Adult-Onset Alexander Disease

Alexander disease is a leukodystrophy from dominant GFAP variants, with accumulation of Rosenthal fibres in astrocytes.

The adult onset form (type II) starts after adolescence, with predominant brainstem, cerebellar and spinal cord disease. Many variants arise de novo.

Pathophysiology

Gain-of-function variants cause toxic GFAP aggregation, astrocyte dysfunction and secondary demyelination.

Bulbar and pseudobulbar signs (dysphagia, dysarthria, palatal myoclonus, hiccups, vomiting), spastic paraparesis, ataxia, autonomic features (bladder, sleep apnoea, orthostatic hypotension), eye movement abnormalities (nystagmus, ocular bobbing), dysautonomia, and sometimes cognitive and psychiatric changes.

Progression is slow over decades. Some have a mild presentation and others are misdiagnosed as multiple sclerosis.

MRI shows atrophy of the medulla and upper cervical cord ("tadpole" appearance), with signal change in the medulla, periventricular rim and brainstem.

Genetic testing of GFAP confirms the diagnosis. CSF GFAP may be raised. Biopsy is not needed.

Differential diagnosis.

• Multiple sclerosis, neuromyelitis optica spectrum disorder and spinocerebellar ataxias.

• Multiple system atrophy, hereditary spastic paraplegia and Chiari malformation.

• Adult polyglucosan body disease, leukodystrophies and syringobulbia.

No disease modifying treatment is established (antisense oligonucleotide therapy is under study).

Spasticity. Baclofen 5 mg three times daily, increased to 30 to 80 mg daily in divided doses, tizanidine, botulinum toxin and physiotherapy.

Bulbar. Speech and swallowing therapy, modified diet, and gastrostomy if aspiration risk is high.

Autonomic. Compression stockings, fluids and salt, fludrocortisone 0.1 mg daily, increased as needed, bladder care, and treatment of sleep apnoea (CPAP).

Palatal myoclonus and vomiting. Clonazepam 0.5 mg at night, increased as tolerated, antiemetics (ondansetron).

Respiratory. Monitor for sleep disordered breathing and aspiration.

Rehabilitation. Physiotherapy, occupational therapy and falls prevention.

Genetic counselling. For the patient and family.

Monitoring. Swallowing, respiratory function and mobility every 6 to 12 months.

Referral and escalation. Refer to neurology and clinical genetics.