Neuromuscular: Large+Small Sensory

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Sensory Disorders - Large + Small Fiber

Toxic
- Metals: Thallium; Mercury (Methyl)
- Drugs: Thalidomide; Taxol; Ethylene oxide; Misonidazole;
  Metronidazole; Trichloroethylene Phenytoin
Immune
- Paraneoplastic - Small Cell Neoplasms (Anti-Hu)
- Anti-Sulfatide
- Anti-MAG
- Sjögren's
- Cryoglobulin (with M-protein; Hepatitis C)
Hereditary
- Mitochondrial Syndromes
- Multiple Symmetric Lipomatosis
  ● Autosomal Dominant
- Hereditary Sensory Neuropathy IIA (HSAN IIA; HSAN2A)
  ● WNK1 ; Chromosome 12p13.33; Recessive
- Hereditary Sensory Neuropathy IIB (HSAN IIB; HSAN2B)
  ● FAM134B ; Chromosome 5p15.1; Recessive
- Hereditary Neuropathy with Ulcero-mutilation
  ● Autosomal Dominant
- Hereditary sensory neuropathy with spastic paraparesis
  ● CCT5 ; 5p15.2; Recessive
- Navajo neuropathy with corneal ulceration
- Mitochondrial
  ● POLG ; Chromosome 15q26.1; Recessive
- Also see
  - Hereditary sensory neuropathies
  - Ulcero-mutilating neuropathies
Neuronopathy: Asymmetric & Proximal sensory loss
- Paraneoplastic (Anti-Hu; ANNA I): Often with limbic encephalitis, or ataxia
- Sjögren's
- Idiopathic (often subacute onset)

Chronic sensory neuropathy
High arches & Hammer toes
Preserved gastrocnemius size

Hereditary Sensory Neuropathy IIA (HSAN IIA; HSAN2A)

● Protein kinase, lysine-deficient 1 (WNK1; WNK1/HSN2)

; Chromosome 12p13.33; Recessive

Epidemiology
- Families in Eastern Canada, Mexico, Japan & Europe
- 1.5% to 3% of HSAN
WNK1 genetics ³: Mutations
- HSN2
  - Nervous system specific exon of WNK1
  - Location: Intron 8 of WNK1 gene
- HSN2 Mutations: Truncating
  - Newfoundland families: 594delA causes frameshift in codon 198; Homozygous; Truncation to 206-aa peptide
  - Nova Scotia
    - 918–919insA: Frameshift in codon 307; Truncation to 318-aa peptide
    - 943C-T nonsense: Changes codon 315 (CAG, glutamine) to a TAG stop codon; Truncates protein to 314 aa
  - Lebanese: 947delC homozygous
  - Mexican: 1219_1226 delTCTCAGCA
  - Japanese: c.3237_3238insT (p.Asp1080*)
  - Other: Insertion, Deletion, Stop, Whole gene deletion
- Allelic disorders
  - Pseudohypoaldosteronism type IIC
  - Hypokalemic Salt-Losing Renal Tubulopathy
WNK1 protein
- Ion channels
  - Participates in regulation of K⁺ channels (ROMK1)
  - Regulates Na⁺, K⁺, 2Cl^– & Na⁺Cl^– cotransporters (NKCCs & NCCs; TRPV4)
- Assembly factor for ER membrane protein complex ⁷
- WNK1 protein with HSN2 exon (WNK1/HSN2 isoform)
  - Location: Sensory components of PNS & CNS associated with relaying sensory & nociceptive signals
  - More abundant in sensory than motor neurons
Clinical features
- Onset
  - Usual: Early childhood or Congenital
  - Range: 1st 2 decades
- Sensory loss
  - Distribution
    - Distal > Proximal
    - Legs > Arms
      - Hands: Up to elbows
      - Feet: Up to knees
    - Trunk: Some patients
  - Modalities
    - Large & Small fiber
    - Touch most severely affected
    - Pain insensitivity
  - Numbness aggravated by cold
- Muscle atrophy: Some patients
- Autonomic: Mild or asymptomatic
  - Sweating
    - Reduced, Distal
    - Hyperhidrosis, episodic
  - Pupils: Tonic
  - Other: Constipation; Apneic episodes.
  - Normal: Blood pressure; Sexual function
  - Absent axon flare after intradermal histamine
    - Indicates defective nociceptive fibers
- Tendon reflex loss: Proximal & Distal
- Mutilation: Hand & Foot; Skin ulcers, Fractures
- Progression
  - Slow change over time
  - Variants: Stable congenital form
- Mental development: Normal
Electrophysiology: Absent sensory nerve action potentials (SNAPs)
Pathology
- Myelinated axons: Severe loss
- Unmyelinated axons: Milder loss
- Degenerating axons: Few
- Cutaneous sensory receptors & nerve fibers: Absent
HSAN comparisons

Hereditary Sensory Neuropathy IIB (HSAN II)

⁵
● Reticulophagy Regulator 1 (FAM134B; RETREG1)

; Chromosome 5p15.1; Recessive

Epidemiology: 10 families
Genetics
- Mutations
  - Loss of function
  - Homozygous: Most
  - p.S309X, p.Q145X, p.P7GfsX133, c.873+2T>C; c.765dupT; Chromosome 5 uniparental (Paternal) isodisomy
  - Missense: G216R
- Consanguinous families: Most
- Allelic syndromes: FAM134B mutations
  - Colorectal adenocarcinoma & oesophageal squamous cell carcinoma: Associated with aggressiveness
FAM134B protein
- Nosology: Family with sequence similarity 134, Member B
- Golgi: Overlaps with cis-Golgi marker giantin
- Expressed in: Sensory & Autonomic ganglia; Low levels in motor neurons
- Induces apoptosis in some primary dorsal root ganglion neurons
- Reticulophagy receptor: Regulates turnover of endoplasmic reticulum (ER) by selective phagocytosis
  - Reticulophagy: Selective autophagy of protein aggregate-containing, or damaged ER, fragments for lysosomal degradation
  - FAM134B interactions: LC3B; GABARAPs
- Cleavage of FAM134B by Dengue, Zika & West Nile virus encoded protease NS2B3: Increased production of infection units
- Tumor suppressor
- Interacts with
  - RTN2
  - Genetic epistasis
    - T-cell CD39 in blood: Allergic rhinitis risk
    - TNFRSF19 in brain: Vascular dementia risk
Clinical
- Onset: Childhood; 1st years to 2nd decade
- Sensory loss
  - Nociception: Impaired
  - Proprioception & Vibration: Reduced but Relatively preserved
- Mutilating ulcerations: Progressive
  - Hands & Feet
  - Osteomyelitis
  - Amputations
- Autonomic (50%)
  - Hyperhidrosis
  - Urinary incontinence
  - Pupillary reactions: Slow
- Weakness: Some patients
  - Distal
  - Legs or Hands
- CNS
  - Spasticity: 60%; Tendon reflexes increased
  - Intelligence: Normal
- Course: Progressive
Laboratory
- NCV: Axon loss, Sensory > Motor neuropathy
- Nerve biopsy: Axon loss, Especially small myelinated axons
- Sympathetic skin response: Reduced

Hereditary Sensory Neuropathy with Spastic Paraparesis: Autosomal recessive

Moroccan ⁴
● Chaperonin containing T-complex polypeptide 1, subunit 5 (CCT5) ; Chromosome 5p15.2; Recessive
- Epidemiology & Nosology
  - Moroccan & Italian families
- Genetics
  - Mutations: Homozygous; His147Arg, Leu224Val
  - Allelic disorder: Cavanagh variant
- CCT5 protein
  - Subunit of 950-kD chaperonin containing TCP1 complex (CCT)
  - Involved in proper folding of cytoskeletal proteins
  - Chaperones
- Clinical
  - Onset: 1 to 5 years
  - Spastic paraplegia
    - Gait disorder
    - Tendon reflexes: Increased with ankle clonus
    - Plantar reflexes: Extensor
    - Progression: Slow
  - Sensory loss
    - Distal > Proximal
    - Pan-modal
    - Legs > Arms
  - Mutilating acropathy
  - Normal: Cranial nerves, Coordination, Cognitive function
  - Course: Most patients remain ambulant
- Laboratory
  - Electrophysiology: Axonal sensory neuropathy, severe
    - SNAP amplitudes: Reduced or Absent (Older patient)
    - Motor: Normal or Reduced (Leu224Val mutation) velocities
    - Autonomic
      - Vagal hyperactivity
      - α-sympathetic responses: Decreased
      - β-sympathetic: Increased
  - Serum: Reduced Apo B, total cholesterol and triglycerides
  - MRI: Spinal cord atrophy
Cavanagh variant

Multiple Symmetric Lipomatosis (Madelung syndrome)

● Autosomal Dominant, Mitochondrial, or Sporadic

Growth of uncapsulated masses of adipose tissue
Epidemiology
- Middle-aged males
- Mediterranean region
- History of alcohol abuse
- Protease inhibitor treatment
Clinical features
- Fat accumulations: Multiple lipomas
  - Distribution: Symmetric; Distal arms & legs are spared
  - Types
    - I
      - Lipomas: Nape of neck, Supraclavicular & Deltoid areas
      - Bull-neck
    - II
      - Lipomas: Extend over the body
      - Appearance: Simple obesity
- Polyneuropathy
  - Distribution: Distal; Symmetric
  - Modalities: Sensory-Motor; ± Autonomic involvement
  - Pathology
    - Distal predominance
    - Axon loss: Large > Small
Metabolic
- Hyperuricemia
- Triglycerides (VLDL, chylomicrons): High
- High-density lipoproteins (HDL): High
Mitochondrial MSL disorder
- A8344G mutation in mitochondrial tRNA^Lys
- Some families also with MERRF syndrome
- Muscle: May have ragged red fibers
Treatment: Surgical removal
- Compression or Cosmetic reasons
- Usually recur

From Johns Hopkins Medicine

Ulcero-mutilating Neuropathies: Dominant

HSN 1F: Sensory Neuropathy with Bone Destruction ⁶
● Atlastin GTPase 3 (ATL3)

; Chromosome 11q13.1; Dominant

Epidemiology: 4 families, 11 patients
Genetics
- Mutations: Tyr192Cys, Pro338Arg; Heterozygous
ATL3 protein ⁸
- Endoplasmic reticulum-shaping GTPase
- Enriched in three-way junctions: Branch points of endoplasmic reticulum
- Sensory neurons: High expression
- Functions
  - May influence morphology of Golgi apparatus
  - Cargo receptor for reticulophagy
  - Interactions: GABARAP subfamily Atg8-family proteins
- Mutated proteins
  - Excluded from axon by block at initial segment
  - Alter endoplasmic reticulum pathways: Tubular ER structure disruption
  - Unable to promote membrane fusion
  - Axonal mitochondria: Reduced
- Paralogue: ATL1
- Endoplasmic reticulum-related protein disorders
  - Neuropathy
    - ATL1: HSN 1D
    - ATL3: HSN 1F
    - RAB7: HMSN 2B
    - MFN2: HMSN 2A2
    - TFG: HMSN-P
    - FAM134B: HSAN 2B
    - BSCL2: HMN 5C
    - DNAJB2: DSMA5
    - DNAJC3: ACPHD
  - Myopathy
    - DPM3: Myopathy + Cardiomyopathy
    - SIL1: Marinesco-Sjögren
    - TANGO2: Encephalocardiomyopathy with Rhabdomyolysis
  - Myelopathy (SPG)
    - ATL1: SPG 3A
    - SPAST: SPG 4
    - RTN2: SPG 12
    - ERLIN2: SPG 18
    - REEP1: SPG 31
    - TFG: SPG 57
    - ARL6IP1: SPG 61
    - ERLIN1: SPG 62
    - REEP2: SPG 72
    - CPT1C: SPG 73
    - ABHD16A: SPG 86
    - AMFR: SPG 89
Clinical
- Onset age: 14 to 35 years
- Foot abnormalities
  - Types: Ulcers (50%), Fractures, Bone destruction, Arthropathy, Amputations
  - Painless
- Sensory loss: Pain; Touch
- Tendon reflexes
  - Ankles: Absent or Reduced
  - May be increased
- Normal: Arms; Strength; Autonomic; CNS
Laboratory
- NCV: Sensory axon loss; Motor mild slowing
- Radiology: Bone damage in feet

Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation ¹
● Autosomal Dominant

Genetics
- No linkage to other mutilating hereditary neuropathies HSAN I or HMSN IIB
- Also see
  - HSN 1D
  - HSMN with ATSV mutations
Epidemiology
- South Austrian family
- Males more severely affected than Females
- Variable severity in family
Onset
- Foot deformities in childhood or teens
- Clinical features: 15 to 30 years
Clinical
- Ulcero-mutilation
  - Callus; Poorly healing ulcers; Amputations
  - Distribution: Feet; Asymmetric
  - Improvement during pregnancy
- Sensory
  - Large & small fiber modalities lost: Symmetric; Legs > Arms; Distal
  - Joint position sense preserved
  - No pain or paresthesias
  - No correlation between foot ulcers & severity of sensory loss
- Weakness (30%)
  - Mild
  - Symmetric
  - Distribution: Intrinsic foot muscles; Toe & Ankle dorsiflexors
- Reflexes
  - Tendon: Always preserved
  - No Babinski
- Sweating: Some patients with hyperhidrosis on Feet & Distal legs
Electrodiagnostic: Axonal loss
- NCV: Normal to mildly slowed motor & sensory velocities
- SNAP: Reduced; Absent in more severely affected individuals
- CMAP: Reduced amplitude; Chronodispersion

Hereditary Sensory-Motor Neuropathy with Ulcero-mutilation ²
● Autosomal Dominant

Genetics
- No linkage to other mutilating hereditary neuropathies HSAN I or HMSN IIB
- Also see: HSMN with ATSV mutations
Epidemiology
- Italian family
- Full penetrance
Onset
- Age: Mean 14 years; Range 2 to 30 years
- Osteomyelitis
- Sensory loss
Clinical
- Ulcero-mutilation
  - Callus; Poorly healing ulcers; Amputations
  - Distribution: Feet & Hands; Asymmetric
- Sensory
  - Large & small fiber modalities lost: Symmetric; Legs > Arms; Distal
  - No pain or paresthesias
- Weakness (100%)
  - Distal
  - Symmetric
  - Feet & Hands
- Tendon Reflexes: Often absent
- Autonomic: Normal
Electrodiagnostic: Axonal loss
- NCV: Normal to mildly slowed motor & sensory velocities
- SNAP: Reduced; Absent in legs
- CMAP: Reduced amplitude; Absent in legs
Nerve Pathology
- Axonal loss: Especially small myelinated & Unmyelinated axons
- Endoneurial fibrosis

Go to Large fiber neuropathies
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References
1. Neurology 2000;54:45-52
2. Neuromuscular Disorders 2002;12:286-291
3. Am J Hum Genet 2004;74: May, J Clin Invest 2008 Jun 2
4. European Journal of Human Genetics 2005; Online December, Int J Mol Sci 2020;21:7631
5. Nature Genetics 2009; Online October, J Cell Physiol 2018;233:4479-4489, Front Genet 2019 Oct 31
6. Brain 2014; Online January, J Peripher Nerv Syst 2019;24:150-155
7. Mol Cell 2021 Apr 30
8. Autophagy 2019;15:1465-1466, Curr Biol 2019;29:846-855

10/24/2024