Home, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

HEREDITARY SENSORY & AUTONOMIC NEUROPATHIES (HSAN)

Hereditary Sensory & Autonomic Neuropathy Syndromes         HSN Disorder Gene Locus Inheritance Onset Age Clinical features Axon loss IA IC SPTLC1 SPTLC2 9q22 14q24 Dominant > 20 years Pan-sensory loss Acromutilation Small > Large IB   3p24 Dominant 20 to 40 years Pan-sensory loss Cough; GE reflux Small & Large ID ATL1 14q11 Dominant Early adult Sensory loss Acromutilation Small & Large IE DNMT1 19p13 Dominant 16 to 35 years Sensory loss Deaf; Dementia Small & Large IF ATL3 11q13 Dominant 14 to 35 years Sensory loss Small & Large IIA WNK1/HSN2 12p13 Recessive Congenital, or Early childhood Sensory loss Acromutilation Large & Small IIB FAM134B 5p15 Recessive Childhood Sensory loss Acromutilation Small > Large IIC ATSV   (KIF1A) 2q37 Recessive 6 to 15 yrs Sensory loss Acromutilation Weakness, Distal Large > Small IID Inability to   experience pain SCN 9A 2q24 Recessive Congenital Absence of pain Autonomic None III IKBKAP (ELP1) 9q31 Recessive Congenital Riley-Day Small > Large IV NTRK1 1q21 Recessive Congenital, or Early childhood Sensory neuropathy   Anhidrosis C V NGF-β 1p13 Recessive Early childhood to Adult Absence of pain   No anhidrosis Aδ & C VI Dystonin 6p12 Recessive Congenital Absent tears Large & Small VII (Absent pain) Episodic pain SCN 11A 3p22 Dominant Congenital Absence of pain Hyperhidrosis; GI Δ None Absent Pain,   Congenital     Recessive Congenital, or Early childhood Absence of pain   No anhidrosis Aδ VIII: Absent Pain, & Temperature   Congenital PRDM12 9q33 Recessive Congenital Absent pain   Sweat reduced Aδ & C IX: Autonomic TECPR2 14q32 Recessive Congenital Autonomic None Insensitivity     to Pain ZFHX2 14q11 Dominant Childhood Absent pain   Sweat reduced None Absent pain,   Congenital CLTCL1 22q11 Recessive Congenital Absent of pain   & Light touch ? Erythromelalgia SCN 9A 2q24 Dominant Childhood Pain, distal   Episodic None Erythromelalgia NMNAT2 1q25 Recessive Childhood Pain, distal   Episodic Large & Small Biemond ataxia     Dominant 19 to 30 years Sensory loss Large SCA46 PLD3 19q13 Dominant After 4th decade Sensory loss Ataxia Large SCA4 ZFHX3 16q22 Dominant After 2nd decade Sensory loss Ataxia Large Ulcero-   Mutilation     Dominant 5 to 30 years Acromutilation Large & Small Spastic   paraparesis CCT5 5p15 Recessive 1 to 5 years Acromutilation Large & Small Thermoanalgesia     Dominant 5th decade Absent pain &   temperature; Ataxia Large & Small AXPC1 (PCARP) FLVCR1 1q31 Recessive Early childhood Proprioceptive loss   Visual loss Large SNAX1 RNF170 8p11 Dominant 3rd to 8th decade Proprioceptive loss Posterior   column HSAN + CNS Prion 20p13 Dominant Early adult Autonomic &   Sensory loss Axon loss CMT 2V NAGLU 17q21 Dominant Adult Pain; Ataxia Axon loss DAIPT PIEZO2 18p11 Recessive Congenital Sensory Axon loss CANVAS RFC1 4p14 Recessive Adult Sensory; Cough Axon loss Hereditary Sensory Neuropathy: Other α-galactosidase (Fabry's) An-α-lipoproteinemia (Tangier's) Anosmia Ataxia telangectasia Ataxia, thermoanalgesia & loss of fungiform papillae CMT 1C Deafness Deafness & Global delay DFNX5: AIFM1 Optic atrophy & Deafness: 8q24.22-ter Dystonia & Ichthyosis: FITM2 Friedreich's ataxia Gastroesophageal reflux & Cough Gyrate atrophy of choroid & retina with hyperornithinemia HSN ± Motor: INSC Minifascicles & 46,XY Gonadal dysgenesis Mitochondrial disorder Maternal: NARP Recessive: Cytopathy Multiple symmetrical lipomatosis Posterior column ataxia + Retinitis pigmentosa Scoliosis & deafness Spastic paraparesis   Neurogenic Joint & Limb syndrome Hereditary Neuropathies with Ulcero-mutilation 3 General features Acro-mutilation Skin ulcers Amputations Neurogenic osteoarthropathy (Charcot's joints) HSAN I: SPTLC1; 9q22; Dominant ID: ATL1; 14q11; Dominant IF: ATL3; 11q13; Dominant II: WNK1/HSN2 12p13 Recessive IIB: FAM134B; 5p15.1; Recessive IID: SCN9A; 2q24; Recessive 3 (Riley-Day): IKBKAP; 9q31; Recessive 4: TRKA/ NGF receptor (NTRK1); 1q23; Recessive V: NGF-β; 1p13; Recessive VI: Dystonin; 6p12; Recessive Navajo Arthropathy: MPV17; 2p23; Recessive VII: SCN11A; 3p22; Dominant Minifascicles & 46,XY Gonadal dysgenesis HSAN: FVLCR1 HMSN 2B: RAB7; 3q13; Dominant Axonal CMT with acrodystrophy: Recessive Navajo Neurohepatopathy: MPV17; 2p23; Recessive Hereditary Sensory > Motor Neuropathy + Ulcero-mutilation ATSV (KIF1A): 2q37; Recessive Dominant: Sensory > Motor Neuropathy Dominant: Sensory-Motor Neuropathy Congenital insensitivity to Pain (CIP) PRDM12: 9q33; Recessive CIP Hereditary sensory neuropathy + Spastic paraparesis Cavanaugh Moroccan SPG 61: ARL6IP1; 16p12 PSATD: PSAT1 Other Occasional patients with CMT 1A Neurogenic osteoarthropathies (Charcot's joints) Animal model: mutilated foot rat Also see Acquired Neurogenic Osteoarthropathies (Charcot's joints) Sensory ataxic neuropathies Hereditary Spinal Sensory Ataxia Congenital indifference to pain

---

Polyneuropathy with Minifascicles, 46,XY Gonadal dysgenesis & Mental retardation (GDMN) 1   ● desert hedgehog (DHH) ; Chromosome 12q13.12; Sporadic (Recessive) Epidemiology: 10 families Genetic Mutations Homozygous Types: Loss of function Point: At initiating codon in exon 1 Null: Ser185X Missense: Leu335Pro Partial duplication Allelic disorders HMSN with Minifascicle Formation & 46XY Pure Gonadal Dysgenesis HMSN with Minifascicle Formation without Gonadal Dysgenesis 46XY sex reversal 7 DHH protein Distribution: Schwann cells; Sertoli cells of developing testis Roles Peripheral nerve sheath (Perineurium) development Spermatogenesis Mouse knockout: Reduced perineurium & epineurium Other hedgehog family members Sonic hedgehog: Defect causes holoprosencephaly Clinical Onset ages: 2 to 39 years Systemic: Most patients Partial gonadal dysgenesis Onset: Primary amenorhea Anatomy Premature female genetalia Testis on one side, streak gonad on other Gynecological: Older patients Breasts: Poorly developed Pubic hair: Sparse Vagina: Blinded Uterus: Immature Gonads: Streak Skin: Black nails; Cyanosis & edema on exposure to cold Few patients with only neuropathic features Neuromuscular (60%) Sensory Loss Pin & Temperature or Panmodal Distal Ataxia: Some patients Motor Normal in 80% Weakness: Distal; Moderate; Arms & Legs Tendon reflexes: Hyopactive or Absent Skin: Cutaneous ulcers (60%) CNS: Normal or Mental retardation, Severe Laboratory Karyotype: 46,XY Hypergonadotropic hypogonadism Hormones: LH & FSH high; Testosterone & Estradiol low Electrophysiology Motor NCV: Normal (37 to 48 M/s) or Mildly slow Sensory NCV: SNAPs small or absent; Conduction velocity slowed EMG: Denervation in distal legs Ultrasound Hyperechogenic texture with hypoechogenic dots Nerve enlargement with minifascicles Nerve pathology Numerous fascicles in sural nerve (~50) Minifascicles within each fascicle: 60 small fascicles in sural nerve Myelinated axons: Reduced number of large & small fibers Axon density Small & large myelinated axons: Reduced Unmyelinated axons: Normal Myelin sheath: Thin Perineurial cells: Abnormal basal lamina Normal teased fibers Thermography: Reduced temperature in distal arms & legs CSF: Normal MRI: Normal Brain & Spinal cord Endocrine: High TSH; FSH; Prolactin Also see Sonic hedgehog External links Hedgehog proteins

From K Sugie Minifascicles

---

Posterior Column Ataxia & Retinitis Pigmentosa (AXPC1; PCARP) ¹¹
  ● Feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) ; Chromosome 1q32.3; Recessive

• Epidemiology: Multiple families
• Genetics
  • Mutations: > 20 described; Asn121Asp, Cys192Arg, Ala241Thr
  • Allelic disorders
    • HSAN
    • Developmental disorder ²¹
  • Diamond-Blackfan anemia
    • Enhanced alternative FLVCR1 splicing
    • No FLVCR1 mutations found
• FLVCR1
  • High expression in retina, spinal cord & cerebellum
  • MFS transporter: Choline & Ethanolamine
    • Single-polypeptide secondary carriers
    • Transport small solutes in response to chemiosmotic ion gradients
    • Exports cytoplasmic heme in erythrocyte precursors
  • Possible disease mechanism
    • Perturbation of neuronal heme transmembrane export
    • Abrogates neuroprotective effects of neuroglobin (NGB)
    • Initiates apoptotic cascade
  • Other iron homeostasis disorder: Friedreich ataxia
• Clinical
  • Onset: Early childhood; Visual loss
  • Visual
    • Ring scotoma
    • Nyctalopia (Night blindness)
    • Progessive loss: Loss of central vision; To blindness
    • Retinitis pigmentosa: Pan-retinal loss of pigment epithelium
  • Sensory
    • Onset: 2nd decade
    • Loss: Large fiber; Position sense; Apallesthesia
    • Pain & Temperature: Preserved
    • Sensory ataxia
    • Progression to severe disability
  • Tendon reflexes: Absent
  • Autonomic
    • GI: Achalasia; Dysmotility
    • GU: Incontinence in some patients
  • Skeletal: Scoliosis; Camptodactyly
• Laboratory
  • Electrodiagnostic: Sensory ganglionopathy; Absent SNAPs
  • MRI: Posterior column abnormality
  • Pathology
    • Peripheral nerve: Loss of large myelinated axons
    • Muscle: Normal
    • Dorsal root ganglia: Neuron loss
    • CNS: Posterior column damage
• FVLCR1 Variant: HSAN
  • Epidemiology: 7 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations: Missense
  • Clinical
    • Onset age: Early childhood
    • Pain insensitivity
    • Autonomic: Hypohidrosis
    • Tendon reflexes: Reduced or Absent
    • Extremity mutilation
    • Strength: Distal arm & leg weakness in some patients
    • Retinitis pigmentosa
    • Developmental delay
  • Laboratory
    • Nerve pathology: Axon loss
    • NCV: Axon loss
    • Muscle pathology: Type grouping; Grouped atrophy
    • Brain MRI: Delayed myelination
• PCARP phenotype without mutations
  • Additional feature: Loss of pain sensation on hands & feet

---

Hereditary Sensory Neuropathy with Gastro-Esophageal reflux & Cough (HSAN IB) ⁴
  ● Chromosome 3p24-p22; Dominant

• Clinical
  • Onset
    • Age: 2nd to 5th decade
    • Cough or Gastro-Esophageal reflux
  • Cough
    • Associated with
      • GE reflux
      • Impaired laryngeal sensation (Denervation hypersensitivity)
    • Triggered by
      • Noxious odors
      • Pressure in external auditory canal (Arnold's ear-cough reflex)
    • May produce syncope
  • Gastro-Esophageal reflux
    • Clinical: Heartburn; Regurgitation
    • pH < 4 in esophagus
    • Onset precedes neuropathy
  • Pharyngeal, other: Some due to reflux
    • Throat clearing
    • Hoarse voice
  • Neuropathy
    • Onset: 3rd to 5th decade
    • Sensory loss
      • Distal: Some patients also with truncal involvement
      • Legs & Arms
      • Pain & Temperature: More severe than large fiber modality involvement
    • Painless injuries: Common
    • Lancinating pains: Occasional
    • Ulcers unusual
  • Other: Some patients
    • Autonomic: Impotence; Alacrima; Hypohidrosis, distal
    • Hearing loss: Sensorineural
    • Retinal detachment
• Laboratory
  • Nerve conduction: Sensory, axonal loss
  • Audiometry: Sensorineural hearing loss (40%)
  • Nerve pathology: Loss of large & small axons

---

Hereditary Sensory Neuropathy with Deafness and Global Delay ²
  ● Autosomal Recessive

• Epidemiology: Lebanese Moslem family
• Onset
  • 2 months to 3.5 years
  • Developmental delay: Motor; Language
• Clinical
  • Developmental delay (100%): Motor; Language
  • Hypotonia (100%)
  • Areflexia (100%)
  • Hearing loss (100%): Sensorineural
  • Ataxia (75%)
  • Weakness (50%): Proximal
  • Dysmorphic features (50%)
  • Other: Optic atrophy; Renal tubular acidosis
• Electrophysiology: Neuropathy
  • Sensory
  • Axonal loss
• Sural nerve biopsy: Axonal loss

---

Hereditary Sensory Neuropathy with Deafness & Dementia (HSN 1E) ¹²
  ● DNA methyltransferase 1 (DNMT1) ; Chromosome 19p13.2; Dominant & Simplex

• Epidemiology: > 33 families
• Genetics
  • Mutations
    • Missense: C353F; T481P, Tyr495Cys; Asp490Glu–Pro491Tyr; P491L; Y524D; I531N; His569Arg
    • Location
      • Target sequence domain: Middle or N-terminus
      • Exons 20 & 21
      • Common mutation: Tyr495Cys
  • Allelic disorders
    • Autosomal Dominant Cerebellar Ataxia, Deafness & Narcolepsy (ADCA-DN)
      • Mutation location: C-terminus of Target sequence domain; Exon 21
    • Spastic paraplegia
      • Mutation: c.2053G>A, p.A685T
      • Inheritance: Dominant
• DNMT1 protein
  • Components of DNA replication machinery during S phase of cell cycle
  • Maintenance of methylation, gene regulation & chromatin stability
    • Transfers methyl groups to cytosine nucleotides
    • Maintains methylation patterns following DNA replication
    • Mediates transcriptional repression: Direct binding to HDAC2
  • Immune cells
    • Highly expressed
    • Required for differentiation of CD4+ into T regulatory cells
  • Mutant proteins: Reduced enzymatic activity & heterochromatin binding
  • Other disorders of DNA methylation related genes
    • Immunodeficiency centromeric instability-facial anomalies (ICF) : DNMT3B ; Recessive
    • Rett syndrome : MECP2 ; X-linked
• Clinical
  • Onset
    • Age: 16 to 51 years; Mean 38 years
    • Hearing loss: Most common
  • Hearing loss
    • Often at onset
    • Sensorineural
    • May be treated with Cochlear implant
  • Sensory
    • Loss
      • Extremities
      • Distal > Proximal
      • Legs > Arms
      • Large & Small axon modalities: Vibration > Joint position
    • Lancinating pain: Some patients
  • Ulcero-Mutilation
    • Neuroarthropathy
    • Painless fractures
  • Tendon reflexes: Reduced distal
  • Weakness: 15%; Distal
  • CNS
    • Ataxia: 15%
      • Gait: Unstable
      • EOM: Square wave jerks
    • Dementia: Cognitive decline
      • Onset 4th & 5th decade
      • Personality changes & Psychiatric manifestations
      • Frontal lobe dysfunction
      • Clouded consciousness
    • Sleep disorders
      • Narcolepsy
      • Hypersomnia
      • Rapid eye movement sleep disorder
    • Seizures: Myoclonic
    • Hallucinations: Auditory & Visual
  • Systemic: Renal failure
  • Death: 5th & 6th decade; Mean 54 years
• Laboratory
  • EEG: Low frequency (delta waves), frontal-predominant
  • Electrodiagnostic
    • SNAPs: Often absent
    • Motor: NCV normal or slightly slow; CMAP normal
  • Brain MRI: Atrophy
  • Pathology
    • Posterior column: Especially medial
    • Cerebellum: Purkinje cell swelling & axonal loss; Hyperplasia of Bergman glia
    • Inferior olivary nucleus: Neuron loss
    • Cerebral atrophy
    • Nerve: Axon loss, Severe, Large & small
    • Mutant DNMT1: Translocate to cytoplasm: May form aggresomes

---

X-linked Sensory Neuropathy with Deafness (AUNX1; DFNX5) ⁸
  ● AIFM1; Chromosome Xq26.1; Recessive

• Epidemiology: Chinese family
• Genetics
  • Allelic disorders
• Clinical
  • Onset
    • Age: Mean 13 years
    • Hearing loss: Low frequency
  • Hearing loss: Auditory neuropathy
    • Early: Low frequency
    • Progression: To all frequencies
    • Poor speech discrimination
    • Absent BAERs: Early
    • Intact outer hair cell function
  • Neuropathy: Sensory
    • Onset
      • 3rd or 4th decade
      • After hearing loss
    • Sensory loss
    • SNAPs: Absent or Reduced amplitude
    • Sensory NCV: Mildly reduced
    • Motor NCV & CMAPs: Normal

---

Gyrate atrophy of choroid & retina with hyperornithinemia (GACR)
  ● Ornithine aminotransferase (OAT) ; Chromosome 10q26.13; Recessive

• Genetics
  • Mutations: Misense & Stop
• OAT protein
  • Catalyzes reversible transamination of ornithine to glutamate semialdehyde
• Clinical
  • Chorioretinal degeneration
  • Cataract formation: Early
• Laboratory
• Hyperornithinemia; No hyperammonemia or homocitrullinuria
• Muscle: Type II fiber atrophy; Tubular aggregates
• Nerve: Sensory axonal neuropathy, by electrophysiology

---

Hereditary Sensory & Autonomic neuropathy (HSAN) with Anosmia ⁶
  ● ? Autosomal Recessive

• Epidemiology: 1 Japanese family
• Clinical
  • Onset
    • Age: 20-50 years
    • Anosmia
  • Special sensory
    • Anosmia: All 3 family members
    • Ageusia: 1 person
  • Autonomic
    • Anhidrosis: Diffuse
    • Orthostatic hypotension
  • Sensory loss
    • Large & Small fiber modalities
    • Distal
  • No skin ulceration
• Laboratory
  • Electrodiagnostic
    • Motor conductions: Normal
    • Sural responses: Absent
    • NCV: Normal
  • Skin biopsy: Eccrine gland - vacuolar degeneration & dilated ducts
  • Sural nerve: Reduced number of myelinated & unmyelinated axons

---

Hereditary sensory & autonomic neuropathy type IID (HSAN2D) ¹³
  ● SCN 9A ; Chromosome 2q24.3; Recessive

• Epidemiology: Japanese patients
• Genetics
  • Mutation: c.3993delGinsTT; Premature stop
  • Allelic disorders
• SCN 9A protein: See SCN 9A & Erythromelalgia
• Clinical
  • Onset age: Congenital to 3rd decade
  • Sensory
    • Pain & temperature loss: Progressive; Distal > Proximal
    • Vibration sense: Preserved
  • Autonomic
    • Hypohidrosis
    • Urinary bladder dysfunction
    • Lacrimation: Reduced in 1 patient
  • Tendon reflexes: Normal, Increased or Reduced
  • Strength: Normal or Reduced in legs
  • Hearing loss: Asymmetric
  • Hyposmia
  • Hypogeusia: Fungiform papillae on tongue reduced
  • Skin: Painless ulcers; Rash
  • Skeletal
    • Recurrent fractures
    • Short digits
    • Bone dysplasia
• Laboratory
  • Sensory nerve conductions: SNAP amplitudes mildly small or Normal; Asymmetric
  • Sural nerve: Loss of large myelinated axons or Normal

---

Congenital inability to experience pain (CIP) ⁹
  ● SCN 9A ; Chromosome 2q24.3; Recessive

• Genetics
  • Mutations: Nonsense (S459X, I767X, W897X); Splicing; Missense (Arg896Gln)
  • CIP also described in mixed breed dogs ¹⁹: Arg921Cys homozygous mutation
  • Allelic disorders
• SCN 9A protein: See SCN 9A & Erythromelalgia
• Clinical
  • Onset age: Congenital
  • Sensory
    • Inability to feel pain
      • Over all body regions
      • Painless injuries present
    • Some patients: Hyposmia; Hypogeusia
    • Normal: Touch; Temperature (warm & cold); Proprioception; Tickle; Pressure
  • Motor: Normal strength
  • Tendon reflexes: Normal
  • Sweating: Present
  • Bladder function: Normal
• Laboratory
  • Nerve conduction studies: Normal
  • Nerve biopsy: Normal
  • Skin pathology: Loss of Meissner’s corpuscles & Epidermal nociceptors
  • CNS MRI: Normal
• Differential diagnosis

---

Paroxysmal Extreme Pain Disorder (PEPD; FEPS4) ¹⁰
  ● SCN 9A ; Chromosome 2q24.3; Dominant

• Nosology: Familial rectal pain; Familial Episodic Pain Syndrome 4 (FEPS4)
• Genetics
  • Mutations: Missense; Present in 2/3 of families with PEPD
  • Allelic disorders
• SCN 9A protein: See SCN 9A & Erythromelalgia
• Mutated protein: Altered inactivation with associated persistent currents
• Onset: Congenital
• Clinical
  • Paroxysmal
  • Pain
    • Severe
    • Burning
    • Locations: Rectal, Genetalia, Face (Ocular, Mandibular)
    • Associated with: Non-epileptic tonic seizures; Cardiac asystole
    • Treatment: Carbamazepine
  • Autonomic dysfunction
    • Flushing of skin: Harlequin colour changes
    • Pupillary abnormalities

---

Polyneuropathy & Erythromelalgia ¹⁶
  ● Nicotinamide Nucleotide Adenylyltransferase 2 (NMNAT2) ; Chromosome 1q25.3; Recessive

• Epidemiology: 2 families, 4 patients
• Genetics
  • Mutations: Missense; T94M, V98M, R232Q
  • Allelic disorders
    • Fetal akinesia deformation sequence
    • Mouse model: Motor neuropathy
• NMNAT2 protein
• Clinical
  • Onset ages: 1 to 4 years
  • Pain: Feet
  • Episodes
    • Stimuli: Exercise, Heat, Infections, Stress
    • Duration: 1 to 30 days
    • Frequency: Every 2 to 3 months
    • Foot pain & swelling
    • Weakness: Some patients; Proximal, Distal, Respiratory
  • Course: Progressive distal weakness + Episodes
  • Skeletal: Pes cavus & equinus; Scoliosis
• Laboratory
  • Nerve biopsy: Axon loss & regeneration
  • Electrodiagnostic: CMAP ± SNAP amplitudes reduced; NCV normal
  • MRI: Normal brain & spinal cord
• NMNAT2 variant syndrome: Fetal akinesia deformation sequence ¹⁷
  • Epidemiology: 1 family, 2 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations: Loss of function; c.403dupC, c.695G>A (p.R232Q)
  • Clinical
    • Onset age: Prenatal
    • Cystic hygroma
    • Skin edema
    • Ascites
    • Pleural effusion
    • Hydrocephalus
    • Muscle: Small; Replaced by fat
    • Contractures: All extremities
  • Laboratory
    • CNS: Small; Hydrocephalus

---

CMT 2V: Hereditary Adult-onset Painful Axonal Polyneuropathy ¹⁴
  ● α-N-acetyl-glucosaminidase (NAGLU) ; Chromosome 17q21.2; Dominant

• Epidemiology: French-Canadian family & North American
• Genetics
  • Mutation: Ile403Thr (French-Canadian), Glu123X
  • Allelic with: Mucopolysacharidosis IIIB, Recessive (Sanfilippo B)
• NAGLU protein
  • Lysosomal
  • Degradation of heparan sulfate (glycosaminoglycan compound)
  • Mutation: 45% reduced enzyme activity
  • Immune disorder of heparan sulfate component: Neuropathy with IgM vs TS-HDS
• Clinical
  • Onset age (Pain): 12 to 61 years
  • Sensory
    • Pain: Legs; Sleep disorder (Cramps or Paresthesias)
    • Ataxia: Reduced tandem walking; With disease progression
    • Loss (50%): Pain & Vibration
  • Tendon reflexes: Normal of Reduced
  • Strength: Normal
• Laboratory
  • NCV: SNAP & CMAP amplitudes normal or reduced with disease progression
  • EMG: Usually normal

---

Sensory (Small fiber) Neuropathy + Deafness-Dystonia & Ichthyosis ¹⁵
  ● Fat-Inducing Transcript 2 (FITM2; FIT2) ; Chromosome 20q13.12; Dominant

• Epidemiology: Pakistani family, 5 patients
• Genetics
  • Mutation: Homozygous, Monsense; c.4G>T (p.Glu2*)
  • Allelic disorder: Siddiqi syndrome
• FITM2 protein
  • Family: Involved in partitioning of triglycerides into cellular lipid droplets
  • Neutral lipid storage & metabolism
  • Lipid droplets
    • Organelles that store neutral lipids
    • Cytoplasmic
    • Surface: Phospholipid monolayer
    • Modulate cellular signaling, lipid metabolism, transcriptional regulation, autophagy & immunity
    • Lipid droplet-ER contact
  • May be depleted by: Tamoxifen
  • Disorders of proteins involved in lipid droplet biogenesis
    • BSCL2 (Seipin): Berardinelli–Seip congenital lipodystrophy; SPG 17; HMN 5C
    • Tamoxifen enteropathy
• Clinical
  • Onset age: 6 months
  • Sensorineural hearing impairment: Earliest feature: Progression to severe deafness
  • Global developmental delay
    • Neuro-regression
    • Walking: Late or None
    • Failure to thrive: Low weight
    • Speech reduced
  • Dystonia: Hands
  • Contractures: Pes cavus
  • Muscle wasting: Legs
  • Sensory abnormalities
    • Not length dependent
    • Pain: Joints; Paresthesias or burning in distal linbsa, joints & trunk
    • Pain sensation: Loss in arms & face; Preserved in trunk &legs
  • Ichthyosis: Especially shin & scarring alopecia
  • No lipodystrophy
• Laboratory
  • Serum CK & aldolase: Normal
  • NCV: CMAPs normal; SNAPs normal
  • EMG: Normal
  • Brainstem-evoked response audiometry: No responses
  • Brain MRI: Normal
  • Muscle pathology: Normal

---

Hereditary Sensory ± Motor Neuropathy ²⁰
  ● INSC Spindle orientation adaptor protein (INSC) ; Chromosome 11p15.2; Dominant

• Epidemiology: Asian family; 8 patients
• Genetics
  • Mutation: Missense; Met70Arg
• INSC protein
  • PAR3(PARD3)/INSC/LGN(GPSM2) complex
  • Cell division, asymmetric
  • Mutation effect
    • Tubulin aggregation: Reversed by microtubule stabilization
    • Haploinsufficiency
• Clinical
  • Onset age: 7 to 29 years
  • Sensory loss: Large fiber or Pan-modal; Distal
  • Paresthesias (40%): Hands & Feet
  • Weakness (40%): Distal; More after 50 years of age
  • Gait disorder
  • Skeletal: Pes cavus
  • Course: Slow progression
• Laboratory
  • NCV
    • Motor: Conduction velocities 48 to 63 M/s; CMAP ampltudes normal to mildly reduced
    • Sensory: SNAPs often absent

---

Animal model of HSN: mutilated foot (mf) rat ⁵
  ● Chaperonin containing T-complex polypeptide 1, subunit 4 (CCT4) ; Recessive

• Genetics
  • Missense mutation: Tyr450Cys
  • Chromosome: Syntenic to human 2p13–p16
  • No human mutations yet identified
• CCT4 protein
  • Involved in folding newly translated peptides: Tubulin, actin, α-transducin & other cytosolic proteins
  • Mechanism: Multiple rounds of ATP-driven release and rebinding of partially folded intermediate forms
• Clinical features
  • Ataxia
  • Insensitivity to pain
  • Foot ulceration
• Pathology
  • Severe loss of sensory ganglia & axons
  • Apoptosis of cells during development

---

Congenital Indifference to Pain ⁷

• Definition: Loss of pain sensation with normal peripheral nerve function & anatomy
• Epidemiology: Individual case reports
• Onset: Congenital
• Clinical
  • Sense of pain to noxious stimulis: Reduced or Absent
  • Temperature: Perception of hot & cold reduced
  • Itch: Reduced or Absent
  • Taste: Normal except reduced perception of spicy foods
  • Normal: Light touch; Proprioception; Vibration; Autonomic
  • Pharmacology: Mild improvement in pain perception with naltrexone
• Laboratory
  • EMG & NCV: Normal
  • Pathology: Normal anatomy of PNS & CNS sensory pathways
• Differential diagnosis: CNS lesions
  • Asymbolia for pain
    • Lesions in cingulate, insular, or somatosensory cortical regions
    • Reduced affective-motivational component of pain perception
  • Right postcentral gyrus lesion
    • Inability to properly discriminate pain stimuli
    • Retained capacity to react appropriately to pain
  • Psychitric disorders

---

Return to Neuropathy differential diagnosis
Go to Neuromuscular home page

References
1. Am J Hum Genet 2000;67, Acta Neuropath 1999;98:309-312, Ann Clin Transl Neurol. 2017;4:415-421, J Peripher Nerv Syst 2020;25:423-428
2. Pediat Neurol 2002;27:49-52
3. Arch Neurol 2003;60:329-334
4. Am J Hum Genet 2003;Online July
5. Hum Molec Genet 2003;12:1917-1925
6. Acta Neurol Scand 2001;104:316-319
7. Pain 2006;122:210-215
8. J Med Genet 2006;43:e33
9. Nature 2006;444:894-898
10. Neuron 2006;52:767–774; Journal of Neurology, Neurosurgery, and Psychiatry 2006;77:1294-1295
11. Am J Human Genet 2010;87:643–654
12. Nat Genet 2011 May 1, Brain 2015; Online Feb, J Peripher Nerv Syst 2023 May 18
13. Neurology 2013;80: Online April
14. Brain 2015; Online March
15. Dis Model Mech 2017;10:105-118
16. Exp Neurol 2019 May 24, J Clin Invest 2022 Oct 26;e159800
17. Exp Neurol 2019 May 25
18. Eur J Med Genet 2020;63:104037
19. J Vet Intern Med 2023 Jan 11
20. EMBO Mol Med 2024 Apr 8
21. Genet Med 2024:101273

9/22/2024