Alexander Disease

Excerpt

Clinical characteristics: Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous GFAP pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult.

The neonatal form begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years.

The infantile form is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form.

The juvenile form typically presents in childhood or adolescence with clinical and imaging features that overlap with the other forms. Manifestations in early childhood are milder than those in the infantile form (e.g., mild language delay may be the only developmental abnormality or, with language acquisition, hypophonia or nasal speech may alter the voice, often prior to appearance of other neurologic features). Vomiting and failure to thrive as well as scoliosis and autonomic dysfunction are common.

The adult form is typically characterized by bulbar or pseudobulbar findings (palatal myoclonus, dysphagia, dysphonia, dysarthria or slurred speech), motor/gait abnormalities with pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign), or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). Others may have hemiparesis or hemiplegia with a relapsing/remitting course or slowly progressive quadriparesis or quadriplegia. Other neurologic features can include sleep apnea, diplopia or disorders of extraocular motility, and autonomic dysfunction.

Diagnosis/testing: The diagnosis of Alexander disease is established in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in GFAP identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is supportive and focuses on management by multidisciplinary specialists to manage general care, feeding, and nutrition; anti-seizure medication; physical and occupational therapy; speech and language therapy; and appropriate educational services.

Surveillance: Monitoring for progression of neurologic manifestations, developmental progress, and educational needs as well as need for services as they relate to physical therapy and occupational therapy, nutrition and safety of oral feeding, speech and language, gastrointestinal involvement, bladder function, evidence of autonomic dysfunction, pulmonary function, psychological/psychiatric manifestations, and sleep.

Genetic counseling: Alexander disease is inherited in an autosomal dominant manner. To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a de novo GFAP pathogenic variant; however, familial cases have been reported, including individuals with slowly progressive adult Alexander disease who have an affected parent. Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce, whereas each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the GFAP pathogenic variant. Once the GFAP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Alexander disease are possible.