Isolated Mitochondrial Myopathy Associated with Muscle Coenzyme Q10 Deficiency
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OBSERVATION Isolated Mitochondrial Myopathy Associated With Muscle Coenzyme Q10 Deficiency Seema R. Lalani, MD; Georgirene D. Vladutiu, PhD; Katie Plunkett, MS; Timothy E. Lotze, MD; Adekunle M. Adesina, MD, PhD; Fernando Scaglia, MD Background: Primary coenzyme Q10 (CoQ10) defi- partial reductions in complex I, I + III, and II + III ac- ciency is rare. The encephalomyopathic form, de- tivities with greater than 200% of normal citrate syn- scribed in few families, is characterized by exercise in- thase activity. The CoQ10 concentration in skeletal muscle tolerance, recurrent myoglobinuria, developmental delay, was 46% of the normal reference mean. The in vitro ad- ataxia, and seizures. dition of 50 µmol/L of coenzyme Q1 to the succinate cy- tochrome-c reductase assay of the patient’s skeletal muscle Objective: To report a rare manifestation of CoQ10 de- whole homogenate increased the succinate cyto- ficiency with isolated mitochondrial myopathy without chrome-c reductase activity 8-fold compared with 2.8- central nervous system involvement. fold in the normal control homogenates. Follow-up of the patient in 6 months demonstrated significant clini- Methods: The patient was evaluated for progressive cal improvement with normalization of creatine kinase muscle weakness. Comprehensive clinical evaluation and and lactate levels. muscle biopsy were performed for histopathologic analy- sis and mitochondrial DNA and respiratory chain en- Conclusions: The absence of central nervous system in- zyme studies. The patient began taking 150 mg/d of a volvement and recurrent myoglobinuria expands the clini- CoQ10 supplement. cal phenotype of this treatable mitochondrial disorder. The complete recovery of myopathy with exogenous Results: The elevated creatine kinase and lactate levels CoQ10 supplementation observed in this patient high- with abnormal urine organic acid and acylcarnitine pro- lights the importance of early identification and treat- files in this patient suggested a mitochondrial disorder. ment of this genetic disorder. Skeletal muscle histochemical evaluation revealed ragged red fibers, and respiratory chain enzyme analyses showed Arch Neurol. 2005;62:317-320 RIMARY COENZYME Q 10 ment and normalization of serum creatine (CoQ10) deficiency (Mende- kinase and lactate values. This report ex- lian Inheritance in Man tends the clinical spectrum of CoQ10 de- 607426) is rare and is char- ficiency to include isolated primary my- acterized by significant clini- opathy without ataxia, seizures, or cal heterogeneity. The clinical spectrum cognitive impairment. P 1-4 varies from encephalomyopathy, famil- ial cerebellar ataxia,5 and Leigh encepha- lopathy6 to widespread multisystem dis- REPORT OF A CASE ease.7 The encephalomyopathic form, Author Affiliations: described in 4 families,1-4 is characterized The patient was initially evaluated at 11.5 Departments of Molecular and by exercise intolerance, recurrent myo- years of age for progressive muscle weak- Human Genetics (Drs Lalani globinuria, developmental delay, ataxia, ness. He was a previously healthy, devel- and Scaglia and Ms Plunkett), and seizures. Herein, we describe a pa- opmentally normal child, born at 34 weeks’ Neurology (Dr Lotze), and tient with exercise intolerance, ragged red gestation to healthy, nonconsanguine- Pathology (Dr Adesina), Baylor fibers, muscle CoQ deficiency, and as- ous parents. Insidious onset of exercise in- College of Medicine, Houston, 10 Tex; and Departments of sociated muscle carnitine deficiency with tolerance and proximal muscle weakness Pediatrics, Neurology, and no evidence of recurrent myoglobinuria or began 4 months prior to evaluation, mani- Pathology, State University central nervous system involvement. Treat- fested by difficulty ascending stairs and lift- of New York, Buffalo ment with CoQ10 supplementation re- ing heavy objects. This was preceded by (Dr Vladutiu). sulted in significant clinical improve- constitutional fatigue for several months. (REPRINTED) ARCH NEUROL / VOL 62, FEB 2005 WWW.ARCHNEUROL.COM 317 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 METHODS A skeletal muscle biopsy was performed at 11.5 years of age. Cryostat sections of flash-frozen muscle were stained with he- matoxylin-eosin, the modified Gomori trichrome stain, succi- nate dehydrogenase, cytochrome-c oxidase, reduced nicotin- A B amide adenine dinucleotide dehydrogenase, and adenosine triphosphatase activities at pH 4.3 and 4.6. Muscle was fixed in 3% glutaraldehyde for electron microscopy. A blood speci- men for mitochondrial DNA mutation analysis was obtained from the proband. Mitochondrial DNA mutation analysis in the proband’s skeletal muscle and blood specimens were per- formed to analyze common point mutations (myopathy, en- cephalopathy, lactic acidosis, and strokelike episodes A3243G and T3271C; myoclonic epilepsy and ragged red fibers A8344G C D and T8356C; neuropathy, ataxia, and retinitis pigmentosa T8993G and T8993C; cardiomyopathy G8363A; and Leber he- redity optic neuropathy G11778A, G3460A, T14484C, and G14459A), deletions, and duplications. The respiratory chain (RC) enzyme analysis in skeletal muscle was performed using standard spectrophotometric analyses.8-11 The carnitine palmi- toyltransferase activity was quantified using the isotope- exchange method of Norum.12 Fatty acid–oxidation enzyme activities were evaluated by spectrophotometric assays with  chain-length specific substrates of -oxidation. The CoQ10 level was analyzed in skeletal muscle by using high- performance liquid chromatography with UV detection (275 13,14 nm) and using coenzyme Q9 as an internal standard. E F RESULTS Figure. Histochemical and electron microscopy images. A, Mild variation in fiber size (hematoxylin-eosin, original magnification ϫ400). B, Modified Gomori trichrome (original magnification ϫ400) with slightly granular fibers Skeletal muscle histochemical evaluation revealed rare suggestive of ragged red fibers (arrows). C, Periodic acid–Schiff (original pale-staining myofibers with the cytochrome-c oxidase magnification ϫ400) with many fibers showing increased subsarcolemmal stain and scattered ragged red fibers with the Gomori tri- ϫ glycogen content (arrow). D, Sudan black (original magnification 400) with chrome stain (Figure). On electron microscopy, there increased lipid droplets. E, Electron microscopy (original magnification ϫ5600) with increased lipid droplets (thin arrows) and subsarcolemmal was an increase in the number of mitochondria, al- accumulation of glycogen (thick arrow). F, Subsarcolemmal aggregate of though no abnormally shaped or enlarged mitochon- mitochondria, some of which have electron dense bodies (arrows) (original ϫ dria were found. A prominent increase in lipid droplets magnification 22400). and subsarcolemmal and intermyofibrillar accumula- tion of free glycogen were found. In muscle, total and He lost weight over this interval and complained of lower free carnitine values were 2.3 SDs below the normal ref- extremity muscle cramps. There was no history of un- erence mean. Fatty acid–oxidation enzymes and carni- explained fever, rash, ataxia, hearing loss, or seizures. tine palmitoyltransferase activities in muscle were nor- Family history was unremarkable for neuromuscular dis- mal. Common mitochondrial DNA point mutations and orders. On physical examination he was noted to have deletions were not detected in skeletal muscle or lym- significantly reduced proximal muscle strength at the phocytes. The RC enzyme analyses showed partial re- shoulders and the hips, with mild wasting of the shoul- ductions in complex I, I + III, and II + III activities (Table) der muscles. The Gower maneuver was noted when aris- with greater than 200% of normal citrate synthase activ- ing from a seated position. There was no evidence of oph- ity, suggestive of increased mitochondrial content and thalmoplegia or ataxia. His creatine kinase level was corroborating histochemical findings. Results of mag- elevated at 359 U/L (reference range, 55-215 U/L), his netic resonance imaging and magnetic resonance spec- lactate level was 33.33 mg/dL (3.7 mmol/L) (reference troscopy of the brain were normal. An echocardiogram range, 1.80-18.01 mg/dL [0.2-2.0 mmol/L]), urinalysis demonstrated normal cardiac function. The patient was did not reveal myoglobinuria, and urine organic acid treated with 150 mg/d of a CoQ10 supplement and 100 analysis detected abnormal metabolites including ethyl- mg/kg per day of carnitine for 3 months. On a 3-month malonic acid, methylsuccinic acid, hexanoylglycine, and follow-up visit, a remarkable improvement in muscle lactic acid. The plasma acylcarnitine profile exhibited el- strength was noted with increased proximal muscle evations of butyrylcarnitine, pentanoylcarnitine, hex- strength and absent Gower sign. Based on his consider- anoylcarnitine, octanoylcarnitine, and decanoylcarni- able improvement with antioxidant therapy, the CoQ10 tine, with no evidence of plasma total carnitine depletion. concentration was analyzed by high-performance liquid Nerve conduction velocity measurements were normal, chromatography in the original skeletal muscle speci- but the electromyogram showed low-amplitude poly- men and found to be 46% of the normal reference mean. phasic units consistent with myopathy. The in vitro addition of 50 µmol/L of coenzyme Q1 to (REPRINTED) ARCH NEUROL / VOL 62, FEB 2005 WWW.ARCHNEUROL.COM 318 ©2005 American Medical Association. All rights reserved.