Early Clinical Heterogeneity in Choreoacanthocytosis

Background  Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene.

Objective  To describe the early clinical features and possible genotype-phenotype correlation in CHAC.

Design and Setting  Case series in a tertiary care center.

Patients and Main Outcome Methods  Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A.

Results  Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear.

Conclusions  These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.

Choreoacanthocytosis (CHAC) is an uncommon neurodegenerative disorder often posing a serious diagnostic challenge. It is characterized by a variable combination of involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy, which may take years to evolve into a classic multisystem involvement.¹ Symptoms typically begin between 20 and 40 years of age, but earlier and later onset occurs as well.² Initial presentation with choreoathetosis, orofacial dyskinesia, buccolingual self-mutilation, tics, and obsessive-compulsive symptoms is suggestive of CHAC. However, the early clinical course is occasionally dominated by dystonia,² parkinsonism,³ seizures,² lower motor neuron signs,⁴ depression, or psychosis.² The inheritance is usually autosomal recessive,¹ although apparent sporadic² and autosomal dominant instances are also known.⁵ When suspected, the diagnosis is supported by the presence of peripheral blood acanthocytosis, but this is not specific¹ and may appear only late.⁶

Since the recent mapping of the CHAC locus to 9q21-22⁷ and the subsequent identification of multiple pathogenic mutations in the gene encoding a sorting-associated protein named chorein,^8-10 definite diagnosis is now possible even in patients with atypical early manifestations. We focus on the marked clinical heterogeneity during early stages of the disease and describe 3 patients with CHAC confirmed by molecular analysis.

Since 2000, we have personally evaluated 3 patients with CHAC, diagnosed after excluding alternative possibilities, such as vitamin E and lipoprotein disorders, Wilson disease, Huntington disease, and McLeod syndrome. Their medical records were reviewed, with particular attention to the early clinical manifestations. The patients belong to 3 apparently unrelated Jewish families residing in Israel, without additional affected members. All studies were performed with informed consent of the participants.

To quantify the acanthocyte transformation, fresh peripheral blood samples were viewed after dilution in 0.9% isotonic sodium chloride and were serially studied by scanning electron microscopy after aging in EDTA from 0 to 6 hours, followed by fixation in 1% glutaraldehyde, in comparison with 3 healthy control samples.¹¹ Acanthocyte percentage was calculated as the mean of 10 sequential viewing fields.

Analysis for homozygosity with the 9q21 microsatellite markers⁷ was performed in patient 1 and her family. Patients 1 and 2 were further included in a multi-institutional study¹⁰ of the mutational spectrum of CHAC, and patient 3 was subsequently studied by screening all 73 exons of CHAC (now renamed VPS13A) for mutations.

Main clinical and laboratory findings at diagnosis are summarized in the Table>. All 3 patients exhibited distinct and atypical early manifestations. Patient 1 presented at the age of 41 years with involuntary movements, generalized seizures, and compulsive lip and tongue biting, which started 2 years previously, soon after her second pregnancy. Since late adolescence, she had experienced recurrent episodes of trichotillomania in stressful situations, only partially responsive to different behavioral and therapeutic interventions. She described difficulty in suppressing urges to pull her hair and a decrease in tension associated with the act. These were replaced by anxiety disorder following her second pregnancy.

Patient 2 was 37 years old when he was admitted because of infected mouth wounds and generalized seizures. The diagnosis of CHAC had been established elsewhere a year earlier with a history of progressive gait disorder and involuntary movements, followed by inappropriate behavior and compulsive lip and tongue biting, which evolved during 10 years. At age 34 years, when treated for a presumed obsessive-compulsive disorder, a transthoracic echocardiogram performed after exacerbation of tobacco-related chronic obstructive lung disease had shown asymmetric left ventricular hypertrophy, later confirmed as hypertrophic nonobstructive cardiomyopathy. His level of serum creatine kinase (CK) was 2146 U/L (normal level, <170 U/L), with normal CK–muscle-brain isoenzyme fraction, cardiac-specific troponin T concentration, electrocardiographic results, and Holter monitoring. The patient died at the age of 38 years, probably of a cardiac arrest.

Patient 3 presented at the age of 38 years with multiple generalized seizures and involuntary movements of 1-year duration. Evaluation 10 years earlier had disclosed diabetes mellitus, hepatosplenomegaly, a CK level of 2865 U/L, slightly elevated lactate dehydrogenase and liver enzymes, normal thyroid functions, and normal liver biopsy findings. Muscle biopsy results were interpreted as nonspecific myopathy, and lymphocyte carnitine palmitoyltransferase II and muscle respiratory chain enzyme function findings were normal. Because he was asymptomatic, idiopathic hyperCKemia was suspected. Three years later, after an episode of seizures, examination showed a persistent elevated CK level and hyporeflexia. Anticonvulsive treatment was initiated and maintained for the next 2 years, and he remained asymptomatic until the age of 37 years. Repeat muscle biopsy at the diagnosis of CHAC at the age of 38 years and reevaluation of the first biopsy samples demonstrated variation in the myofiber size, an increased number of internally displaced nuclei, and some angulated fibers. Results of enzyme histochemistry showed fiber type grouping, and no significant ultrastructural alterations were identified. These findings were consistent with chronic denervation and secondary myopathic changes. Results of a comprehensive cardiac evaluation were normal.

Homozygosity analysis in patient 1 provided evidence for linkage with the 9q21 markers, and mutational screening identified a homozygous approximate 7-kilobase deletion spanning exon 23, EX23del. Patients 2 and 3 were homozygous for a 1–base pair deletion in exon 46, 6059delC, leading to a shift in the reading frame and predicted to result in a premature stop codon. All available parents and 3 of 4 available siblings were heterozygous for the corresponding mutations.

Diagnosis of CHAC in these patients was based on the typical clinical and laboratory findings and was confirmed by molecular analysis. The full clinical spectrum developed late and was preceded by unusual and markedly variable early manifestations.

In patient 1, initial compulsive hair pulling preceded all other manifestations by 2 decades. Trichotillomania is an impulse control disorder, which has not been previously observed in CHAC, to our knowledge. Although it can occur in isolation, the known association with obsessive-compulsive symptoms, tics, and morphometric abnormalities in the lentiform nucleus provides the relevant link to her primary disease.¹² This patient also experienced postpartum deterioration, with the development of additional CHAC symptoms, which may suggest a modifying hormonal effect on the expression of the disease.

Patient 2 developed hypertrophic cardiomyopathy, which may have contributed to his death. In contrast to McLeod syndrome, heart involvement is not considered characteristic of CHAC.¹ This may be surprising in view of the high degree of chorein expression in the heart,⁹ but only instances of mitral valve prolapse,¹³ bradycardia,¹⁴ myocardial infarction,² and a biventricular disease in the proband’s niece¹⁵ have been described thus far. The normal cardiac evaluation results in patient 3, carrying the same genetic alteration, may imply a causally unrelated and genetically separate disorder. In fact, many of the early-onset hypertrophic cardiomyopathies prove to be hereditary and have a defined genetic basis. Therefore, the cause of the heart disease in this patient remains at present unknown.

In patient 3, raised CK levels and organomegaly were followed by a prolonged asymptomatic period and were misdiagnosed as idiopathic hyperCKemia. Similar presentation has not been reported in CHAC, to our knowledge, and is more characteristic of McLeod syndrome.¹ The origin of elevated CK levels in CHAC is unclear and may be multifactorial, with the contribution of neurogenic muscular atrophy, involuntary movements, and seizures.¹⁶ Myopathy is also mentioned,⁹ although histologically confirmed muscle changes have been regarded as secondary to chronic denervation,¹⁷ as in our patient. Tissue transglutaminase–mediated sarcolemmal alteration is another recently suggested mechanism for hyperCKemia in CHAC.¹⁶ It may be associated with the formation of inclusion bodies in some degenerating myofibers,¹⁶ which we did not see in our patient.

Our patients are homozygous for the EX23del or 6059delC mutations segregating autosomal recessive inheritance. To our knowledge, these mutations have not been identified in other patients with CHAC, and both are predicted to result in aberrant protein production.¹⁰ However, the phenotype associated with either seems to be markedly different. Whereas patients 2 and 3 manifested clinical and electrophysiologic signs of overt neuromuscular involvement accompanied by high CK levels, patient 1 showed only hyporeflexia but had a higher acanthocyte count (Table>). So far, no obvious genotype-phenotype correlation has emerged in CHAC.^10,18 High CK levels have been occasionally noted,¹⁸ and acanthocyte count does not seem to predict the severity of disease.¹ Therefore, our observation needs further confirmation and awaits functional analysis of chorein and its mutants.

Occurring worldwide in individuals of different ethnic background, CHAC has been previously described only once, to our knowledge, in Jewish patients.¹⁹ Similar to our patients with the 6059delC mutation, these 2 brothers were of Ashkenazi origin and manifested prominent neuromuscular involvement, although it presented at a later age. Taken together, it is conceivable that CHAC may be more frequent in the Jewish population than now appreciated. Given the apparent rarity of recurrent CHAC mutations,¹⁰ a common founder effect is possible among families with Ashkenazi ancestry.

In conclusion, our findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early clinical features may prevent misdiagnosis and enable appropriate genetic counseling.

Correspondence: Alexander Lossos, MD, Department of Neurology, Hadassah–Hebrew University Hospital, PO Box 12000, Jerusalem 91120, Israel (alos@hadassah.org.il).

Accepted for Publication: August 9, 2004.

Author Contributions:Study concept and design: Lossos and Meiner. Acquisition of data: Lossos, Dobson-Stone, Monaco, Soffer, Rahamim, Newman, Mohiddin, Fananapazir, Lerer, Linetsky, Reches, Argov, Abramsky, Gadoth, Sadeh, Gomori, Boher, and Meiner. Analysis and interpretation of data: Lossos, Dobson-Stone, Monaco, Soffer, Rahamim, Newman, Lerer, Linetsky, Reches, Argov, Abramsky, Gadoth, Sadeh, Gomori, Boher, and Meiner. Drafting of the manuscript: Lossos and Meiner. Critical revision of the manuscript for important intellectual content: Lossos, Dobson-Stone, Monaco, Soffer, Rahamim, Newman, Mohiddin, Fananapazir, Lerer, Linetsky, Reches, Argov, Abramsky, Gadoth, Sadeh, Gomori, Boher, and Meiner. Administrative, technical, and material support: Lossos, Mohiddin, Argov, Abramsky, and Meiner. Study supervision: Mohiddin, Fananapazir, Argov, and Abramsky.