🧬 653.7 · Giant Axonal Neuropathy (GAN)

Nelson Textbook of Pediatrics 22nd Edition — Autosomal recessive neurodegenerative disorder caused by GAN gene (gigaxonin) mutations. Characterized by kinky/frizzy hair (tightly curled), progressive sensorimotor peripheral neuropathy, central nervous system white matter changes (leukodystrophy-like), ataxia, optic atrophy, scoliosis. Sural nerve biopsy: giant axons (neurofilament accumulation). No cure; supportive care.

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    GAN: Clinical & Diagnostic Features

    FeatureDetails
    Gene / ProteinGAN (16q24) / Gigaxonin (cytoskeletal BTB/kelch protein)
    InheritanceAutosomal recessive
    Hair findingKinky, tightly curled, frizzy hair (pathognomonic)
    Neurologic onsetEarly childhood (age <5 years) — progressive gait ataxia, peripheral neuropathy (distal weakness, areflexia, sensory loss)
    CNS involvementWhite matter changes on brain MRI (leukodystrophy-like, T2 hyperintensities), cerebellar signs, nystagmus, dysarthria, optic atrophy, seizures, cognitive decline
    Peripheral neuropathyMixed axonal sensorimotor (NCS: reduced amplitudes, mild slowing)
    Sural nerve biopsyGiant axons (axonal swellings filled with neurofilaments), segmental demyelination
    Other featuresScoliosis (progressive), foot deformities (pes cavus), optic atrophy
    TreatmentSupportive only — no cure. Physical therapy, orthotics, scoliosis surgery, respiratory support, seizure management
    🔬 Pathognomonic Sign — KINKY HAIR

    Giant axonal neuropathy presents with tightly curled, frizzy hair (present from birth or early childhood). Microscopic hair examination shows variation in shaft diameter and twisting (pili torti-like).

    Gigaxonin is a cytoskeletal protein involved in intermediate filament degradation. Defects lead to accumulation of neurofilaments in axons → axonal swelling (giant axons). Also affects other intermediate filaments (hair cytokeratin, glial filaments).

    Differential diagnosis: Menkes disease (kinky hair, but copper metabolism disorder, early onset, seizures, failure to thrive) — very different presentation.

    MRI brain: Diffuse white matter hyperintensities (T2/FLAIR) resembling leukodystrophy, with cerebellar and brainstem involvement.

    Data from Nelson 653.7; Manzur AY. Giant axonal neuropathy.

    📖 Summary: Giant Axonal Neuropathy — Nelson 653.7