Clinical Guidance

To date, available data are inconclusive with regard to genotype-phenotype correlations involving clinical manifestations and laboratory findings for VPS13A disease.

Source: GeneReviews — "VPS13A Disease"

Diagnostic Criteria

"VPS13A disease" refers to the disorder commonly known as chorea-acanthocytosis; the genetically precise term "VPS13A disease" is preferred because the presence of chorea and/or acanthocytosis is neither necessary nor sufficient to diagnose the disorder .

Suggestive Findings

VPS13A disease should be suspected in probands with the following clinical, laboratory, and imaging findings and family history. "Red flag" findings are summarized in , and more detailed information follows the table.

Table 1.

VPS13A Disease: Red Flag Findings

VPS13A Disease: Red Flag Findings

Clinical findings

| Triad of progressive movement disorder (e.g., chorea, dystonia, in later stages parkinsonism), cognitive alterations, behavioral alterations ("huntingtonism")

Source: GeneReviews — "VPS13A Disease"

Differential Diagnosis

Because of the protean manifestations of VPS13A disease, a wide range of disorders needs to be considered in the differential diagnosis, including the general categories of parkinsonian syndromes (see Parkinson Disease Overview), hereditary dystonia, choreiform and other movement disorders, epilepsy disorders, and neuromuscular disorders.

Table 4.

Genes of Interest in the Differential Diagnosis of VPS13A Disease

Gene(s) | Disorder | MOI | Features of Disorder

Overlapping w/VPS13A Disease | Distinguishing from VPS13A Disease

ANGPTL3

APOB | Hypobetalipoproteinemia (See APOB-Related Familial Hypobetalipoproteinemia.) | AR | • Acanthocytosis

• Dysarthria, neuropathy, areflexia

| • Absence of basal ganglia movement disorder

Source: GeneReviews — "VPS13A Disease"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with VPS13A disease, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with VPS13A Disease

Source: GeneReviews — "VPS13A Disease"

Clinical Guidance

Avoid the following:

• Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)

• Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)

Source: GeneReviews — "VPS13A Disease"

Therapies Under Investigation

Several studies showed pathologically elevated tyrosine kinase Lyn activity in individuals with VSP13A disease and in disease models [, , , ]. Lyn kinase inhibition was able to rescue the blood phenotype and the neuronal phenotype . This evidence encouraged off-label treatment with the tyrosine kinase inhibitor dasatinib in three affected individuals. Although the reduction of both elevated Lyn kinase activity and accumulated autophagy markers suggested target engagement in red blood cells during treatment, clinical parameters remained essentially unchanged; of note, no clinically relevant side effects occurred. Putative biomarkers such as creatine kinase, serum neurofilament levels, and acanthocyte count failed to show consistent effects .

Source: GeneReviews — "VPS13A Disease"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended . Table 7. Recommended Surveillance for Individuals with VPS13A Disease

Source: GeneReviews — "VPS13A Disease"