Early onset dystonia

Gene: TUBB4A

Green List (high evidence)

Comment from the Parkinson panel: Monoallelic mutations (de novo) cause hypomyelinating leukodystrophy 6. The phenotypic spectrum characterized by 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 and usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity. PMID: 27809427 (gene review). Monoallelic mutations also cause Dystonia (DYT4) laryngeal dysphonia or whispering dysphonia (also known as DYT4 dystonia), in which brain MRI is normal. Keep this gene in both this gene to both the dystonia panel and pd (complex parkinsonism). Discuss any potentially pathogenic result with clinician and considering MRI. Also consider adding to the hsp panel (can present as complex hsp, PMID: 26477786)

Created: 15 Dec 2016, 11:11 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 27809427

Comment on list classification: Discussed internally and decided to promote to green.

Created: 2 Sep 2016, 11:49 a.m.

Comment on list classification: A recent screening paper PMID: 26318963 "In accordance with previous work, our data indicate that TUBB4A coding mutations do not play a critical role in the broad population of isolated dystonia patients. Rather, isolated dystonia as seen in DYT4 might be an exceptional feature occurring in the heterogeneous phenotypic spectrum due to TUBB4A mutations."

Created: 25 Aug 2016, 10:47 a.m.

Comment on list classification: Promoted from amber to green due to feedback from Huw Morris (UCL).

Created: 19 Aug 2016, 9:30 a.m.

Is on the Complex Parkinson's Disease/Dystonia NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.

Created: 10 Jun 2016, 8:59 a.m.

Comment on list classification: Promoted to green due to information within the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual for dystonia.

Created: 10 Jun 2016, 7:37 a.m.

Comment on list classification: Insufficient families. Keep under review

Created: 27 May 2016, 9:25 a.m.