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HEREDITARY SENSORY & AUTONOMIC NEUROPATHIES (HSAN)

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

Cajal
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 9q31 Recessive Congenital Riley-Day Syndrome 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
VIII: Absent pain,
& temperature
  Congenital
PRDM12 9q33 Recessive Congenital Absent pain
  Sweat reduced
Aδ & C
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
Ataxic
  Neuropathy
PLD3 19q13 Dominant After 4th decade Sensory loss
Ataxia
Large
Ataxic
  neuropathy 2
  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
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: SN + Pain NAGLU 17q21 Dominant Adult Pain; Ataxia Axon loss
Autonomic TECPR2 14q32 Recessive Congenital Autonomic None
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 1
  desert hedgehog (DHH) ; Chromosome 12q13.12; Sporadic (Recessive)
  • Epidemiology: 3 families, 5 patients
  • Genetic
  • DHH protein
    • Distribution: Schwann cells; Sertoli cells of developing testis
    • Roles
      • Peripheral nerve sheath development
      • Spermatogenesis
      • Mouse knockout: Reduced perineurium & epineurium
    • Other hedgehog family members
      • Sonic hedgehog: Defect causes holoprosencephaly
  • Clinical
    • Onset ages: 2 to 39 years
    • Systemic
      • Partial gonadal dysgenesis
        • Onset: Primary amenorhea
        • Anatomy: Premature female genetalia; Testis on one side, streak gonad on other
      • Skin: Black nails; Cyanosis & edema on exposure to cold
    • Neuromuscular (60%)
      • Sensation: Pin & Temperature or Panmodal loss
      • Motor
        • Normal in 80%
        • Distal; Moderate; Arms & Legs
      • Tendon reflexes: Hyopactive or Absent
      • Skin: Cutaneous ulcers (60%)
    • CNS: Normal or Mental retardation, Severe
    • Gynecological: Older patient
      • Breasts: Poorly developed
      • Pubic hair: Sparse
      • Vagina: Blinded
      • Uterus: Immature
      • Gonads: Streak
  • Laboratory
    • Karyotype: 46,XY
    • Hormones: LH & FSH high; Testosterone & Estradiol low
    • Electrophysiology
      • Motor NCV: Normal (37 to 48 M/s)
      • Sensory NCV: SNAPs small or absent; Conduction velocity slowed
      • EMG: Denervation in distal legs
    • 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: Reduced small & large myelinated fibers; Normal unmyelinated axons
      • 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
Minifascicles



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) 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

    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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    References
    1. Am J Hum Genet 2000;67, Acta Neuropath 1999;98:309-312, Ann Clin Transl Neurol. 2017;4:415-421
    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
    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
    17. Exp Neurol 2019 May 25

    5/29/2019