What is chorea acanthocytosis and what are its clinical findings?

Chorea-Acanthocytosis: Definition and Clinical Findings

What is Chorea-Acanthocytosis?

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the VPS13A gene (chromosome 9q21) that codes for the protein chorein, characterized by progressive basal ganglia degeneration, involuntary movements, psychiatric symptoms, cognitive decline, and the presence of spiculated red blood cells (acanthocytes) in peripheral blood. 1, 2

• The disease typically presents with an average age of onset around 27 years (range 18-35 years), though manifestations can be variable 2
• ChAc belongs to the neuroacanthocytosis syndrome group, which combines neurological abnormalities with acanthocytes 3
• The inheritance pattern is autosomal recessive with genetic linkage to a 6-cM region of chromosome 9q21 2

Core Clinical Findings

Movement Disorders

The hallmark motor features include choreatic hyperkinesia and dystonia, with particular predominance in the orofacial region, resembling Huntington disease-like involuntary movements. 3, 4

• Orofacial dyskinesia is a characteristic finding that helps distinguish ChAc from other choreiform disorders 2
• Patients develop progressive involuntary movements affecting gait and motor coordination 4, 1
• Tics may be present as part of the movement disorder spectrum 2
• Motor clumsiness and unsteady gait are common early manifestations 4

Neuropsychiatric Manifestations

Psychiatric symptoms may dominate the clinical picture early in the disease course and include behavioral changes, affective disturbances, emotional instability, impulsivity, and aberrant behavior. 4, 2

• Personality changes related to basal ganglia dysfunction are prominent features 4
• Progressive cognitive deterioration occurs with mild to moderate cognitive decline 3, 4
• Repetitive activities and behavioral abnormalities are frequently observed 3
• Emotional lability is a common associated feature 4

Neurological Features

Seizures are a major neurological manifestation, often appearing as a presenting symptom, along with hyporeflexia and axonal polyneuropathy. 2, 5

• Seizures may precede other neurological symptoms by years (documented onset as early as age 35 in one case) 4
• Hyporeflexia is characteristic and helps differentiate ChAc from Huntington disease 2
• Axonal neuropathy with neuropathic changes on electromyography is present 3, 5
• Upper and lower motor neuron signs can occur, potentially mimicking motor neuron disease in atypical presentations 5

Neuroimaging Findings

Brain MRI characteristically shows marked atrophy of the caudate nucleus and putamen (striatal atrophy), which is a key diagnostic feature. 3, 4, 2

• Striatal atrophy is visible on structural imaging and correlates with clinical severity 3, 2
• 18-fluorodeoxyglucose PET scanning demonstrates hypometabolism in the striatum 2
• These imaging findings reflect progressive degeneration of the basal ganglia 4

Hematological and Laboratory Findings

Acanthocytes (10-40% of red blood cells) are detected on phase-contrast microscopy or electron microscopy of peripheral blood smears, though their absence does not exclude the diagnosis. 3, 2

• Critical caveat: Acanthocytes may be absent or appear late in the disease course, and ChAc can occur without detectable acanthocytes 3
• When acanthocytes are absent, chorein Western blot showing absent or markedly reduced chorein levels in erythrocyte membranes confirms the diagnosis 3
• Elevated creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels are common laboratory abnormalities 3
• Lipoprotein profiles are typically normal, distinguishing ChAc from abetalipoproteinemia 3, 2
• Kell antigen expression is normal, unlike McLeod syndrome (another neuroacanthocytosis syndrome) 3

Myopathy

Myopathy is part of the clinical spectrum, evidenced by elevated muscle enzymes (CPK and LDH). 3

Diagnostic Approach

Definitive diagnosis is established by either genetic analysis demonstrating VPS13A mutations or chorein Western blot showing absent/reduced chorein protein expression. 3, 1

• Genetic testing for VPS13A mutations provides molecular confirmation 1, 2
• Chorein Western blot is particularly useful when acanthocytes are not detected on blood smears 3
• Novel mutations continue to be identified, including double heterozygous mutations that may cause atypical presentations 5
• Molecular testing for Huntington's disease should be negative to exclude this more common cause of chorea 3