Clinical characteristics: TUBB4A-related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages 1-3 years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity.
Diagnosis/testing: The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygous TUBB4A pathogenic variant identified by molecular genetic testing.
Management: Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.
Prevention of secondary complications: Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.
Surveillance: Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications.
Genetic counseling: TUBB4A-related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of a de novo pathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals with TUBB4A-related leukodystrophy are not known to reproduce.
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