranuclear (Hyaline) Inclusion Disease (NIID)

l Dominant or Sporadic

Onset
- Age: Usually childhood
- Autonomic disorders
Clinical
- 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
- Peripheral neuropathy: Some families²³
  - 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
- Pathologic Inclusions
  - Eosinophilic,
  - Ubiquitinated
  - Neuronal nuclear
  - Locations
    - Neuronal, Rectal or Skin biopsy (Ubiquitin staining)
    - Peripheral nerve with sensory involvement
- MRI: Cerebellar ± Cortical atrophy
- EMG: Distal denervation; Sphincter abnormalities
- Muscle biopsy: Normal
- Serum CK: Elevated in some patients
Pathology
- Neuronal & glial nuclear inclusions: Widespread in CNS & PNS
- Neuronal loss & gliosis: Sympathetic & sensory ganglion neurons; Spinal & brainstem motor neurons

Dementia with Lewy bodies^²⁰

Onset age: 65 years
Clinical
- Cognitive decline: Progressive
- Fluctuating cognition or arousal
- Recurrent formed visual hallucinations
- Parkinsonism: Spontaneous
- Autonomic dysfunction
  - Anhidrosis: Distal
  - Hypotension, Orthostatic
  - Urinary symptoms (35%)

From Horsley Gantt

Return to Neuromuscular home page
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Return to Autonomic physiology & Pharmacology

References

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2. Mayo Clinic Proc 1999;74:1106-1110, Nat Rev Neurol 2011;8:22-34
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5/15/2012

AUTONOMIC DISORDERS

AUTONOMIC DISEASE SYNDROMES

AUTONOMIC SYNDROMES: System disorders

Multiple Systems Atrophy (Shy-Drager)

Riley-Day (HSAN 3) 19

HSAN 3: Clinical Diagnosis

Congenital sensory neuropathy with anhidrosis (HSAN 4)

Lethal autonomic sensory neuropathy (HSAN 6) 28

Parkinson disease, juvenile onset

Dopamine β-Hydroxylase deficiency

Dopamine receptor D4

Hereditary Orthostatic Hypotension

Aniridia, Type 2

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

Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED)

Postural Orthostatic Tachycardia Syndrome (POTS) 2

Hypotension in the elderly6

Adult-onset Leukodystrophy (ADLD)3

Cold-Induced Sweating Syndrome12

Cold-Induced Sweating Syndrome 2

Harlequin Syndrome

Neuronal Intranuclear (Hyaline) Inclusion Disease (NIID)

Dementia with Lewy bodies20

Riley-Day (HSAN 3) ¹⁹

Lethal autonomic sensory neuropathy (HSAN 6) ²⁸

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

Postural Orthostatic Tachycardia Syndrome (POTS) ²

Hypotension in the elderly⁶

Adult-onset Leukodystrophy (ADLD)³

Cold-Induced Sweating Syndrome¹²

Dementia with Lewy bodies^²⁰