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Adult Onset Alexander's Disease

Summary

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  • Rare leukodystrophy characterised by progressive neurological deterioration
  • Caused by mutations in the GFAP gene, leading to astrocyte dysfunction
  • Typical MRI findings include atrophy and white matter abnormalities in the brainstem and cerebellum

Pathophysiology

  • Caused by mutations in the glial fibrillary acidic protein (GFAP) gene
  • Leads to accumulation of Rosenthal fibres in astrocytes
  • Results in progressive demyelination and neurodegeneration
  • Astrocyte dysfunction impairs blood-brain barrier integrity and neurotransmitter homeostasis

Demographics

  • Adult-onset form typically presents after age 20
  • Rare disease with an estimated prevalence of 1 in 2.7 million
  • No significant gender predilection
  • Most cases are sporadic, but autosomal dominant inheritance has been reported

Diagnosis

  • Based on clinical presentation, imaging findings, and genetic testing
  • Clinical features may include:
    • Bulbar symptoms (dysarthria, dysphagia)
    • Pyramidal signs
    • Cerebellar ataxia
    • Palatal myoclonus
  • Genetic testing for GFAP mutations is confirmatory
  • Brain biopsy (rarely performed) may show Rosenthal fibres

Imaging

  • MRI is the imaging modality of choice
  • Characteristic findings include:
    • Atrophy of the medulla oblongata and upper cervical spinal cord
    • Periventricular white matter abnormalities
    • T2 hyperintensities in the hilum of the dentate nucleus
    • "Tadpole" appearance of the brainstem and spinal cord
  • Advanced MRI techniques:
    • Diffusion tensor imaging may show reduced fractional anisotropy in affected white matter
    • MR spectroscopy may demonstrate reduced N-acetylaspartate and elevated myo-inositol

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  • A 50-year-old patient presented a 1 year history of progressive upper limb weakness and bulbar symptoms.
  • MRI showed well demarcated symmetrical linear hyperintensity within the medulla without enhancement.
  • Brainstem and cord volume loss against preserved pontine volume gives rise to the 'tadpole' sign.

Treatment

  • No curative treatment available
  • Management is supportive and symptomatic:
    • Physical therapy for mobility and balance
    • Speech therapy for dysarthria and dysphagia
    • Antispasmodics for spasticity
    • Anticonvulsants for seizures (if present)
  • Experimental treatments under investigation:
    • Gene therapy approaches targeting GFAP
    • Small molecule therapies to reduce GFAP aggregation

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Multiple Sclerosis Ovoid periventricular and callosal lesions; no frontal-predominant white matter signal change or medullary involvement
Leukodystrophy (other types) Different white matter distribution patterns (e.g. posterior in MLD, peritrigonal in Krabbe)
Progressive Multifocal Leukoencephalopathy (PML) Ill-defined and diffusion restricting, unlikely to enhance