Clinical Guidance

TUBB4A-related neurologic disorders have a heterogeneous presentation and represent a spectrum of disease. Two primary phenotypes have emerged, TUBB4A-related leukodystrophy and DYT-TUBB4A (previously called DYT4 dystonia). TUBB4A-related leukodystrophy typically presents in childhood; age of onset ranges from a few months in more severe forms to later childhood or adulthood in some instances of isolated hypomyelination . The disorder is progressive and the rate of progression varies with disease severity. DYT-TUBB4A, formerly known as whispering dysphonia, is a rare cause of isolated dystonia that ranges from mild to severe with onset from early childhood to the third decade of life. While spasmodic dysphonia and/or craniocervical dystonia are often the presenting signs, progression to limbs and/or generalized dystonia is common . Laryngeal dystonia is the most common feature, present in more than three quarters of affected individuals . Brain MRI is typically normal. To date, at least 200 individuals have been identified with a pathogenic variant in TUBB4A . The following description of the phenotypic features associated with this condition is based on these reports. Table 2. TUBB4A-Related Neurologic Disorders: Comparison of Clinical Manifestations Clinical Manifestations | Frequency of Neurologic Findings TUBB4A-related leukodystrophy1 | DYT-TUBB4A2

Diagnostic Criteria

No consensus clinical diagnostic criteria for TUBB4A-related neurologic disorders have been published to date.

Suggestive Findings

TUBB4A-related neurologic disorders should be suspected in individuals with the following clinical and brain imaging findings and family history. Neurologic and neurodevelopmental features variably reported in affected individuals include:

• Neurodevelopmental delays

Management Guidelines

Standard of care guidelines have been proposed for TUBB4A-related leukodystrophy .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TUBB4A-related neurologic disorders, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. TUBB4A-Related Neurologic Disorders: Recommended Surveillance