What are the hereditary sensory and autonomic neuropathy (HSAN) types, their associated genes, typical age of onset, and clinical presentation?

Hereditary Sensory and Autonomic Neuropathy (HSAN) Types: Classification by Gene, Age of Onset, and Clinical Presentation

HSAN comprises at least 7 distinct genetic subtypes with varying ages of onset from congenital to adulthood, each characterized by progressive sensory loss, autonomic dysfunction, and ulcerative mutilations, with specific genes determining the clinical phenotype and severity. 1, 2, 3

HSAN Type I (Autosomal Dominant)

HSAN IA

• Gene: SPTLC1 mutations
• Age of Onset: Adolescence to early adulthood (typically 2nd-3rd decade)
• Clinical Presentation:
  • Progressive distal sensory loss (pain and temperature predominantly)
  • Chronic foot ulcers and infections
  • Lancinating pains in legs
  • Distal muscle weakness and atrophy
  • Minimal autonomic involvement
  • Small fiber sensory neuropathy pattern 3

HSAN IB

• Gene: SPTLC2 mutations
• Age of Onset: Similar to HSAN IA (adolescence to adulthood)
• Clinical Presentation: Phenotypically similar to HSAN IA 3

HSAN IC

• Gene: SPTLC2 (Ser384Phe mutation specifically)
• Age of Onset: Variable, can present in childhood to adulthood
• Clinical Presentation:
  • Typical HSAN-1 sensory features
  • Unique features: Upper motor neuron signs, early demyelinating features on nerve conduction studies
  • Type II juxtafoveal retinal telangiectasias (MacTel II) with macular depigmentation 4

HSAN ID (CMT2B Phenotype)

• Gene: RAB7 mutations
• Age of Onset: Adolescence to early adulthood
• Clinical Presentation:
  • Sensory-motor axonal neuropathy
  • Pronounced ulcero-mutilations (more severe than other HSAN I types)
  • Distal muscle weakness
  • Charcot-Marie-Tooth type 2B overlap phenotype 3

HSAN Type II (Autosomal Recessive)

• Gene: WNK1/HSN2
• Age of Onset: Early childhood (infancy to early school age)
• Clinical Presentation:
  • Early-onset ulcero-mutilating sensory neuropathy
  • Progressive sensory loss affecting all modalities
  • Chronic skin ulcers on hands and feet
  • Spontaneous fractures
  • Neuropathic arthropathy (Charcot joints)
  • Acral mutilations requiring amputations
  • Minimal autonomic features 3, 5

HSAN Type III (Familial Dysautonomia/Riley-Day Syndrome)

• Gene: IKBKAP
• Age of Onset: Present from birth (congenital)
• Clinical Presentation:
  • Cardinal diagnostic features:
    • Absence of fungiform papillae on tongue
    • Absence of axon flare after intradermal histamine injection
    • Decreased or absent deep tendon reflexes
    • Absence of overflow emotional tears
  • Autonomic features (40% have autonomic crises):
    • Gastrointestinal dysfunction
    • Vomiting crises
    • Cardiovascular instability
    • Altered pain and temperature sensitivity
  • Hypotonia with delayed motor milestones
  • Recurrent pneumonia
  • Progressive neuronal degeneration throughout life
  • Ethnicity: Predominantly Ashkenazi Jewish population (carrier frequency 1 in 31; birth prevalence 1 in 3,800) 6

HSAN Type IV (Congenital Insensitivity to Pain with Anhidrosis - CIPA)

• Gene: NTRK1 (encodes TrkA, the NGF receptor)
• Age of Onset: Congenital (present from birth)
• Clinical Presentation:
  • Hallmark triad:
    • Complete congenital insensitivity to pain
    • Anhidrosis (inability to sweat)
    • Intellectual disability (variable severity)
  • Recurrent fevers (due to anhidrosis and thermoregulation failure)
  • Self-mutilations (tongue, lips, fingers)
  • Recurrent burns and trauma
  • Chronic non-healing ulcers
  • Recurrent osteomyelitis
  • Corneal ulcers and scarring
  • Multiple fractures with delayed/abnormal healing
  • Charcot joints
  • Bone deformities
  • Orthopedic complications: Physeal fractures, excessive joint laxity, recurrent painless dislocations 3, 5, 7, 8

Critical diagnostic challenge: Average time to diagnosis is 53 months due to protean manifestations; whole-exome sequencing expedites diagnosis 7

HSAN Type V

• Gene: NGFB (nerve growth factor beta)
• Age of Onset: Early childhood
• Clinical Presentation:
  • Congenital insensitivity to pain
  • Preserved sweating (distinguishes from HSAN IV)
  • Normal intelligence (distinguishes from HSAN IV)
  • Self-mutilations
  • Painless injuries
  • Minimal autonomic involvement 3

HSAN Type VI

• Gene: DST (dystonin/BPAG1)
• Age of Onset: Infancy to early childhood
• Clinical Presentation:
  • Severe sensory and autonomic neuropathy
  • Progressive sensory loss
  • Autonomic dysfunction
  • Variable phenotypic expression 5

HSAN Type VII

• Gene: PRDM12
• Age of Onset: Congenital to early infancy
• Clinical Presentation:
  • Congenital insensitivity to pain
  • Self-mutilations
  • Recurrent injuries
  • Variable autonomic features 5

Additional Genetic Variants

• CCT5: Rare autosomal recessive form with variable presentation 3
• FLVCR1: Novel compound heterozygous variants identified with HSAN phenotype 5

Key Diagnostic Approach

Electrophysiology findings vary by type:

• HSAN I: Predominantly axonal sensory neuropathy (though HSAN IC shows early demyelinating features)
• HSAN II-VII: Predominantly sensory axonal neuropathy with reduced or absent sensory nerve action potentials 5, 4

Genetic testing strategy: Next-generation sequencing panels covering all known HSAN genes provide definitive diagnosis, with inheritance pattern (autosomal dominant vs. recessive) and age of onset guiding initial gene selection 3, 9

Critical pitfall: Approximately 81% of clinically diagnosed HSAN patients do not have mutations in the currently known genes, indicating substantial genetic heterogeneity remains undiscovered 3