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Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred

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Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred OBSERVATION Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred Antonio Velayos-Baeza, PhD; Elke Holinski-Feder, MD, PhD; Birgit Neitzel; Benedikt Bader, MD; Edmund M. R. Critchley, DM(Oxon), FRCP; Anthony P. Monaco, MD, PhD; Adrian Danek, MD; Ruth H. Walker, MB, ChB, PhD Objective: To determine the molecular nature of the neu- Main Outcome Measures: Mutations in the VPS13A rological disease in the seminal family reported by Critch- gene. ley et al in the 1960s, characterized by a hyperkinetic move- ment disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syn- Results: A mutation was identified in the VPS13A drome, subsequently termed neuroacanthocytosis, has been gene, responsible for autosomal recessive chorea- applied to symptomatically similar, but genetically distinct, acanthocytosis. Haplotype reconstruction suggested that disorders, resulting in clinical and diagnostic confusion. this mutation was homozygous in the proband. Design: DNA analysis. Conclusion: These findings strongly support the diag- Setting: Molecular biology research laboratories. nosis of chorea-acanthocytosis as the disorder de- scribed in the original report. Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky. Arch Neurol. 2011;68(10):1330-1333 EUROACANTHOCYTOSIS X-linked McLeod syndrome,8 autosomal (NA) is an umbrella term recessive pantothenate kinase–associ- for a genetically and phe- ated neurodegeneration,9 and autosomal notypically heteroge- dominant Huntington disease–like 2.10 neous group of neuro- Chorea-acanthocytosis and McLeod syn- Nlogical conditions that occur together with drome are considered the “core” NA spiny red blood cells known as acantho- syndromes, as acanthocytosis is a fre- cytes. Some of the earliest cases of NA re- quent finding in both disorders, while it ported in the Western literature were given is only occasionally seen in Huntington the eponym Levine-Critchley syndrome in disease–like 210 and pantothenate kinase– Author Affiliations: The recognition of the work of Irvine Levine, associated neurodegeneration.9 Wellcome Trust Centre for MD, and Edmund Critchley, DM(Oxon), From the literature, all of the Critchley Human Genetics, Oxford FRCP. In the 1960s, these authors inde- et al cases2,3 appear to have a phenotype (Drs Velayos-Baeza and pendently reported a neurological condi- identical to that seen in patients in whom Monaco), and University of tion characterized by acanthocytes and a molecular diagnosis of ChAc has been con- Central Lancashire, Preston 4,5,11 (Dr Critchley), England; normolipoproteinemia in patients from 3 firmed, but the same does not apply to 1 Medizinisch Genetisches different families from New England, Ken- the New England family described by Zentrum (Dr Holinski-Feder tucky,2 and the United Kingdom.3 Levine,1 and no assumption can be made in and Ms Neitzel) and Advances in molecular medicine have this regard without genetic testing. Neurologische Klinik led to the recognition of several different A nephew of the proband from the origi- und Poliklinik, disorders covered by the term neuroacan- nal Critchley et al Kentucky pedigree con- Ludwig-Maximilians-Universita¨t thocytosis4,5 and have made contempo- tacted one of us (R.H.W.) via the Internet, (Drs Bader and Danek), rary use of this ambiguous term obsolete, expressing an interest on behalf of the fam- Munich, Germany; and apart from as a descriptor for a group of ily in participating in any further research Department of Neurology, James J. Peters Veterans Affairs hyperkinetic disorders in which acantho- on the disorder affecting his uncle. Samples Medical Center, Bronx, and cytosis may be seen. The main NA syn- were obtained from several surviving fam- Mount Sinai School of dromes are defined by at least 4 geneti- ily members allowing us to determine the Medicine, New York, cally distinct conditions: autosomal molecular nature of the neurological dis- New York (Dr Walker). recessive chorea-acanthocytosis (ChAc),6,7 ease in this seminal NA family. ARCH NEUROL / VOL 68 (NO. 10), OCT 2011 WWW.ARCHNEUROL.COM 1330 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A 1 2 3 4 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 I 1 273 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 II 1 2 3 4 5 III B C A T G T A A T A G C T C T A C G A A G A A A T T A T C T T C C Male Neurological illness Female Acanthocytosis Deceased Friedreich ataxia-resembling disorder Control Original proband Family members first tested (whole-gene mutation screening) Additional family members analyzed II-29 Analyzed family members carrying mutation c.7867C > T (heterozygous) Black Data as in original article2 Blue New data, not in original article2 C A T G T A A T A G C T C T A C G A A G A A A T T A T C T T C C His Val Ile Ala Leu Arg Arg Asn Tyr Leu Pro T Stop Figure. Updated pedigree for the Kentucky family and their mutation. A, Information about all family members examined by Critchley et al (original Figures 4 and 6 from Critchley et al2), with new data shown in blue. The proband and family members tested in the present work are indicated. B, Chromatograms obtained after sequencing exon 56 of the VPS13A gene in an unaffected individual (control) and in the Kentucky family member II-29 showing the CϾT transition at position c.7867 (p.R2623X) detected in this family. Identical chromatograms showing this mutation in heterozygosis were obtained for family members carrying haplotype 1 (eTable 3 and eFigure, http://www.archneurol.com) as well as for “proband 23”11 and her father. METHODS (II-6, II-29, II-30, II-31, and II-32) of an affected indi- vidual would be a heterozygous carrier of a VPS13A mu- To determine whether the original condition reported for this tant allele. Blood samples were collected from family mem- family was indeed ChAc, we screened the causative gene, bers II-29, II-30, II-31 (presumably heterozygous), II-7 VPS13A, for mutations.11 The study was approved by the rel- (probably heterozygous), and I-8 (50% probability of being evant institutional review boards. Consent was obtained and heterozygous). After DNA amplification and sequenc- DNA was isolated from blood (Nucleon BACC2 kit; Tepnel Life ing, a nonsense mutation in exon 56 of the VPS13A gene Sciences, Manchester, England) or saliva (Oragene OG-500; (c.7867CϾT; p.R2623X) was found in family member DNA Genotek, Kanata, Ontario, Canada) samples from the ap- II-7. We then checked for this mutation in the other 4 propriate family members. For the initial mutation screening, available samples and found this mutation in all indi- all translated exons plus flanking regions were amplified by poly- viduals (Figure, B). This mutation has previously been merase chain reaction and sequenced using standard proto- described in a patient with ChAc (“proband 23”), re- cols. For genotyping, 10 polymorphic microsatellite markers 11 on chromosome 9 flanking the VPS13A gene and single- ported as compound heterozygous. nucleotide polymorphism rs10869920 (c.9077-133, intron 67) A second change was also detected in all 5 analyzed were analyzed (eTable 1, http://www.archneurol.com). Hap- samples in the amplified flanking region of exon 68 lotypes were constructed manually by minimization of recom- (c.9077-262CϾT, in intron 67). This change does not bination events between markers and confirmed using Mer- appear as a single-nucleotide polymorphism in any da- lin.12 Original medical records from the initial evaluation of the tabase and we could not detect it in 180 control chro- proband at the University of Kentucky, Lexington, were re- mosomes. However, its location in an intronic position viewed for additional information. far away from the splicing consensus sequences sug- gests that it probably does not have any pathogenic effect. RESULTS To have a clearer genetic picture for this family, ad- ditional (saliva) samples from other available poten- Part A of the Figure shows the updated pedigree of the tially informative members were collected (Figure, A) to Kentucky family reported by Critchley et al.2 The pro- perform genotyping. These samples were examined for band’s only surviving sibling (I-8 in the Figure), now aged the 2 changes mentioned earlier. Blood samples were ob- 78 years, has features consistent with Parkinson dis- tained from both parents of proband 23. This family trio ease. No family members were affected outside the pro- was analyzed as described earlier and additionally for the band’s generation. If the underlying disease in this fam- 2 mutations previously reported (c.7867CϾT and ily is autosomal recessive ChAc, any direct descendant c.1208_1211del),11 which we found were from paternal ARCH NEUROL / VOL 68 (NO. 10), OCT 2011 WWW.ARCHNEUROL.COM 1331 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 and maternal origin, respectively. Haplotypes were con- cidental. The presence of acanthocytosis in confirmed structed with these data (eTable 2) and for all analyzed or deduced heterozygotes I-1, I-6, and II-7 in the origi- individuals and all family members for whom they could nal report2 is intriguing. Heterozygotes have not been be deduced (eTable 3 and eFigure). routinely examined using a standard protocol for the Medical records from the evaluation of the proband presence of hematological abnormalities, and indeed, at the University of Kentucky in the 1960s confirmed the the detection of acanthocytes is often problematic even presence of marked dysarthria, dysphagia, weight loss, in affected subjects; thus, the effect of a single mutation hypotonia, areflexia, distal sensory loss, chorea, dysto- on erythrocyte membranes remains an unanswered nia, and severe tongue biting.
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