Small Fiber Sensory

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SENSORY DISORDERS: Small Fiber

Definition
Differential Diagnosis
Features

Anatomic definition

Small-fiber neuropathies selectively involve
- C-axons
  - Transmitters: CGRP; Substance P
- Aδ-axons
Diagnosis
- Skin biopsy
- Nerve biopsy

Small Fiber Neuropathy Features: Symptoms, Signs, Laboratory ⁷

Sensory loss
- Modalities
  - Thermal
  - Pain
  - Scratch
- Patterns of distribution
  - Length dependent: Earliest & most severe in distal legs
  - Partial length dependent: Early & most severe in both hands & feet
  - Non-length dependent: Early involvement in proximal & distal areas
- Insensitivity to pain
Discomfort
- Pain: Aching, Burning, Shooting, Prickling, Myalgias
- Itch
- Paraesthesias
- Allodynia
Other associated features
- Autonomic involvement
  - Postganglionic unmyelinated small axons
  - May occur without sensory features
- POTS
- Restless legs syndrome
Unexpected Motor Features
- Cramps ¹⁷
- Fasciculations
- Myalgias ¹⁶
- Denervation: Intrinsic foot muscles ¹⁵
- Serum CK: Moderate elevation
Serum antibodies ¹⁸
- IgM vs TS-HDS
- IgG vs FGFR3

Unmyelinated axons

Differential Diagnosis

Hereditary ²⁵
- Amyloidosis
- Hereditary Sensory Neuropathy I (HSAN I)
  - IA: SPTLC1
  - IC: SPTLC2
- Insensitivity to pain
  - Congential insensitivity to pain sensation
    - Without anhidrosis
    - With reduced hidrosis: PRDM12
  - Congenital sensory neuropathy with anhidrosis (HSAN4)
  - Hereditary sensory neuropathy with loss of pain perception (HSAN5)
  - Congenital absence of pain perception (HSAN7)
- HSAN3: Riley-Day
- Hereditary ataxia with thermoanalgesia & loss of fungiform papillae
- An-α-lipoproteinemia (Tangier's)
- α-galactosidase (Fabry's)
- Pain syndromes
  - SCN9A (Na_v1.7) mutations: Erythromelalgia
  - SCN10A
  - SCN11A
- Hereditary sensory neuropathy + Spastic paraparesis (Cavanagh's variant)
- Sensory neuropathy + Deafness-Dystonia & Ichthyosis: FITM2
- Congenital indifference to pain
- Navajo Neuropathy + Arthropathy (MTDPS6): MPV17
- Cold-Induced Sweating
- PRNP
Metabolic
- Diabetes mellitus: Not Pre-diabetes ¹⁹
- Hypertriglyceridemia
Toxic: Kepone; Ciguatera
Infection: Leprosy
Immune
Idiopathic: Often painful
CNS disorders that may have loss of small skin axons
- Parkinson disease
- α-Synucleinopathies : REM sleep behavior disorder (RBD)
- Progressive Supranuclear Palsy (PSP) ²¹
  - Axon loss Types: Sensory & Autonomic
  - Axon loss Pattern: Length dependent
- ALS ²⁰

Hereditary Sensory Neuropathy I (HSAN I; HSN I)

● HSAN IA

; Serine palmitoyltransferase, long-chain base subunit 1 (SPTLC1)

; Chromosome 9q22.31; Dominant
● HSAN IC

; Serine palmitoyltransferase, long-chain base subunit 2 (SPTLC2)

; Chromosome 14q24.3; Dominant

SPTLC Genetics
- SPTLC1
  - Misense mutations identified: C133Y, C133W, V144D, Ala352Val +
  - S331F: Severe, early onset disease
  - Founder effect in Australian & English families
  - Frequency in HSAN families: 19%
  - Allelic disorders
- SPTLC2 ⁵
  - Mutations: A182P; G382V; V359M; I504F
  - Frequency in HSAN families: 7%
  - Allelic disorders
- SPTLC3 : HMSN, Dominant
Serine palmitoyltransferase (SPT) enzyme: Sphingolipid biosynthesis
- Subunits: SPTLC1; SPTLC2; SPTLC3
- SPTLC2: Colocalizes with ER marker calreticulin
- Associated regulatory proteins: ORMDL3, ssSPTa, ssSPTb
- Function
  - Catalyzes pyridoxal-5'-phosphate-dependent condensation of L-serine & palmitoyl-CoA to 3-oxosphinganine
  - Rate limiting step in de novo biosynthesis of sphingolipids
- Mutation effects
  - Increased Glucosyl ceramide synthesis: ? Leads to apoptosis
  - Reduced serine palmitoyltransferase (SPT) activity
  - Shift SPT amino acid usage from serine to alanine → Elevated levels of deoxysphingolipids
  - Normal levels of protein
  - Accumulation of abnormal toxic metabolites⁴
    - Deoxy-sphingoid bases (DSB): 1-deoxy-sphinganine (1-deoxy-SA) & 1-deoxymethyl-sphinganine
    - DSBs have neurotoxic effects on neurite formation in vitro
Clinical features
- Features similar in: SPTLC1 & SPTLC2 mutations
- Onset age
  - Usual: 2nd to 3rd decade; Average 25 years; Up to 52 years
  - Occasional mutations: < 10 years
  - Males may develop symptoms earlier than females
- Sensory
  - Loss
    - Pain & Temperature (Small fiber)
    - Large fiber loss also occurs
    - Legs earlier (10 years) than arms
    - Distribution
      - Distal > Proximal
      - Symmetric
      - Legs > Arms
    - Sensory, Autonomic & Tendon reflex loss
    - Balance disorders: After 10 years of disease
    - Course: Progressive
  - Spontaneous sensations
    - Paresthesias: Rare to Occasional
    - Lancinating pains: Some kindreds
    - Burning pain: Some
- Charcot joints (Neurogenic osteoarthropathy) & Skin ulceration
  - Ulcero-Mutilation
  - Progression: Succession of exacerbations
  - Location: Feet, Severe mutilation & shortening; Occasional hands, Thickened fingers
  - X-rays: Distal demineralization; Metatarsal tapering (Licked candy-stick)
- Weakness
  - Common late in course
  - Distal
- Autonomic involvement
  - Rare
  - Occasional: Horner syndrome
- Sensorineural deafness: Variably present
- Skin: Blistering; Edema & discoloration of foot; Chronic ulcers; Painless injuries
- Eye: Macular telangiectasia type 2
  - Parafoveal telangiectatic retinal vessels
  - 'Right angle' venules
  - Retina: Opacification, Pigment clumping, Macular carotenoid pigment low
  - Leakage on fluorescein angiography,
  - Blue light-reflectance abnormalities
  - Intraretinal cysts & ellipsoid zone defects
- Time course: Slow progression
- Possible treatment
  - L-serine: High dose (400 mg/kg/day in divided doses)
Laboratory
- Electrophysiology
  - Loss of C > Aδ & Aα axons
  - Nerve conduction velocities: Normal or Intermediate (< 38 m/s in arms)
  - Axon loss: legs more severe than arms
- Skin biopsy: Axon loss, distal & proximal
- Immune: Increased Synthesis of IgA
- Plasma 1-deoxysphingolipids (1-deoxySLs): High
Pathology
- Loss of dorsal root ganglion cells & later motor neurons
- Predominant loss of small myelinated & unmyelinated axons
- No CNS changes
SPTLC variant syndrome: HSAN 1 + Motor, Child onset ²²
- Epidemiology: 8 patients
- Genetics
  - Inheritance: Dominant
  - Mutations
    - SPTLC1 Exon 11; S331F & S331Y
    - SPTLC2 I504F
- SPTLC1 protein
  - Mutations: Increased SPT activity
- Clinical
  - Onset earlier: Childhood
  - Autonomic: Sweating disturbances
  - Sensory
    - Postural instability
    - Loss: Less prominent
  - Muscle
    - Atrophy
    - Tongue: Fasciculations
    - Weakness: Distal
    - Respiratory dysfunction
  - Tendon reflexes: Brisk
  - Stereotyped movements: Swinging; Trunk & Legs
  - Growth retardation
  - Skeletal
    - Metacarpophalangeal joint hypermobility
    - Pes cavus
    - Scoliosis
  - Cataracts
  - Course: Wheelchair < 15 years
  - Treatment: L-serine supplementation may be detrimental
- Laboratory
  - NCV: Intermediate velocities; Axon loss
  - Brain MRI: Normal
SPTLC1 variant: Amyotrophic Lateral Sclerosis 27, Childhood (ALS27) ²³
- Epidemiology: 11 families
- Genetics
  - Inheritance: de novo or Dominant
  - Mutations
    - General location: Membrane-spanning domain
    - Exon 2; A20S (Exon 2 skipping), Y23F, L38R, L39del, F40_S41del
  - Mutation mechanism
    - Disrupts normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins
    - Result in
      - Impeded enzyme regulation by ORMDL3
      - Unregulated SPT activity
        
        Elevated levels of SPT products
        
        Increased formation of sphingolipids
- Clinical
  - Onset age: Early childhood; 1st decade
  - Spasticity: Legs; Toe walking
  - Lower motor neuron
    - Weakness: Loss of ambulation
    - Respiratory insufficiency (50%)
  - Sensory: Normal
  - Course: Progressive
  - Macular telangectasias
  - Variant syndrome: 1 adult patient with sensory-motor neuropathy
- Laboratory
  - Muscle: Denervation, Acute & Chronic
  - Sural nerve: Normal
  - Muscle MRI: Global atrophy
  - Muscle ultrasound: Fasciculations
  - Serum: Sphingolipid levels high
SPTLC2 variant: Amyotrophic Lateral Sclerosis, Childhood ²⁷
- Epidemiology: 6 patients
- Genetics
  - Inheritance: Dominant; de novo
  - Mutation: Glu260Lys; Recurrent
- SPTLC2 protein
  - Mutation effect: Sphingolipid synthesis unrestrained
- Clinical
  - Onset age: Early childhood; Congenital to 4 years
  - Lower motor neuron
    - Weakness: Proximal > Distal
    - Tongue fasciculations
    - Muscle atrophy
    - Respiratory: Support neded in 60%
  - Upper motor neuron
    - Spasticity: Distal legs
    - Tendon reflexes: Brisk
  - Loss of ambulation: 3 to 10 years
  - Bulbar: Dysphagia; Dysphonia
  - Sensory: Normal
  - Course: Progressive; More rapid than SPTLC1-ALS
  - Cognitive disorder: Some patients
  - May be exacerbated by: Serine supplementation
- Laboratory
  - NCS: CMAP amplitudes reduced; Sensory: Normal
  - EMG: Denervation, Acute & Chronic
  - Muscle pathology: Chronic neurogenic; Grouped atrophy
  - Muscle Ultrasound: Fasciculations; Echogenicity increased
  - Brain MRI: Normal
See: Other Hereditary sensory neuropathies

Hereditary sensory neuropathy with loss of Pain perception (HSAN5)

²
● Nerve growth factor-β (NGFB)

; Chromosome 1p13.2; Recessive

Epidemiology: Northern Swedish & Arab families
Genetic: Mutations (Homozygous)
- Missense: Arg211Trp (Arg100Trp in mature NGFB)
- Null: c.[680C>A]+[681_682delGG]
- Carriers
NGF-β protein
- Neurotrophin family
- Functions: Role in development & maintenance of sympathetic & sensory nervous systems
- Cellular location: Secreted
Clinical: Variable degrees of severity
- Onset: Early childhood to adult
- Sensory loss
  - Pain perception: Reduced; Insensitivity to pain
  - Temperature: Reduced
- Skeletal: Charcot joints & Fractures
  - Onset: Childhood or Adult (3rd & 4th decade)
  - Lower extremities: Feet; Ankles; Knees
- Autonomic
  - Sweating: Normal or Reduced
  - Fainting: 1 patient
  - GU & GI disorders: 1 patient
- CNS: Mental retardation (1 family)
Laboratory
- Electrophysiology
  - Nerve conduction velocity: Normal
  - Sensory loss: Temperature ± Vibration
  - R-R interval: Normal
- Nerve pathology
  - Axon loss: Thinly myelinated & Unmyelinated
  - Less axon loss in adult onset cases

NGFB variant syndrome: Heterozygote carriers
- Inheritance: Dominant, Incomplete penetrance
- Clinical: Neuropathy
  - Sensory loss: Temperature
  - Arthropathy: Adult onset, few patients
  - Carpal tunnel syndrome
  - No insensitivity to pain, anhidrosis or mental retardation
- Laboratory
  - Nerve: Loss of small myelinated (Aδ) & unmyelinated (C) axons

Congenital absence of pain perception (HSAN7)

⁸
● Sodium channel, voltage-gated, Type XI, alpha subunit (SCN11A)

; Chromosome 3p22.2; Dominant (Sporadic)

Epidemiology: German & Swedish patients
Genetics
- Mutations: Heterozygous; Leu811Pro, Leu1302Phe
- Allelic disorders
  - HSAN7
  - Familial Episodic Pain 3 (FEPS 3)
  - Neuropathy, Painful & Autonomic
  - Post-surgical pain sensitivity: SCN11A variants (rs33985936; rs13080116) ¹³
SCN11A protein (Na_v1.9)
- Mutated SCN11A protein (Gain of function)
  - Channel activation: Left shift
    - Diminished peak current densities at depolarized voltages
    - Greater inward current under resting conditions
  - Slow channel inactivation
Clinical
- Sensory
  - Pain perception: Absent
  - Temperature: Sensation present; Intolerance of moderate cold & heat
  - Pruritis
  - Abnormal postures
- Autonomic
  - Hyperhidrosis
  - GI dysfunction: Diarrhea & Constipation; Colon enlarged
- Anosmia
- Wounds: Slow healing
- Skeletal
  - Fractures: Painless; Multiple
  - Charcot joints
  - Self-mutilation
  - Joint hypermobility
- Development: Motor delay
- ? Weakness
- Intellectual: Normal
Laboratory
- Muscle biopsy: Normal
- EMG: Normal
- NCV: Slightly slowed Motor & Sensory CV; Normal amplitudes
- Nerve biopsy: Normal numbers of large & small axons
- Brain MRI: Normal
- Intestinal biopsies: Normal

Variant syndrome: Familial Episodic Pain 3 (FEPS3) ²⁶
- Epidemiology: > 20 families
- Genetics
  - SCN11A mutations: Missense; Arg222His, Arg225Cys, Ala808Gly, N816K, N820Y
  - Inheritance: Dominant
- SCN11A protein
  - Mutation effect: Gain of function
- Clinical
  - Onset age: 1 month to 9 years
  - Pain sensation: Cold
  - Pain locations
    - Common: Distal legs
    - Other: Upper body; Joints of fingers & Arms
  - Pain episodes
    - Onset: Late in day
    - Duration: 5 to 20 minutes
    - Cycles: Every 2 to 5 days; 9 to 19 recurrences per cycle; 1 to 24 cycles per year
    - Associated with: Sweating
  - Pain exacerbation: Fatigue, Infections; Exercise.
  - Pain relief: Anti-inflammatory analgesics (Ibuprofen); Heat
  - Course: Reduced pain with increasing age
  - Examination: Normal large & small fiber sensory modalities
  - GI: Constipation
- Laboratory
  - NCV: Normal
  - QST: Abnormal cold & warm temperature thresholds
  - Nerve pathology: Mild axon loss
  - Intraepidermal nerve fiber density: Often reduced
Variant syndrome: Neuropathy: Painful ± Autonomic ⁹
- Epidemiology
  - 12 patients
  - 3% of painful neuropathies
- Mutations
  - Missense
  - Gain of function
- SCN11A protein
- Clinical: Neuropathy
  - Sensory
    - Pain & Paresthesias
    - Loss: Distal; Hands & Feet
  - Autonomic
    - Dry eyes
    - Diarrhea
    - Urinary
    - Cardiac: Palpitations, Orthostatic dizziness
  - Laboratory
    - Axon loss: Small > Large
Also see
- Hereditary sensory neuropathies
- Familial episodic pain syndromes

Familial Episodic Pain 2 (FEPS2)

● Sodium channel, voltage-gated, Type X, alpha subunit (SCN10A)

; Chromosome 3p22.2; Dominant (Sporadic)

Epidemiology: 3 patients; 2 families
Genetics
- Mutations: Missense; Leu554Pro, Ala1304Thr
- Other missense mutations: Cys1523Tyr, Gly1662Ser; Associated clinical syndrome not described
SCN10A protein: Na_v1.8
- Mutation effects in FEPS2: Gain of function
Clinical
- Onset age: 4th to 7th decade
- Discomfort
  - Pain: Burning or Shooting
  - Itch: Intense paroxysmal
  - Allodynia & Hyperalgesia
  - Location: Distal; Feet, Some hands
  - Warmth: Some relief
Laboratory
- Skin: Loss of small axons or Normal
- NCV: Small SNAP ampltiudes or Normal
Also see
- Hereditary sensory neuropathies
- Familial episodic pain syndromes

Congential insensitivity to pain without anhidrosis (HSAN)

● Recessive

Clinical
- Onset age: Congenital
- Sensory loss
  - Pain
  - Temperature
  - Location: Extremities
- Acromutilation
- Normal: Large fiber sensation; Strength; Tendon reflexes
Nerve pathology
- Small myelinated A-delta fibers: Absent
- Unmyelinated axons: Normal
Differential diagnosis: Insensitivity to pain

Congenital Insensitivity to Pain with Preserved Temperature sensation ¹¹
● Clathrin, heavy polypeptide-like 1 (CLTCL1; CHC22)

; Chromosome 22q11.21; Recessive

Epidemiology: Balochi (Iran) family, 3 patients
Genetics
- Mutation: p.E330K; Missense; Homozygous
Protein
- Nosology: Clathrin heavy chain 22
- High expression: Skeletal muscle, Testis, Heart
- Functions
  - Neural crest development
  - Genesis of pain & touch sensing neurons
  - Muscle: Formation of insulin-responsive GLUT4 compartments
Clinical
- Onset age: Congenital
- Sensory
  - Loss: Pain; Soft touch
  - Preserved: Hot & Cold
- Mutilation
- Motor: Normal strength
- Autonomic
  - Bladder distention
  - Vomiting
  - Sweat & Tearing: Normal
- Eyes: Strabismus; See-saw nystagmus
- Dysmorphic features: Palpebral fissures, short; Nose large
- CNS
  - Developmental delay
  - Learning difficulties, severe & non-progressive
  - Seizures: 1 patient
- Death: 5 to 7 years in some
Laboratory
- Brain MRI: Delayed myelination
- No diabetes
Differential diagnosis: Insensitivity to pain

Congenital Insensitivity to Pain with Hypohidrosis (HSAN8; HSAN VIII)

¹⁰
● PR domain zinc finger protein 12 (PRDM12)

; Chromosome 9q33-q34; Recessive

Epidemiology: > 40 patients
Genetics
- Mutations
  - Homozygous in many
  - Types: Missense most common; Also alanine repeat expansion, splice & frameshift
- Allelic disorder: Midface toddler excoriation syndrome
PRDM12 protein
- Expressed in: Sensory neurons in Sensory spinal (dorsal root) ganglia
- Cell location: Nucleus
- Functions
  - Transcriptional regulator
  - Nociceptor neurogenesis
- Mutations: Impair histone methylation
Clinical
- Onset age: Congenital to 57 years
- Sensory loss
  - Pain: Acute or Inflammatory
  - Temperature: Noxious Heat & Cold
  - May be restricted to limbs
- Large fiber sensory: Normal
- Mutilation
  - Regions: Limbs; Mouth; Tongue; Cornea
  - Recurrent infections: Skin; Bones
- Autonomic
  - Sweating & Tearing: Reduced but present
  - Other: Normal
- Eyes
  - Conjunctival hyperemia
  - Tears: Reduced
  - Cornea: Sensitivity Reduced; Ulcers; Reflexes reduced
- Smell & Hearing: Normal
- CNS: Global developmental delay in some
Laboratory
- Axon loss
  - Aδ
  - Small axons in skin
  - Subepidermal neural plexus & autonomic sweat glands
Differential diagnosis: Insensitivity to Pain ²⁴
- General onset age: Congenital
- CMT (HMSN): Adult onset
  - 2B: RAB7
  - 2EE: MPV17
- HSAN: Congenital to Adult onset
  - 1A: SPTLC1; Adult onset
  - IC: SPTLC2; Adult onset
  - ID: ATL1; Adult onset
  - IE: DNMT1; Adult onset
  - IF: ATL3; Adult onset
  - 2A: WNK1; Child onset
  - 2B: RETREG1/FAM134; Child onset
  - 2C: ATSV (KIF1A); Child onset
  - 2D (CIP): SCN9A (Normal intelligence; Anosmia)
  - 3: ELP1/IKAP
  - 4: NTRK1 (Cognitive disorder; Anhidrosis)
  - 5: NGFB
  - 6: DST
  - 7: SCN11A (Hyperhidrosis; GI)
  - 8: PRDM12 (Sensory loss more in limbs)
  - 9: TECPR2
  - Other
- Congenital Insensitivity to Pain (CIP)
  - CIP: CLTCL1 (CHC22)
  - PAINQTL1: FAAH + FAAH pseudogene (Digenic)
  - MARSIS (CIP): ZFHX2
  - + Preserved Temperature sensation: CLTCL1 (Cognitive disorder; Temperature preserved)
- Multisystem
  - AAMR: GMPPA
  - CANVAS: RFC1; Adult onset
  - DEEAH: MADD
  - Marbach-Schaaf Neurodevelopmental Syndrome (MASNS): PRKAR1B
  - Intellectual Disability, Ataxia & Facial Dysmorphism (HADDS): EBF3
  - MICPCH: CASK
  - PCARP: FLVCR1
  - PSATD: PSAT1
  - SPG: CCT5; Child onset
  - SPG61: ARL6IP1 (Spastic paraplegia)
- Also see: Hereditary Sensory Neuropathies (HSN)

Insensitivity to Pain (Marsili syndrome)

¹²
● Zinc finger homeobox protein 2 (ZFHX2)

; Chromosome 14q11.2; Dominant

Epidemiology: 1 family, 6 patients
Genetics
- Mutation: Missense; R1913K; Heterozygous
ZFHX2 protein
- Cell location: Nucleus
- Nervous system: Expressed in
  - Brain
  - Dorsal root ganglia: Peripherin-positive small diameter neurons
- Transcriptional regulator
Clinical
- Onset age: Childhood
- Sensory loss
  - Painful thermal & Capsaicin stimulation
  - Painless: Bone fractures; Burning
  - Cornea: Hyporeflexia
  - Heat pain: Variably reduced
  - Cold pain: Reduced to Hyperalgesia
- Sensory: Other
  - Pain present: Back; Headache; Childbirth
  - Light touch: Normal
  - High force: Pleasure
- Autonomic
  - Sweating: Reduced
  - Hyperthermia episodes
- Recurrent infections (50%)
- Motor: Normal strength
- Cognition: Normal
Laboratory
- Skin biopsy: Normal numbers of axons

Pain Insensitivity (PAINQTL1)

¹⁴
● FAAH-OUT (FAAH pseudogene; FAAH1)

; Chromosome 1p33; Digenic
● Fatty acid amide hydrolase (FAAH)

; Chromosome 1p33; Digenic

Epidemiology: 1 family
Genetics
- FAAH polymorphism (C385A): No phenotype; Higher frequency of drug addiction
- FAAH pseudogene microdeletion: Partial hypoalgesia
- FAAH polymorphism + pseudogene microdeletion: Hypoalgesia
- FAAH-OUT: Non-coding RNA
FAAH protein
- Catabolic enzyme for: Fatty-acid amides (FAAs) (Bioactive lipids)
- FAAs
  - N-acyl ethanolamines: Anandamide (AEA)
    - Endogenous ligands for cannabinoid receptors
    - Roles in: Nociception, Fear-extinction memory, Anxiety, Depression
  - Palmitoylethanolamide (PEA)
  - Oleoylethanolamine (OEA)
  - N-acyl-taurines
- Effect of digenic mutations: Reduced FAAH \levels & activity
- FAAH inhibitor drug (BIA 10-2474); May cause acute encephalopathy
Clinical: Digenic patient
- Onset: Childhood
- Pain after surgery or trauma: Absent
- Morphene: Causes vomiting
- Skin: Multiple scars; Normal sweating
- CNS
  - Fear & Memory symptoms: Altered
  - Personality: Non-anxious
Laboratory
- Blood lipids: Increased AEA, OEA, PEA

Hereditary Ataxia with Thermoanalgesia & Loss of fungiform papillae

¹
● ? Autosomal Dominant with incomplete penetrance or Recessive

Epidemiology: Japanese & New Zealand families
Clinical
- Onset age: 5th decade
- Neuropathy
  - Sensory
    - Pain & Temperature sensation: Lost or reduced globally
    - Vibration: Reduced distally
    - Unsteady gait
  - Motor: Normal
- Ataxia: Benign
  - Nystagmus
  - Dysarthria
  - Limb ataxia
- Autonomic
  - Fungiform papillae of tongue: Absent
  - Lacrimation: Reduced
  - Taste: Reduced
  - Temperature control: Abnormal, Fevers
  - GI: Constipation/diarrhea
  - Vasomotor instability
  - Bladder dysfunction: Urinary frequency
  - Sweating: Normal
  - Sympathetic & Parasympathetic involvement
- Other
  - Emotional instability
  - IQ: Reduced
  - Hearing loss
  - Eye
    - Saccadic pursuit
    - Corneal sensation: Reduced
Laboratory
- NCV
  - SNAPs: Absent
  - CMAPs: Normal or mildly reduced
- EMG: Chronic denervation
- Caloric responses: Absent
- CNS imaging
  - CNS MRI: Atrophy of spinal cord, cerebellum, brainstem & corpus callosum
- Sural nerve biopsy
  - Axon loss: Myelinated & Unmyelinated

Hereditary Ataxia with Thermoanalgesia

³
● ? Autosomal Dominant with incomplete penetrance

Epidemiology: Northeast Spanish family
Genetics
- Not linked to known SCA loci
- Incomplete penetrance
Clinical
- Onset
  - Age: 4th to 7th decade
  - Gait instability
  - Fatigue
- Cerebellar
  - Ataxia: Limbs, dysmetria; Gait imbalance
  - Dysarthria
  - Eye: Nystagmus (30%); Slow saccades
- Sensory
  - Paresthesias: Face & Extremities
  - Pain sensation: Reduced early & diffusely
  - Vibration: Early preserved; Late reduced distally in legs
- Strength: Normal
- Tendon reflexes: Present
- Other CNS: Dementia (50%); Cognitive affective syndrome
- Course: Progressive ove decade
Laboratory
- Nerve conductions
  - Sensory: SNAPs absent
  - Motor: Normal
  - Autonomic: Absent sudomotor response
- EMG: Denervation
- MRI: Cerebellum, Medulla & Spinal cord atrophy
- Pathology
  - Cerebellum & Medulla: Atrophy
  - Spinal cord: Abnormal posterior column, lateral & anterior spinothalamic & posterior spinocerebellar tracts

Sensory & Autonomic Neuropathy with Chronic Diarrhea ⁶
● Prion protein (PRNP)

; Chromosome 20p13; Dominant

Epidemiology: 1 British family, 11 patients
Genetics
- Mutation: Y163X
- Allelic with
  - Cerebral amyloid angiopathy, PRNP-related
  - Creutzfeldt-Jakob disease
  - Gerstmann-Straussler disease
  - Huntington disease-like 1
  - Insomnia, fatal familial
  - Prion disease with protracted course
Clinical
- Onset: 4th decade
- Polyneuropathy
  - Sensory loss: Symmetric; Legs > Arms
  - Weakness: Later in course; Distal legs
- Autonomic dysfunction
  - Diarrhea: Chronic; Weight loss
  - Urinary retention
  - Impotence
  - Postural hypotension
- Later features (5th to 6th decade)
  - Cognitive decline: Impairment of memory & executive function
  - Seizures
- Death: Mean age 57; Range 40 to 70 years
Laboratory
- CNS
  - Prion protein deposition
  - Congophilic angiopathy: Prion protein in vessel walls
  - Spinal cord: Posterior column axon loss
- Brain MRI
  - Volume loss or Normal
- Duodenum: Prion protein deposition
- NCV: Axon loss
  - Distal > Proximal
  - Sensory > Motor
- Peripheral nerve pathology
  - Deposition of prion protein amyloid
- CSF
  - tau: High
  - S100b: High
  - 14-3-3: High

Marbach-Schaaf neurodevelopmental syndrome (MASNS)

● Protein kinase, cAMP-dependent, regulatory, type I, Beta (PRKAR1B)

; Chromosome 7p22.3; Dominant (de novo)

Epidemiology: 6 patients
Genetics
- Mutations: Missense; Heterozygous; Arg335Trp (Common)
PRKAR1B protein
- RIβ Regulatory subunit of Protein kinase A (PKA) holoenzyme (cyclic AMP (cAMP)-dependent)
- PKA: Essential enzyme in signaling pathway of cAMP
- R1β-deficient mice: Diminished nociceptive pain & inflammation
- Expressed in CNS
Clinical
- Onset: Infancy
- BMI: Increased
- Face: Dysmorphic
- Pain: Insensitivity
- Hypotonia
- CNS
  - Global developmental delay: Speech & Behavior
  - Dyspraxia
  - Seizures: Some patients
  - Sleep disturbances
  - Behavioral: Autism ADHD; Aggression
  - Hyperphagia: Some patients
- Course: Progressive in some

Developmental Delay + Endocrine, Exocrine, Autonomic & Hematologic abnormalities (DEEAH)

● MAP kinase-Activating death Domain (MADD)

; Chromosome 11p11.2; Recessive

Epidemiology: 15 patients
Genetics
- Mutations: Missense, Deletion
- Allelic disorder: Neurodevelopmental disorder with dysmorphic facies, impaired speech & hypotonia
MADD protein
- TNF signalling
Clinical
- Onset age: Early infancy
- Respiratory: Distress; Apnea
- Hypotonia
- Failure to thrive
- Sensory: Loss; Pain insensitivity; Mutilation
- Autonomic: Hypohidrosis
- Intellectual development: Impaired
- Seizures
- Hearing loss
- Eyes: Strabismus
- GI: Feeding disorders, GE reflux, Hepatosplenomegaly, Exocrine pancreas insufficiency
- Endocrine: Hypoglycemia, Thyroid Δ, Growth hormone ↓, Panhypopituitarism
- Face: Dysmorphism
- Course: Some with death < 3 years
Laboratory
- Hemoglobin: Low

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References

1. Brain 1996;119:1011-1021
2. Hum Mol Genet 2004; April 2004, J Med Genet 2010 Oct 26
3. J Neurol Neurosurg Psychiatry 2009;80:518-523
4. J Biol Chem 2010; Online Jan
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6. N Engl J Med 2013;369:1904-1914
7. Nat Rev Neurol 2012 May 29
8. Nature Genet 2013; Online Sept
9. Brain 2014 Apr 27
10. Nature Genetics 2015; May 25, Front Genet 2023;14:1139161
11. Brain 2015; Online June
12. Brain 2017; Online Dec
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14. Brit J Anaesthesia 2019; March
15. Muscle Nerve 2020 Feb 7
16. Muscle Nerve 2015;51:514-521
17. Muscle Nerve 2013 Aug;48(2):252-255
18. Muscle Nerve 2019 Oct 25
19. Muscle Nerve 2020 Feb 3
20. Lancet Neurol 2017;16:144-157, Muscle Nerve 2020 Jan 14
21. Neuropathol Appl Neurobiol 2021 Jan 9
22. J Peripher Nerv Syst 2020;25:308-311, Neuropathol Appl Neurobiol 2022;e12842
23. Nat Med 2021 May 31
24. Nat Rev Dis Primers 2022;8:41
25. Muscle Nerve 2022 Nov 30
26. J Pain Res 2022:15:2505-2515
27. J Neurol Neurosurg Psychiatry 2023 Nov 24

12/3/2023

SENSORY DISORDERS: Small Fiber

Anatomic definition

Small Fiber Neuropathy Features: Symptoms, Signs, Laboratory 7

Differential Diagnosis

Small Fiber Neuropathy Features: Symptoms, Signs, Laboratory ⁷