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Heterogeneity of Coenzyme Q10 Deficiency Patient Study and Literature Review

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Heterogeneity of Coenzyme Q10 Deficiency Patient Study and Literature Review NEUROLOGICAL REVIEW Heterogeneity of Coenzyme Q10 Deficiency Patient Study and Literature Review Valentina Emmanuele, MD; Luis C. Lo´pez, PhD; Andres Berardo, MD; Ali Naini, PhD; Saba Tadesse, BS; Bing Wen, MD; Erin D’Agostino, BA; Martha Solomon, BA; Salvatore DiMauro, MD; Catarina Quinzii, MD; Michio Hirano, MD oenzyme Q10 (CoQ10) deficiency has been associated with 5 major clinical pheno- types: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cer- ebellar ataxia, and isolated myopathy. Primary CoQ10 deficiency is due to defects in CoQ10 biosynthesis, while secondary forms are due to other causes. A review of 149 Ccases, including our cohort of 76 patients, confirms that CoQ10 deficiency is a clinically and ge- netically heterogeneous syndrome that mainly begins in childhood and predominantly manifests as cerebellar ataxia. Coenzyme Q10 measurement in muscle is the gold standard for diagnosis. Iden- tification of CoQ10 deficiency is important because the condition frequently responds to treat- ment. Causative mutations have been identified in a small proportion of patients. Arch Neurol. 2012;69(8):978-983. Published online April 9, 2012. doi:10.1001/archneurol.2012.206 Coenzyme Q10 (CoQ10 or ubiquinone) de- creased in 1 member of the family with similar ficiency in humans is associated with clini- phenotype and/or genetic mutation were con- cally heterogeneous diseases.1 Five ma- sidered to have CoQ10 deficiency. jor phenotypes have been described: (1) Dideoxy sequencing was performed on all encephalomyopathy, (2) cerebellar ataxia, exons and flanking intronic regions of genes involved in CoQ biosynthesis, associated with (3) infantile multisystemic form, (4) ne- 10 secondary CoQ10 deficiencies, or encoding pro- phropathy, and (5) isolated myopathy teins with similar function, structure, or both Table 1 ( ). as proteins associated with CoQ10 deficiency. In addition, we sequenced PSAP-encoding sa- METHODS posin B, a cytosolic protein that binds and trans- fers CoQ10, and POLG (eTable 1, http://www .archneurol.com). Seventy-six patients with CoQ10 deficiency (36 previously unreported) were studied at the H. Houston Merritt Clinical Research Center, Co- CLINICAL FEATURES lumbia University Medical Center, New York, New York, under the center’s institutional re- view board’s protocols. Coenzyme Q10 levels Since the first description of human ubi- were measured in muscle, cultured fibro- quinone deficiency, 113 patients have been 8,17 blasts, and/or lymphoblasts. Coenzyme Q10 reported (Tables 1, 2, and 3). Of 455 levels reduced more than 2 standard devia- patients referred to our center for pos- tions below mean control values were consid- sible CoQ10 deficiency from 1997 to 2010, ered deficient. Patients with CoQ10 levels de- 76 patients (64 families) had CoQ10 defi- ciency, 40 of which were previously de- Author Affiliations: Departments of Neurology (Drs Emmanuele, Lo´pez, Berardo, scribed. The reported patients and our 36 Naini, Wen, DiMauro, Quinzii, and Hirano; and Mss D’Agostino, Solomon, and Tadesse) and Pathology (Dr Naini), Columbia University Medical Center, New new patients composed 149 cases: 4 pa- York, New York; Human Genetics, PhD Program, University of Genoa, Genoa, tients with encephalomyopathy, 14 with Italy (Dr Emmanuele); and Institute of Biotechnology (Lab 139), Biomedical isolated myopathy, 17 with infantile- Research Center (CIBM), Health Science Technological Park (PTS), University of onset multisystemic disease, 11 with ne- Granada, Granada, Spain (Dr Lo´pez). phropathy (with our without sensorineu- ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 978 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Clinical Features of Major Forms of CoQ10 Deficiency Cases (New Responsible Genes (No. of Syndrome Cases), No. Clinical Features Natural History Patients/Families) Encephalomyopathy2-4 4 (0) Juvenile-onset mitochondrial Slow progression of None known myopathy, recurrent weakness myoglobinuria, encephalopathy Isolated myopathy4-7 14 (4) Juvenile- or adult-onset Slow progression of ETFDH (7/5) muscle weakness, weakness myoglobinuria, exercise intolerance, cramps, myalgias, elevated creatine kinase level Nephropathy8-16 11 (0) Infantile- or early May progress to renal failure, COQ2 (2/2) childhood-onset encephalopathy, may steroid-resistant nephrotic become fatal syndrome Infantile- or juvenile-onset Nephropathy typically COQ6 (8/4) steroid-resistant nephrotic progresses to renal failure, syndrome typically with seizures and ataxia may congenital sensorineural develop, may be fatal deafness Infantile multisystemic disease11-14 17 (2) Infantile-onset psychomotor Typically progresses rapidly COQ2 (3/3), PDSS2 (1/1), regression, with high mortality COQ9 (1/1), PDSS1 (2/1), encephalopathy, optic (9/17 = 53%) COQ6 (3/3) atrophy, retinopathy, hearing loss, renal dysfunction (mainly nephrotic syndrome) Cerebellar ataxia17-32 94 (23) Typically juvenile-onset Slow or minimal progression ADCK3 (22/15), APTX (12/8) cerebellar ataxia, of ataxia additional manifestations may occur Abbreviation: CoQ10, coenzyme Q10. ral hearing loss), 94 with cerebellar ataxia, and 9 with transplantation.13,15 In addition, liver, cardiac, and pan- atypical presentations. creatic involvement, as well as obesity have been de- Onset was predominantly in childhood (82% were aged scribed in literature and in our cohort.10,16,33 Eleven pa- Ͻ13 years) including 23% in infancy (aged Ͻ12 months). tients (65%) died in early infancy, and causes of death Onset during adolescence (7% were aged 13-18 years) were opportunistic infections, kidney failure, encepha- and adulthood (11% were aged Ͼ18 years) were uncom- lopathy, or multi-organ failure. mon. The mortality rate was low (8%) and mainly seen Early-onset isolated steroid-resistant nephrotic syn- in the infantile multisystemic and renal forms. drome owing to collapsing glomerulopathy and focal The encephalomyopathic form of CoQ10 deficiency, segmental glomerulosclerosis has been reported in manifesting as a triad of mitochondrial myopathy, re- 2 patients.12 Moreover, the association between current myoglobinuria, and encephalopathy, has been re- steroid-resistant nephrotic syndrome with sensorineu- ported in 4 patients (eTable 2).2-4 Neurologic features in- ral hearing loss has been described in patients with cluded cerebellar ataxia, seizures, mental retardation, mutations in the CoQ10 biosynthetic gene, COQ6; delayed motor development, progressive external oph- however, CoQ10 level was not measured in these thalmoplegia, and ptosis. patients (eTable 5).14 The myopathic form of CoQ10 deficiency presents with Cerebellar ataxia is the most common phenotype, with muscle weakness, myoglobinuria, exercise intolerance, 94 patients (including 23 new patients) (eTable 6).17-32 cramps, myalgia, and elevated creatine kinase. This con- Other manifestations include neuropathy, seizures, men- dition has been described in 10 patients.4-7 We identi- tal retardation, migraine, psychiatric disorders, muscle fied 4 additional patients (eTable 3). weakness and exercise intolerance, congenital hypoto- Among the 17 patients (including 2 new patients) with nia, upper motor neuron signs, dystonia and chorea, pto- the infantile multisystemic form, the combination of en- sis and ophthalmoplegia, retinitis pigmentosa, optic cephalopathy and nephropathy has been the most com- atrophy, oculomotor apraxia, deafness, lipomas, Dandy- mon presentation (eTable 4).8-14,33 Neurologic manifes- Walker syndrome, agenesis of corpus callosum, hypo- tations include psychomotor regression, ataxia, hypotonia, gonadism and other endocrinological problems, hypo- seizures, pyramidal syndrome, optic atrophy and reti- albuminemia, and hypercholesterolemia. nopathy, deafness, and Leigh syndrome. The renal in- Among the patients classified as atypical cases, there volvement is mainly nephrotic syndrome but occasion- were 2 adult sisters with childhood-onset Leigh syn- ally tubulopathy. Three patients required kidney drome, growth retardation, infantilism, ataxia, deaf- ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 979 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Laboratory Features of Major Forms of CoQ10 Deficiency Mitochondrial Respiratory Chain Syndrome Blood Lactate Serum Creatine Kinase Muscle Histology Enzyme Activitiesa CoQ10 Levels Encephalomyopathy Elevated in 3/3 patients Increased in 4/4 Mitochondrial changes ↓ IϩIII, IIϩIII in 4/4 3.7%-39% of normal in patients (2- to in 4/4 patients patients muscle, normal in 37-fold elevation) fibroblasts in 1 patient Isolated myopathy Elevated in 5/10 1.5- to 150-fold Mitochondrial changes ↓ IIϩIII ± other 12.4%-49% of normal patients elevation in 8/11 patients complexes 8/10 in muscle, normal in patients fibroblasts in 1 patient Isolated nephropathy Elevated in 1/2 patients NA Mitochondrial changes ↓ IϩIII, IIϩIII in 38% of normal in in 1 patient fibroblasts in 1 muscle in 1 patient, patient; ↓ IIϩIII in 17% of normal in muscle in 1 patient fibroblasts in 1 patient Infantile multisystemic Elevated in 8/9 patients NA Mitochondrial changes ↓ IIϩIII ± other 2.5%-37% of normal in disease in 4/8 patients complexes in muscle muscle, reduced in in 4/7 patients; ↓ fibroblasts in 10/11 IIϩIII fibroblast in 1; patients ↓ IIϩIII ± other complexes in liver in 2 Cerebellar ataxia Elevated in 11/34 20- to 23-fold elevation
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