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Hereditary Sensory & Autonomic Neuropathy Syndromes
HSN Disorder Gene Locus Inheritance Onset Age Clinical features Axon loss

Dominant > 20 years Pan-sensory loss
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
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
Large & Small
IIB FAM134B 5p15 Recessive Childhood Sensory loss
Small > Large
2q37 Recessive 6 to 15 yrs Sensory loss
Weakness, Distal
Large > Small
Inability to
  experience pain
SCN 9A 2q24 Recessive Congenital Absence of pain
III IKBKAP (ELP1) 9q31 Recessive Congenital Riley-Day Small > Large
IV NTRK1 1q21 Recessive Congenital, or
Early childhood
Sensory neuropathy
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
Absent pain,
    Recessive Congenital, or
Early childhood
Absence of pain
  No anhidrosis
VIII: Absent pain,
& temperature
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
Absent pain,
CLTCL1 22q11 Recessive Congenital Absent of pain
  & Light touch
Erythromelalgia SCN 9A 2q24 Dominant Childhood Pain, distal
Erythromelalgia NMNAT2 1q25 Recessive Childhood Pain, distal
Large & Small
Biemond ataxia     Dominant 19 to 30 years Sensory loss Large
PLD3 19q13 Dominant After 4th decade Sensory loss
  neuropathy 2
  16q22 Dominant After 2nd decade Sensory loss
    Dominant 5 to 30 years Acromutilation Large & Small
CCT5 5p15 Recessive 1 to 5 years Acromutilation Large & Small
Thermoanalgesia     Dominant 5th decade Absent pain &
  temperature; Ataxia
Large & Small
PCARP FLVCR1 1q31 Recessive Early childhood Proprioceptive loss
  Visual loss
SNAX1 RNF170 8p11 Dominant 3rd to 8th decade Proprioceptive loss Posterior
HSAN + CNS Prion 20p13 Dominant Early adult Autonomic &
  Sensory loss
Axon loss
CMT 2V: SN + Pain NAGLU 17q21 Dominant Adult Pain; Ataxia Axon loss
Scoliosis PIEZO2 18p11 Recessive Congenital Sensory Axon loss

Hereditary Sensory Neuropathy: Other  
Neurogenic Joint & Limb syndrome

Hereditary Neuropathies with Ulcero-mutilation 3
Also see

Polyneuropathy with Minifascicles, 46,XY Gonadal dysgenesis & Mental retardation (GDMN) 1
  desert hedgehog (DHH) ; Chromosome 12q13.12; Sporadic (Recessive)
  • Epidemiology: 10 families
  • Genetic
  • 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

From K Sugie

Posterior column ataxia & Retinitis pigmentosa (AXPC1; PCARP) 11
  Feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) ; Chromosome 1q32.3; Recessive
Hereditary Sensory Neuropathy with Gastro-Esophageal reflux & Cough (HSAN IB) 4
  Chromosome 3p24-p22; Dominant
Hereditary Sensory Neuropathy with Deafness and Global Delay 2
  Autosomal Recessive
Hereditary Sensory Neuropathy with Deafness & Dementia (HSN 1E) 12
  DNA methyltransferase 1 (DNMT1) ; Chromosome 19p13.2; Dominant & Simplex
  • X-linked Sensory Neuropathy with Deafness (AUNX1; DFNX5) 8
      AIFM1; Chromosome Xq26.1; Recessive
    Gyrate atrophy of choroid & retina with hyperornithinemia (GACR)
      Ornithine aminotransferase (OAT) ; Chromosome 10q26.13; Recessive
    Hereditary Sensory & Autonomic neuropathy (HSAN) with Anosmia 6
      ? Autosomal Recessive
    Hereditary sensory & autonomic neuropathy type IID (HSAN2D) 13
      SCN 9A ; Chromosome 2q24.3; Recessive
    Congenital inability to experience pain (CIP) 9
      SCN 9A ; Chromosome 2q24.3; Recessive
    Paroxysmal Extreme Pain Disorder (PEPD; FEPS4) 10
      SCN 9A ; Chromosome 2q24.3; Dominant
    Polyneuropathy & Erythromelalgia 16
      Nicotinamide Nucleotide Adenylyltransferase 2 (NMNAT2) ; Chromosome 1q25.3; Recessive
    CMT 2V: Hereditary Adult-onset Painful Axonal Polyneuropathy 14
      α-N-acetyl-glucosaminidase (NAGLU) ; Chromosome 17q21.2; Dominant
    Sensory (Small fiber) Neuropathy + Deafness-Dystonia & Ichthyosis 15
      Fat-Inducing Transcript 2 (FITM2; FIT2) ; Chromosome 20q13.12; Dominant
    Hereditary Sensory ± Motor Neuropathy 20
      INSC Spindle orientation adaptor protein (INSC) ; Chromosome 11p15.2; Dominant
    Animal model of HSN: mutilated foot (mf) rat 5
      Chaperonin containing T-complex polypeptide 1, subunit 4 (CCT4) ; Recessive
    Congenital Indifference to Pain 7

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