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Congenital Megaconial Myopathy Due to a Novel Defect in the Choline Kinase Beta Gene

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Congenital Megaconial Myopathy Due to a Novel Defect in the Choline Kinase Beta Gene OBSERVATION Congenital Megaconial Myopathy Due to a Novel Defect in the Choline Kinase Beta Gene Purificacion Gutie´rrez Rı´os, PhD; Arun A. Kalra, MD; Jon D. Wilson, MD; Kurenai Tanji, MD; Hasan O. Akman, PhD; Estela Area Go´mez, PhD; Eric A. Schon, PhD; Salvatore DiMauro, MD Objectives: To describe the first American patient with mitochondrial respiratory chain, and sequencing of the a congenital muscle dystrophy characterized by the pres- CHKB gene. ence in muscle of gigantic mitochondria displaced to the periphery of the fibers and to stress the potential origin Main Outcome Measures: Definition of unique mi- and effects of the mitochondrial changes. tochondrial changes in muscle. Results: This patient had the same clinical and labora- Design: Case report and documentation of a novel mutation in the gene encoding choline kinase beta tory features reported in the first cohort of patients, but (CHKB). he harbored a novel CHKB mutation and had isolated cy- tochrome c oxidase deficiency in muscle. Setting: Collaboration between 2 tertiary care aca- Conclusions: Besides confirming the phenotype of CHKB demic institutions. mutations, we propose that this disorder affects the mi- tochondria-associated membrane and the impaired phos- Patient: A 2-year-old African American boy with weak- pholipid metabolism in the mitochondria-associated mem- ness and psychomotor delay. brane causes both the abnormal size and displacement of muscle mitochondria. Interventions: Detailed clinical and laboratory stud- ies, including muscle biopsy, biochemical analysis of the Arch Neurol. 2012;69(5):657-661 ECENTLY,MITSUHASHI AND mitochondrial dysfunction may have an coworkers1 described 15 important role in pathogenesis. patients with a new con- genital myopathy charac- terized clinically by early- METHODS onset muscle weakness and mental R REPORT OF A CASE retardation. The hallmark of the disease was the presence in the muscle biopsy specimen of greatly enlarged mitochon- A 2-year-old African American boy was born dria displaced to the periphery of the fi- after a normal pregnancy and delivery to a 32- year-old woman, who had chronic hyperten- bers. Ten of their patients were Turkish; sion, Wolff-Parkinson-White syndrome, and 4, Japanese; and 1, British, and they all har- type 2 diabetes mellitus. He was the only child bored a variety of mutations in the gene of this nonconsanguineous couple. Apgar scores Author Affiliations: encoding choline kinase beta (CHKB), the were 8 at 1 minute and 9 at 5 minutes; head Author Affil Departments of Neurology enzyme that catalyzes the first step in the circumference was 35 cm; length, 47 cm; and Departments (Drs Gutie´rrez Rı´os, Tanji, weight, 2.94 kg. Soon after he was discharged Gutie´rrez Rı´ Akman, Area Go´mez, Schon, de novo biosynthesis of phosphatidyl cho- Area Go´mez home, the mother noticed rhythmic jerking of and DiMauro), Pathology line (PtdCho) and phosphatidylethanol- DiMauro), P (Dr Tanji), and Genetics and amine (PtdEtn) via the Kennedy path- arms with stiff legs, occurring 3 to 4 times per Tanji), and G Development (Dr Schon), way. We now report an African American night. These episodes were labeled “muscle Developmen Columbia University Medical boy with the same clinical and pathologi- spasms” by the general practitioner. Columbia Un When first seen at age 11 months, the child Center, New York, New York; cal features and a novel mutation in CHKB. Center, New and Departments of Neurology could roll over both ways, sit without support and Departm (Dr Kalra) and Pathology Although the muscle biopsy specimen for 1 minute (if placed), stand holding onto a (Dr Kalra) an (Dr Wilson), Louisiana State in our patient also shows dystrophic fea- chair for a few seconds, and speak a few words. Wilson), Lou University Health Sciences tures, we think that the striking mitochon- At age 22 months, he was still not able to sit University H Center, Shreveport. drial abnormalities cannot be ignored and up and did not utter any intelligible word. Center, Shre ARCH NEUROL / VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM 657 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A B C D Figure 1. Muscle biopsy specimen, light microscopy. A, Variation in fiber size, occasional basophilic regenerating fibers, and irregularly distributed areas of granular basophilic material (hematoxylin-eosin, original magnification ϫ200). B, The coarse granules were highlighted by the modified Gomori trichrome stain (original magnification ϫ200). C and D, The granule also stained with cytochrome c oxidase (C) and succinate dehydrogenase (D) (original magnification ϫ200). Scattered fibers showed absence of staining for cytochrome c oxidase and succinate dehydrogenase except in the areas of abnormal mitochondrial accumulation. At age 25.5 months, physical examination showed an irri- HISTOLOGY AND BIOCHEMISTRY table and uncooperative child, who fell asleep intermittently. Head circumference was 51 cm; weight, 12.5 kg; and height, Histochemical studies of muscle using 8-µm-thick sections 211 cm. He had a broad flat face, large philtrum, wide nasal were carried out as described.2 The activities of respiratory bridge, and low-set ears. There was no organomegaly. Neuro- chain enzymes were measured in 10% muscle extracts as pre- logical examination showed normal cranial nerves but bilat- viously described.3 eral facial weakness. There was marked hypotonia (on vertical suspension, he slipped through the examiner’s hands) and limb MOLECULAR ANALYSIS weakness, more pronounced in the legs. Sensory examination appeared normal and there was no ataxia, tremor, or nystag- Total DNA was extracted from muscle by standard procedures mus. He had episodes of unresponsiveness, with staring, drool- (Purogene; Gentra System Inc) according to the manufactur- ing, and slow turning of the head and eyes to one side. Al- er’s instructions. The entire coding sequence of CHKB was am- though these appeared to be seizures, the electroencephalogram plified by polymerase chain reaction using specific primers de- was normal. scribed by Mitsuhashi et al.1 The polymerase chain reaction Chromosomal analysis was normal. Normal laboratory ex- fragments were sequenced with an ABI 3130XL genetic ana- aminations included serum lactate and pyruvate levels, car- lyzer (Applied Biosystems). diac evaluation, nerve conduction velocities, and brain audi- tory evoked responses. The serum creatine kinase level was consistently elevated and varied between 318 and 522 U/L (nor- RESULTS mal, Ͻ176 U/L) (to convert to microkatals per liter, multiply by 0.0167). Electromyography showed polyphasic units with low amplitudes, consistent with myopathy. Brain magnetic reso- A left quadriceps muscle biopsy specimen was snap- nance imaging at 1 year of age showed prominent cerebrospi- frozen in isopentane–liquid nitrogen and cryosections nal fluid spaces over the frontal convexities and ventricular en- were stained with a standard battery of histological and largements of the lateral ventricles. histochemical reactions (Figure 1). Dystrophic fea- ARCH NEUROL / VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM 658 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table. Respiratory Chain Enzyme Activities in the Patient’s Musclea Controls, Activity, Patient, Activity Enzyme/Complex Mean±SD (% of Normal) 4.28 µm NADH–cytochrome c reductase 0.319±0.11 0.407 (128) NADH–CoQ reductase 0.119±0.01 0.099 (83) Succinate–cytochrome 0.071±0.02 0.066 (93) c reductase Cytochrome c oxidase 0.283±0.05 0.086 (30) SDH 0.101±0.05 0.048 (48) Abbreviations: CoQ, coenzyme Q10; NADH, reduced nicotinamide adenine dinucleotide; SDH, succinate dehydrogenase. a Activities are micromoles substrate used/minute/gram fresh tissue. Values are corrected for citrate synthase activity. Normal values are the mean of 78 samples ± SD. Figure 2. Ultrastructural study demonstrated the presence of markedly enlarged mitochondria (“megaconia”) with abnormal cristae (electron microscopy, original magnification ϫ25 000). No paracrystalline inclusions were noted. p. E292X E tures, evident in the hematoxylin-eosin stain (Figure 1A), YTHEG A A WP F included extreme variation in fiber size, excessive inter- T A T A C T C A C G A G to T G G C C T T T C T A A stitial fibrosis, and necrotic “hyaline” fibers. The most X striking changes, however, were seen in the modified Go- mori trichrome stain (Figure 1B) and in the histochemi- cal reaction for cytochrome c oxidase (Figure 1C). Greatly enlarged mitochondria (looking like dabs rather than points) were apparent at the periphery of most fibers, leav- ing the central areas empty. Electron microscopy confirmed the presence of giant 4 mitochondria (megaconia ), containing densely packed Figure 3. Electropherogram showing the p.E292X homozygous mutation and whorled cristae (Figure 2). detected in the eighth exon of the patient’s choline kinase beta gene (CHKB). Biochemical analysis of mitochondrial enzymes showed Nucleotides are denoted by the colors of the corresponding peaks. Each slightly increased activity of citrate synthase, a matrix pro- codon is labeled with the single letter identifying the encoded amino acid. tein and a good marker of mitochondrial mass, suggest- ing that the increased volume of mitochondria made up mitochondria that were not only gigantic but also pecu- for the lack of organelles in the empty areas. When the liarly displaced toward the periphery of muscle fibers,
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