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Phenotypic Variation in a Caucasian Kindred with Chorea-Acanthocytosis

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Authors:  Áine Merwick MB, PhD, Tzehow Mok MB, Brian McNamara MB, MD, Nollaig A. Parfrey MB, MD, Helena Moore MB, Brian J. Sweeney FRCP, Collette K. Hand PhD and Aisling M. Ryan MB, PhD

Article first published online:  6 DEC 2014 | DOI: 10.1002/mdc3.12117


Chorea-acanthocytosis (ChAc) is an autosomal recessive (AR) disorder caused by a VPS13A (CHAC) mutation on chromosome 9q21, encoding the chorein protein[1] for which a protein sorting role has been suggested.[1, 2]

Presentation is usually in the third to fifth decade with a progressive movement disorder (chorea, dystonia, bradykinesia, ataxia, or rigidity), seizures, and red cell acanthocytes.[1-5] Intrafamilial phenotypic variation is described, along with myopathy, neuropathy, and cardiomyopathy.[6-10]

Characteristic of ChAc are involuntary movements affecting face, tongue, and oropharynx. Involuntary vocalizations (phonic tics) are present in two thirds of cases.[11] Swallowing and speech difficulties may occur as a result of orofacial dystonia and pseudobulbar palsy, and ChAc may mimic anterior horn cell disease.[12]

ChAc can be diagnosed with some certainty on clinical grounds, with supporting evidence from reduced chorein expression on western blot.[10] This report highlights the spectrum of presenting features, severity, and variety of movement disorder, neuromuscular, and radiological features in a new, genetically confirmed ChAc kindred.

Methods

Three brothers with features suggestive of ChAc presented to neurology services. Blood samples were obtained from the 3 siblings, their parents, and their clinically unaffected brother. Genomic DNA was extracted (QIAamp Blood Kit; Qiagen, Hilden, Germany) and samples were assigned a unique “PATH” number. Haplotype analysis was performed by polymerase chain reaction genotyping of fluorescently labeled microsatellite markers from the VPS13A gene region. Genotypes of single-nucleotide polymorphisms (SNPs) in the locus were determined by sequencing using specifically designed primers. Mutation screening of exons 68 to 73 of VPS13A was performed by sequencing using previously reported primers.[13]

Results

Case 1

A 25-year-old Irish male developed unprovoked generalized seizures treated sequentially with valproate and levetiracetam, remaining seizure free for several years. He had phonic and orofacial motor tics. When reviewed at a specialist service 9 years later, he reported dysarthria and dysphagia, partly ameliorated by neck extension. Self-biting of tongue and lips necessitated mouth guard usage.

Orofacial tics included pursed lip movements with an audible “click.” Choreiform movements were evident in the left lower limb, with a “rubber man” irregular gait, truncal instability, and impulsivity. He had distal atrophy of limb musculature, but normal power and preserved reflexes. Creatine kinase (CK) level was elevated at 600 to 1,800 U/L (range, 40–180) with elevated transaminases and lactate dehydrogenase (LDH; Table 1, clinical features). Acanthocytes were detected on blood film.

Table 1. Clinical, neurophysiology, and radiology findings in a series of 3 brothers with ChAc
Case No. Age at Presentation Initial Main Presenting Feature Movement Disorder Neuromuscular Features Seizures EEG Blood Results Imaging
1 25 y Generalised seizure

Tics: motor and vocal at presentation

Subsequent choreiform lower-limb movements

Atrophy of distal lower-limb musculature Generalized Interictal EEG: abnormal with encephalopathic features and diffuse underlying slow wave activity

CK 670 to 1,800 U/L

(range, 40–180)

Acanthocytes detected

CT brain: normal
2 22 y Stammering Vocal tics

Ataxia and chorea

Orofacial dystonia including tongue

Tics (motor and verbal)

Axonal neuropathy (sensorimotor)

Muscle biopsy shows features of denervation/reinnnervation

Nil EEG: Normal

CK 300 to 3,800 U/L

(range, 40–180)

Acanthocytes detected

MRI brain: Normal
3 29 y Multiple generalized seizures

Subtle

Involuntary orofacial grimacing movements at presentation

Distal and proximal lower-limb muscle atrophy

Myopathic features on EMG

Generalized Interictal EEG: Abnormal showing encephalopathic pattern, with notched rhythmical 3 to 4 Hz delta and generalized irregular 5 to 6 Hz theta activity

CK 1,500 to 4,200 U/L

(range, 40–180)

Acanthocytes detected

MRI brain: Normal

MRI lower-limb musculature: normal

 

Case 2

A younger brother first attended neurology services at age 22 with stammering and dysfluency. Birth history and early milestones were normal. He attended third-level education. No movement disorder or abnormal signs were evident.

At age 29, he represented with a choreiform disorder, prominent orofacial dyskinesia, involuntary vocalizations, and dystonia. Continuous tongue and lip biting had caused soft tissue mutilation. Tongue protrusion dystonia caused severe dysphagia. Rigidity was present, with two to three beats of clonus. Gait examination showed dystonic upper- and lower-limb posturing and a bouncing or “rubber man”–type appearance[14] (see Video).

CK was elevated at 2,728 U/L (range, 40–180), aspartate aminotransferase (AST) 88 U/L (range, 6–42), alanine aminotransferase (ALT) 71 U/L (range, 4–45), and LDH 681 U/L (range, 220–450). Acanthocytes were detected on blood film. Nerve conduction studies and electromyography (EMG) showed features of a mild sensory axonal polyneuropathy, but no evidence of myopathy or denervation. Right quadriceps biopsy showed a single degenerated fiber undergoing necrosis with some small fibers and fiber grouping, reported as suggestive of a denervation/reinnervation pattern.

Now, 17 years after presentation, he requires feeding by percutaneous gastrostomy, botulinum toxin injection for orofacial dystonia, uses an electronic communication device, and is wheelchair bound.

Case 3

At age 29, another younger brother, who had attained third-level education, presented with de novo status epilepticus without a history of movement disorders. Subtle involuntary facial grimacing, temporalis thinning, and symmetrical distal lower-limb muscle wasting without fasciculations or weakness was noted.

Deep tendon reflexes were reduced at the ankle. Sensory examination was normal. Over time, mild wasting of vastus medialis and lateralis along with mild hip flexion weakness (Medical Research Council grading scale: 4–5/5) became appreciable. Tongue biting and teeth grinding was reported at age 34. Mild orofacial dystonia and chorea developed. Seven years following initial presentation, seizures remain well controlled and he is physically active and independently mobile.

Nonictal CK was elevated (1,500–4,200 U/L), with transaminases AST at 572 U/L (range, 6–42) and ALT at 687 U/L (range, 4–45). Acanthocytes were detected on blood film. EEG was encephalopathic with notched rhythmical 3 to 4 Hz delta and generalized irregular 5 to 6 Hz theta activity. Neuropsychological testing showed attentional deficits, but preserved memory and language.

Initial EMG showed mild myopathic motor units in proximal upper limbs (right deltoid and biceps brachii). Interestingly, repeat study 6 years later did not replicate these findings. MRI of proximal lower-limb musculature after presentation was normal, without significant atrophy. A repeat study (coronal T1, coronal short tau inversion-recovery, and axial T2 sequences) of proximal and distal lower limbs 6 years later remained normal.

Both parents are asymptomatic with normal CK and liver function tests, despite detection of acanthocytes in the 79-year-old father.

Genetics Results

Haplotype analysis of the VPS13A gene region in the family detected a shared haplotype in both parents, with each of the 3 affected sons homozygous across this 9.6 cM/5.2 Mb locus (Fig. 1). There is no known consanguinity. An unaffected brother does not carry a copy of the shared haplotype. Each parent has two distinguishable haplotypes across the interval.

Pedigree of ChAc family with haplotype data.Figure 1. Pedigree of ChAc family with haplotype data. Affected individuals are denoted by filled symbols. All participants have a unique sample (PATH) number. Genotypes for the investigated microsatellite markers and SNPs in the region are indicated. Haplotypes were generated based on parental genotypes. The location of the VPS13A gene is indicated and lies within the disease haplotype, which is bound by the box.

Mutation screening of exons at the C-terminus of the VPS13A gene identified a sequence variant c. 9431_9432delAG (p. 3134Rfsx5). Both parents are heterozygous for this mutation, all 3 affected sons are homozygous for the 2-base-pair (bp) deletion, and the unaffected son is homozygous wildtype (Fig. 1).

Discussion

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.[13] Electrophysiological tests may demonstrate a sensory axonopathy with normal conduction velocities and butreduced sensory action potentials, similar to case 2 here.[13] 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.[18] Reports of MRI imaging in ChAc describe symmetric increased signal in both gastrocnemius on T1 sequences, but not in our imaged patient.[19]

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.[22] McLeod syndrome has myopathic features and sensorimotor axonopathy, but, in contrast to ChAC, frequently has cardiomyopathy and inheritance is X linked.[18]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.[22]

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”).[1]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.[23]

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.

 

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