HSN

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	Chromosome	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
II	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	Large & Small
IV	NTRK1	1q21	Recessive	Congenital, or Early childhood	Sensory neuropathy Anhidrosis	C
V	NGF-b	1p13	Recessive	Early childhood to Adult	Absence of pain No anhidrosis	Aδ- & C
VI	Dystonin	6p12	Recessive	Congenital	Absent tears	Large & Small
Absent pain, congenital			Recessive	Congenital, or Early childhood	Absence of pain No anhidrosis	Aδ
Erythromelalgia	SCN 9A	2q24	Dominant	Childhood	Pain, distal Episodic	None
Biemond ataxia			Dominant	19 to 30 years	Sensory loss	Large
Ataxic Neuropathy			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
HSAN + Diarrhea	PRNP	2pter	Dominant	Adult	Diarrhea & Sensory loss
PCARP	FLVCR1	1q31	Recessive	Early childhood	Proprioceptive loss Visual loss	Large
SNAX1	RNF170	8p11	Dominant	3rd to 8th decade	Proprioceptive loss	Posterior column

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 Optic atrophy & Deafness: 8q24.22-ter Posterior column ataxia + Retinitis pigmentosa Scoliosis & deafness Spastic paraparesis	Neurogenic Joint & Limb syndrome
Hereditary Neuropathies with Ulcero-mutilation³ General features Acro-mutilation Skin ulcers Amputations Neurogenic osteoarthropathy (Charcot's joints) HSAN I: SPTLC1; 9q22; Dominant; Sensory ID: ATL1; 14q11; Dominant; Sensory II: WNK1/HSN2 12p13 Recessive IIB: FAM134B; 5p15.1; Recessive IID: SCN9A; Recessive 3 (Riley-Day): IKBKAP; 9q31; Recessive 4: TRKA/ NGF receptor (NTRK1); 1q21-q22; Recessive Navajo Arthropathy HMSN 2B: RAB7; 3q13; Dominant; Sensory + Motor Axonal CMT with acrodystrophy: Recessive Navajo Neurohepatopathy: MPV17; 2p23; Recessive Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation ATSV (KIF1A): 2q37; Recessive Dominant: Sensory > Motor Neuropathy Dominant: Sensory-Motor Neuropathy Congenital insensitivity to pain Hereditary sensory neuropathy with spastic paraparesis Cavanaugh Moroccan Other 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 12q13.12; 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; PCARP)

¹¹
l Feline leukemia virus subgroup C cellular receptor 1 (FLVCR1)

; Chromosome 1q32.3; Recessive

Epidemiology: Dutch-German (Swiss), French & Spanish families
Genetics
- Mutations: Asn121Asp; Cys192Arg; Ala241Thr
- Allelic with: Diamond-Blackfan syndrome
FLVCR1
- High expression in retina, spinal cord & cerebellum
- MFS transporter
  - 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
Onset: Early childhood; Visual loss
Clinical
- 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
- 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
PCARP phenotype without mutations
- Additional feature: Loss of pain sensation on hands & feet

Hereditary Sensory Neuropathy with Gastro-Esophageal reflux & Cough (HSAN IB) ⁴

l Chromosome 3p24-p22; Dominant

Onset
- Age: 2nd to 5th 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 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
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

Hereditary Sensory Neuropathy with Deafness & Dementia (HSN 1E)

¹²
l DNA methyltransferase 1 (DNMT1)

; Chromosome 19p13.2; Dominant & Simplex

Epidemiology: American & Japanese families
Mutations
- Missense: Tyr495Cys; Asp490Glu�Pro491Tyr; His569Arg
- Location: Targeting sequence domain; Exons 20 & 21
- Allelic with: Autosomal Dominant Cerebellar Ataxia, Deafness & Narcolepsy (ADCA-DN)
DNMT1 protein
- Components of DNA replication machinery during S phase of cell cycle
- Maintenance of methylation, gene regulation & chromatin stability
- 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
Clinical
- Onset age: 16 to 35 years
- Hearing loss: Often at onset; Sensorineural
- Sensory
  - Loss
    - Extremities, Distal > Proximal; Legs > Arms
    - Large & Small axon modalities: Vibration > Joint position
  - Lancinating pain: Some patients
- Ulcero-Mutilation
- Tendon reflexes: Reduced distal
- Weakness: 15%; Distal
- Ataxia: 15%; Unstable gait
- Dementia
  - Onset 4th & 5th decade
  - Frontal lobe dysfunction
  - Clouded consciousness
- Death: 5th & 6th decade
Electrodiagnostic
- SNAPs: Often absent
- Motor: NCV normal or slightly slow; CMAP normal
Pathology
- Posterior column: Especially medial
- Cerebellum: Purkinje cell swelling & axonal loss; Hyperplasia of Bergman glia
- Inferior olivary nucleus: Neuron loss
- Cerebral atrophy
- Nerve: Severe loss of large & small axons

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 10q26.13; 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 Anosmia ⁶

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

Hereditary sensory and autonomic neuropathy type IID ¹³
l 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

⁹
l SCN 9A

; Chromosome 2q24.3; Recessive

Genetics
- Mutations: Homozygous nonsense; S459X, I767X, W897X
- Allelic disorders
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 2q24.3; Dominant

Nosology: Familial rectal pain
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

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 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
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
13. Neurology 2013;80: Online April

4/20/2013