Clinical characteristics: VPS13A disease, caused by VPS13A loss-of-function pathogenic variants, is characterized by a spectrum of movement disorders (chorea, dystonia, tics, sometimes parkinsonism); predominant orofacial choreic and dystonic movements and tics (with involuntary tongue protrusion on attempted swallowing, habitual tongue and lip biting resulting in self-mutilation, involuntary vocalizations); dysarthria and dysphagia; psychiatric, cognitive, and behavioral changes ("frontal lobe type"); seizures; and progressive neuromuscular involvement. Huntingtonism (triad of progressive movement disorder and cognitive and behavioral alterations) is a typical presentation. Phenotypic variability is considerable even within the same family, including for monozygotic twins. Mean age of onset is about 30 years. VPS13A disease runs a chronic progressive course and may lead to major disability within a few years. Some affected individuals are bedridden or wheelchair dependent by the third decade. Age at death ranges from 28 to 61 years; several instances of sudden unexplained death or death during epileptic seizures have been reported.

Diagnosis/testing: The diagnosis of VPS13A disease is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13A identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for VPS13A disease. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields of neurology, psychiatry, physiatry, physical therapy (PT), occupational therapy (OT), speech-language therapy, feeding, neuropsychology, and medical genetics. Pharmacotherapy for movement disorders may include dopamine antagonists/depleters such as atypical neuroleptics or tetrabenazine (or its derivatives) for limb and trunk dystonia and orofaciolingual dystonia (which may also benefit from botulinum toxin). Issues with mobility, activities of daily living, and need for assistive devices can be addressed by physiatry, PT, and OT. In persons with dysphagia, feeding assistance can include speech therapy and gastrostomy tube placement as needed to reduce weight loss and/or risk of aspiration. For dysarthria or mutism, therapy can include the use of technical means for augmentative and alternative communication, such as speech-generating devices. Seizure management can include use of phenytoin, clobazam, valproate, and levetiracetam. For psychiatric/behavioral issues, antidepressant or antipsychotic medications are used per conventional approaches.

Surveillance: Regular monitoring of existing manifestations, the individual's response to pharmacotherapy and other supportive care, and the emergence of new manifestations is recommended per the multidisciplinary treating specialists.

Agents/circumstances to avoid: Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake) and anticonvulsants that may worsen involuntary movements (e.g., carbamazepine, lamotrigine).

Genetic counseling: VPS13A disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a VPS13A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the VPS13A pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.