- Epidemiology: > 70 patients
- Genetics
- Mutation types; Missense; Nonsense; Frameshift; Recurrent uniparental isodisomy
- > 46 mutations: All regions of gene
- Founder mutations
- Mexico: c.851+1G>A
- Turkey: c.1502+1G>T
- Few genotype-phenotype corelations
- Variants
- Heterozygotes
- ? Subclinical polyneuropathy on electrophysiology
- Gigaxonin protein
- Subcellular localization: Cytoskeletal
- Binds to Microtubule-associated protein (MAP)1B light chain
- Associated with microtubules: Stabilizes microtubule network
- Tissue localization: Ubiquitous expression
- Functions
- Ubiquitin ligase adapter protein
- Needed for regulation of intermediate filament turnover
- Loss of function
- Accumulation of intermediate filaments in many cell types
- Disregulated intermediate filaments: Vimentin, Desmin, Cytokeratins,
Glial fibrillary acidic protein (GFAP), Peripherin, Neurofilaments
- BTB/kelch superfamily
- Intracellular proteins
- Functions
- Coordinate cell morphology & growth: Calicin
- Cytoplasmic sequestration of transcription factors: Keap 1
- BTB domain: Interacts with proteins involved in ubiquitination & protein chaperones
- Kelch domain: Interacts with intermediate filaments targeted for degradation or turnover
- Ubiquitin-proteasome system
- Controls degradation of ubiquitin-mediated microtubule-associated protein 1B (MAP1B)
- Interacts with UBE1
- May function as scaffold protein
- Association with actin & cytoskeleton
- Over-expression: Enhanced degradation of MAP1B-LC
- May contribute to viral pathogenesis
- Kelch disorders, other
- Clinical features
- Onset
- Age: Mean = 2 to 3 years; Most < 10 years
- Gait disorder
- Polyneuropathy
- Distribution: Legs > Arms
- Weakness: Diffuse; Distal > Proximal
- Sensory loss: Especially vibratory & proprioception
- Tendon reflexes: Reduced in Lower limbs or Generally
- Cranial nerves: Facial weakness; Dysarthria
- Onset
- Autonomic
- Respiratory
- Later in disease course
- FVC may be reduced
- Sleep disorders
- Gastrointestinal
- Dysphagia (31%)
- Constipation (45%)
- Lactose intolerance (40%)
- Episodic vomiting
- CNS: Variable
- Ataxia: Clumsy gait; Present in most patients
- Eyes: Optic atrophy; Nystagmus
- Mental retardation
- Corticospinal tract: Spastic paraplegia; Plantar responses extensor
- Hair (100%)
- Frizzy (Tightly curled) scalp hair; Long curly eyelashes
- Changes more common in severe cases
- Skeletal
- Short stature
- Forehead: Prominent, High
- Macrocephaly
- Progression
- Differential diagnosis: GAN2, Dominant
- Laboratory
- CSF: Normal
- MRI
- Diffuse T2 hyperintensities: Cerebral & cerebellar white matter
- Spinal cord: Atrophy
- Electrophysiology: Axonal, length-dependent neuropathy
- SNAPs: Absent or Reduced amplitude
- CMAPs: Reduced amplitude
- Motor nerve conduction velocity: Normal or Mild reduction
- Pathology
- Axon loss: Distal; Progressive with age; All axon sizes
- Axon swellings
- Contain densely packed, swirled neurofilaments
- Begin at nodes of Ranvier
- Myelin sheaths: Thin or absent around swellings
- Size: Average 20 μM; Up to 50 μM
- Microtubule distribution: Abnormally clustered
- Axon atrophy: Distal to swellings
- Microfilament accumulations
- Locations: Schwann cells, Fibroblasts, Vascular endothelium
- GAN Variant: Giant axonal neuropathy, Tunisian form
- Genetics
- Inheritance: Recessive
- GAN mutation: Arg15Ser
- Clinical
- Onset age: Infancy
- Weakness: Distal; Bulbar
- Sensory loss: Legs
- Tendon reflexes: Brisk
- Hair: Normal
- CNS
- Progression: Slow
- Laboratory: Sensory-Motor polyneuropathy
- GAN Variant: CMT+
34
- Epidemiology: 20% of GAN
- Genetics
- Inheritance: Recessive
- Mutations: At least 1 missense; P315L
- Clinical
- Onset age: Mean = 5 years
- Polyneuropathy
- Spasticity: Legs > Arms; Hyperreflexia
- Curly hair: Mild
- CNS & Systemic features: Few
- Laboratory
- Brain imaging: Normal or Minimal white matter changes
- Other: Cytoskeletal disorders
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