Neuroacanthocytoses (including VPS13A disease [chorea-acanthocytosis] and McLeod syndrome)

Neuroacanthocytoses are a group of rare genetic disorders that can affect neuropsychiatric function, movement, cognition, and multiple organ systems. They include several genetically distinct conditions, most notably VPS13A disease (preferred to the term chorea-acanthocytosis, as neither chorea nor acanthocytosis is required for diagnosis) and McLeod syndrome. Pantothenate kinase-associated neurodegeneration (PKAN) has also been included in some classifications because of its association with acanthocytosis and overlapping neurologic and psychiatric features, although it is more naturally classified within the neurodegeneration with brain iron accumulation (NBIA) group and is discussed further there. Huntington disease-like 2 (HDL2) has also historically been described as a neuroacanthocytosis, although its association with the group is less well established.

These are inherited genetic disorders, although the inheritance pattern varies: VPS13A disease and PKAN are autosomal recessive, McLeod syndrome is X-linked, and HDL2 is autosomal dominant. Absence of a relevant family history therefore does not exclude the diagnosis. McLeod syndrome predominantly affects males.

They can present with psychiatric features such as depression, anxiety, obsessive-compulsive symptoms, irritability, emotional instability, behavioural disinhibition, impulsivity, aggression, paranoia, and psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood and may precede the characteristic movement disorder. Psychotic disorders have been reported in VPS13A disease, McLeod syndrome, PKAN, and HDL2; in McLeod syndrome, psychosis may occur with otherwise preserved cognition and a clear sensorium. In VPS13A disease, prominent orofacial chorea and dystonia may be associated with involuntary tongue and lip biting with self-mutilation.

Other characteristic features include progressive movement disorders, which may include chorea, dystonia, tics, parkinsonism, dysarthria, and dysphagia, as well as seizures and cognitive decline. In VPS13A disease, prominent orofacial chorea and dystonia may cause involuntary tongue protrusion during feeding and involuntary vocalizations; peripheral neuropathy, reduced or absent tendon reflexes, impaired vibration sense, and progressive muscle weakness or wasting may also occur. PKAN is characterized by iron accumulation in the basal ganglia and may present with dystonia, rigidity, choreoathetosis, dysarthria, and pigmentary retinal degeneration. HDL2 produces a progressive Huntington disease-like phenotype with chorea, dystonia, and cognitive decline.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: cardiomyopathy and cardiac arrhythmias may occur, particularly in McLeod syndrome.

• Hematologic: acanthocytosis and laboratory evidence of hemolysis may occur, particularly in VPS13A disease and McLeod syndrome; acanthocytosis may also occur in a minority of individuals with PKAN and HDL2.

• Musculoskeletal: muscle weakness, wasting, and myopathy may occur in VPS13A disease and McLeod syndrome; osteopenia or osteoporosis and an increased risk of atraumatic fractures may occur in PKAN.

Early diagnosis is important to recognize these progressive neurodegenerative disorders, distinguish them from other causes of chorea, psychosis, seizures, and behavioural change, identify potentially serious complications such as dysphagia, aspiration, seizures, self-injury, cardiac disease, and progressive weakness, guide appropriate genetic counselling and family testing, and enable timely multidisciplinary treatment and supportive care to preserve function and quality of life.