HSN

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HEREDITARY SENSORY & AUTONOMIC NEUROPATHIES (HSAN)

Hereditary Sensory & Autonomic Neuropathy Syndromes
HSN Disorder	Gene	Chromosome	Inheritance	Onset Age	Clinical features	Axon loss	Cajal
I	SPTLC1	9q22	Dominant	> 20 years	Pan-sensory loss Acromutilation	Small > Large
II	WNK1/HSN2	12p13	Recessive	Congenital, or Early childhood	Sensory loss Acromutilation	Large & Small
III	IKBKAP	9q31	Recessive	Congenital	Riley-Day Syndrome	Large & Small
IV	TRKA/ NGF receptor	1q21	Recessive	Congenital, or Early childhood	Sensory neuropathy Anhidrosis	C-axon
V			Recessive	Congenital, or Early childhood	Absence of pain No anhidrosis	Aδ-axons
Absent pain	NGF-b	1p13	Recessive	Early childhood to Adult	Absence of pain No anhidrosis	Aδ- & C-axons
Inability to experience pain	SCN 9A	2q24	Recessive	Congenital	Absence of pain No anhidrosis	None
Erythromelalgia	SCN 9A	2q24	Dominant	Childhood	Pain, distal Episodic	None
Biemond ataxia			Dominant	19 to 30 years	Sensory loss	Large axons
Ataxic neuropathy			Dominant	After 4th decade	Sensory loss Ataxia	Large axons
Ulcero-mutilation			Dominant	5 to 30 years	Acromutilation	Large & Small
Spastic paraparesis		5p15	Recessive	1 to 5 years	Acromutilation	Large & Small

Hereditary sensory neuropathy with α-galactosidase (Fabry's) An-α-lipoproteinemia (Tangier's) Anosmia Ataxia telangectasia Ataxia, thermoanalgesia & loss of fungiform papillae Deafness & Global delay Deafness - X-linked Friedreich's ataxia Gastroesophageal reflux & Cough Gyrate atrophy of choroid & retina with hyperornithinemia Minifascicles & 46,XY Gonadal dysgenesis Mitochondrial disorder Maternal: NARP Recessive: Cytopathy Multiple symmetrical lipomatosis Posterior column ataxia + Retinitis pigmentosa Scoliosis & deafness Spastic paraparesis
Hereditary Neuropathies with Ulcero-mutilation³ HSAN I: Dominant; Sensory HMSN 2B: Dominant; Sensory + Motor Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation: Dominant; Sensory > Motor Hereditary Sensory-Motor Neuropathy with Ulcero-mutilation: Dominant Axonal CMT with acrodystrophy: Recessive Hereditary sensory neuropathy with spastic paraparesis Cavanaugh Moroccan Navajo neuropathies Neurohepatopathy Arthropathy Also see Occasional patients with CMT 1A Neurogenic osteoarthropathies (Charcot's joints) Animal model: mutilated foot rat
Also see Sensory ataxic neuropathies Hereditary Spinal Sensory Ataxia Congenital indifference to pain

Polyneuropathy with Minifascicles, 46,XY Gonadal dysgenesis & Mental retardation¹
l desert hedgehog (DHH)

; Chromosome 12q12-q13.1; Sporadic (Recessive)

Epidemiology: Single patient
Genetic: Homozygous point mutation at initiating codon in exon 1
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
- 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
  - Sensation: Pin & Temperature loss
  - Motor: Normal
  - Tendon reflexes: Hyopactive or Absent
- CNS: Mental retardation, Severe
Laboratory
- Karyotype: 46,XY
- Electrophysiology
  - Motor NCV: Normal
  - Sensory NCV: SNAPs small or absent; Conduction velocity slowed
  - EMG: Denervation in distal legs
- Nerve pathology
- Thermography: Reduced temperature in distal arms & legs
- CSF: Normal
- MRI: Normal Brain & Spinal cord
- Endocrine: High TSH; FSH; Prolactin
Also see
- HMSN with Minifascicle Formation & 46XY Pure Gonadal Dysgenesis
- Sonic hedgehog
- External links
  - Hedgehog proteins
  - Hedgehog database

Posterior column ataxia & Retinitis pigmentosa (AXPC1)

l Chromosome 1q31-q32

Onset: Early childhood; Visual loss
Clinical
- Visual
  - Ring scotoma
  - Progessive loss to blindness
  - Retinitis pigmentosa: Pan-retinal loss of pigment epithelium
- Sensory
  - Large fiber loss
  - Pain & temperature preserved
  - Sensory ataxia
  - Progression to severe disability
- Tendon reflexes: Absent
- GI: Achalasia; Dysmotility
- Skeletal: Scoliosis; Camptodactyly
Pathology: Dorsal root ganglia & Posterior columns

Hereditary Sensory Neuropathy with Gastro-Esophageal reflux & Cough⁴

l Chromosome 3p22-p24; Dominant

Onset
- Age: 2nd to 4th decade
- Cough or Gastro-Esophageal reflux
Clinical
- 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 with truncal involvement as well
    - 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
  - Hearing loss: Sensorineural
  - Retinal detachment
Laboratory
- Nerve conduction: Sensory, axonal loss
- Audiometry: Sensorineural hearing loss (40%)

Hereditary Sensory Neuropathy with Deafness and Global Delay ²
l 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

X-linked Sensory Neuropathy with Deafness (AUNX1)

⁸
l Chromosome Xq23–27.3; Recessive

Epidemiology: Chinese family
Onset
- Age: Mean 13 years
- Hearing loss: Low frequency
Clinical
- 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
l Ornithine aminotransferase (OAT)

; Chromosome 10q26; Recessive

Clinical
- Chorioretinal degeneration
- Cataract formation: Early
Laboratory

Hyperornithinemia; No hyperammonemia or homocitrullinuria
Muscle: Type II muscle fiber atrophy; Tubular aggregates
Nerve: Sensory axonal neuropathy, by electrophysiology

Hereditary sensory & autonomic neuropathy (HSAN) with Anosmia⁶

l ? Autosomal Recessive

Epidemiology: 1 Japanese family
Onset
- Age: 20-50 years
- Anosmia
Clinical
- 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

Animal model of HSN: mutilated foot (mf) rat⁵
l 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 inability to experience pain⁹
l SCN 9A

; Chromosome 2q31-32; Recessive

Genetics
- Mutations: Homozygous nonsense; S459X, I767X, W897X
- Allelic with: Erythromelalgia; Paroxysmal Extreme Pain Disorder
SCN 9A protein: See SCN 9A & Erythromelalgia
Onset: Congenital
Clinical
- Sensory
  - Inability to feel pain
    - Over all body regions
    - Painless injuries present
  - 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
- CNS MRI: Normal

Paroxysmal Extreme Pain Disorder (PEPD)

¹⁰
l SCN 9A

; Chromosome 2q31-32; Dominant

Nosology: Familial rectal pain
Genetics
- Mutations: Missense; Present in 2/3 of families with PEPD
- Allelic with: Erythromelalgia; Congenital inability to experience pain
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

Congenital Indifference to Pain⁷

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
- Eletrophysiology: 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

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References
1. Am J Hum Genet 2000;67, Acta Neuropath 1999;98:309-312
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

12/16/2006