This report illustrates the variation in presenting features and temporal evolution of ChAc within a family, adding the phenotypic description clinically and with radiological characterization of its neuromuscular aspects.
Notable in this kindred is the hyper-CK-emia, muscle thinning, and variability in severity of neuromuscular involvement. Case 1 demonstrated generalized muscle atrophy and elevated CK. Case 2, with a more severe presentation overall, had an axonal polyneuropathy and a muscle biopsy showing mild denervation. Case 3 also had generalized muscle thinning, which evolved to measurable weakness over time, but without corresponding neurophysiological or MRI evidence of neuropathy or myopathy.
Neuromuscular features may be underappreciated in this hyperkinetic movement disorder, although amyotrophy featured in its early descriptions.[8, 9, 15] Pathophysiological correlates of muscle CK and transaminase elevation in ChAc is unclear.[13, 16, 17] Axonal neuropathy is described in ChAc, but may be limited to vibration sensation loss. Electrophysiological tests may demonstrate a sensory axonopathy with normal conduction velocities and butreduced sensory action potentials, similar to case 2 here. EMG and muscle biopsy in ChAc have been reported to have nonspecific myopathic changes.[5, 7] Myopathy may be progressive, characterized by distal muscle wasting and weakness, or can remain subclinical. CT imaging of leg muscles in one report showed a selective pattern of symmetric fatty change. Reports of MRI imaging in ChAc describe symmetric increased signal in both gastrocnemius on T1 sequences, but not in our imaged patient.
The differential diagnosis of a movement disorder with neuromuscular features includes mitochondrial disorders, GM2 gangliosidosis (Tay Sachs disease), or oculomotor apraxia type 2 as well other disorders associated with acanthocytes.[20-22] ChAc belongs to the neuroacanthocytosis group of progressive movement disorders that includes pantothenate-kinase associated neurodegeneration, Huntington's disease–like type 2, abetalipoproteinemia, hypobetalipoproteinemia, and McLeod syndrome. McLeod syndrome has myopathic features and sensorimotor axonopathy, but, in contrast to ChAC, frequently has cardiomyopathy and inheritance is X linked.Abetalipoproteinemia and hypobetalipoproteinemia share neuropathy, dysarthria, and areflexia with ChAc, but differ in their hallmark findings of retinopathy, steatorrhea, vitamin E deficiency, and absence of movement disorder.
Using a combination of haplotype analysis and mutation screening approach, the causative mutation was identified in this family, confirming autosomal recessive inheritance. Genotype data revealed a haplotype shared by both parents and supported the involvement of the VPS13A gene. Owing to the large gene size (73 exons), mutation screening began with exons at the 3′ end. The 2-bp deletion detected in exon 72 was previously reported as one of two distinct mutations in a compound heterozygote ChAc patient (“proband 29”).Our study is the first report of this mutation in a homozygous state. Both parents are heterozygous for the 2-bp deletion and remain asymptomatic, except for acanthocytes detected in the father. This is similar to a previous report of this single feature of ChAc in a heterozygous carrier in an AR choreoacanthocytosis pedigree.
The striking variability of presenting features in this kindred ranges from early dysarthria with a movement disorder to status epilepticus and distal muscle atrophy. Interestingly, the most severely affected sibling (case 2) has a normal EEG and no seizures. Chorea, gait abnormalities, and phonic tics are prominent features in cases 1 and 2, but not in case 3. Absence of clear markers of disease severity or progression is noted in this family and is a challenge in ChAc patient management.
Although dystonia, chorea, dysarthria, and dysphagia are common presenting features of ChAc, this kindred illustrates the variability in phenotype, presentation, and progression. A movement disorder combined with neuromuscular features should prompt consideration of the diagnosis of ChAc.