Heterogeneity of Coenzyme Q10 Deficiency Patient Study and Literature Review

NEUROLOGICAL 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 phenotypes: 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 cases,C including our cohort of 76 patients, confirms that CoQ10 deficiency is a clinically and genetically 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 treatment. 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) decreased 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 review 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 deficiency, 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

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

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 Mitochondrial changes Reduced in 27/51 4%-66% of normal in patients in 2 patients, normal in 15/49 patients patients in muscle muscle, reduced in in 1 patient fibroblasts in 18/30 patients

Abbreviations: CoQ10, coenzyme Q10; NA, not available. a Mitochondrial changes included ragged-red fibers, cytochrome c oxidase–negative fibers, and lipid accumulation.

Table 3. Clinical Response to CoQ10 Supplementation in Major Forms of CoQ10 Deficiency

Syndrome (No. of Patients) CoQ10 Doses; Duration Response to Therapy Encephalomyopathy (4) 150 mg/d; 3-8 mo Improvement of muscle symptoms in 4/4 and encephalopathy in 1 patient Isolated myopathy (8) 150-500 mg/d; 4-12 mo Improvement in 6 patients Isolated nephropathy (4) 30 mg/kg/d-100 mg/d; 2-50 mo Reduced proteinuria in 3 patients; hearing improvement in 1/2 patients; no follow-up data in 1 patient Infantile multisystemic disease (4) 30 mg/kg/d-300 mg/d; 5-36 mo Improvement of myopathic symptoms and stabilization of encephalopathy in 1 patient; neurological, but not renal improvement in 1 patient Cerebellar ataxia (54) 5 mg/kg/d-3000 mg/d; 1 mo-12 y Improvement of muscle symptoms in 13/20 patients; seizures in 3/14 patients; ataxia in 25/54 patients.

Abbreviation: CoQ10, coenzyme Q10.

ness, and lactic acidosis,34 a 4-year-old girl with cardio- mitochondrial proliferation or lipid droplets, but they can faciocutaneous syndrome,35 2 unrelated patients with be normal or show only nonspecific changes. neonatal hypotonia and infantile spasm (1 reported),36 Reduced biochemical activities of respiratory chain 2 sisters with adult-onset cerebellar ataxia and ne- complexes, in particular complexes IϩIII (nicotin- phrotic syndrome, and a 16-year-old girl with onset at amide adenine dinucleotide–cytochrome c oxidoreduc- age 4 years of exercise intolerance, fatigue, recurrent head- tase) and complexes IIϩIII (succinate–cytochrome c oxi- aches, short stature, deafness, retinopathy, and mental doreductase) in muscle, suggest CoQ10 deficiency, retardation. One new patient was the father of a child with although activities of these enzymes may be normal par- cerebellar ataxia (P119 in eTable 6) who had mild cre- ticularly when the deficiency is mild. Reduction of these atine kinase elevation but normal examination and brain enzyme activities and deficiency of CoQ10 in skin fibro- magnetic resonance imaging results. blasts can be an important confirmation of ubiquinone deficiency; however, normal levels do not exclude defi- DIAGNOSIS ciency in muscle. Direct measurement of CoQ10 in skel- etal muscle by high-performance liquid chromatogra- Initial biochemical evaluation of patients with sus- phy is the most reliable test for the diagnosis. In contrast, pected CoQ10 deficiency should include blood lactate mea- plasma concentrations of ubiquinone are significantly in- surement, although normal values do not exclude ubi- fluenced by dietary uptake, therefore not reliable. Mea- quinone deficiency. Muscle biopsies occasionally show surements of CoQ10 in peripheral blood mononuclear cells

ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 980

PDSS1 PDHC PDSS2

Para-hydroxybenzoate Decaprenyl-PP Acetyl CoA

COQ2

Krebs cycle Decaprenyl-PHB COQ3 COQ4 H+ COQ5 + + + H NADH FADH2 COQ6 H H ADP ATP COQ7 ADKC3 COQ9 Matrix

– e – – Inner e e e– Cyt c membrane e– CoQ10

Complex I Complex II Complex III Complex IV Complex V

Outer membrane

Figure. Biosynthesis of coenzyme Q (CoQ)10. Mutations in CoQ10 biosynthetic genes (red ovals) cause primary CoQ10 deficiency. Coenzyme Q10 transports electrons from mitochondrial respiratory chain complexes I and II to complex III. ADP indicates adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; Cyt c, cytochrome c; e, electron; FADH, flavin adenine dinucleotide; H, hydrogen; NADH, nicotinamide adenine dinucleotide; PDHC, pyruvate dehydrogenase complex; PHB, para-hydroxybenzoate; and PP, pyrophosphate.

has detected deficiency in a small number of patients; how- cumulation in 15 of 49 patients and reduced respiratory ever, correlations with muscle CoQ10 measurements in chain enzyme activities in 27 of 51 patients with the ataxic a larger cohort of patients will be necessary to assess clini- form. Levels of CoQ10 were low in muscle but reduced cal use of mononuclear cell ubiquinone levels. in 18 of 30 fibroblasts. Morphologic and biochemical findings differ in the various clinical forms. In patients with the encephalo- GENETICS myopathic, myopathic, or infantile multisystemic forms, muscle biopsies have typically revealed abnormal mitochondrial proliferation (ragged-red fibers or excessive suc- Primary CoQ10 deficiency is due to mutations in genes in- cinate dehydrogenase histochemical activity) and lipid volved in CoQ10 biosynthesis (Figure). Secondary defi- accumulation as well as reduced biochemical activities ciencies include diseases caused by mutations in genes un- of respiratory chain enzyme complexes IϩIII and IIϩIII, related to ubiquinone biosynthesis, for example, the while all muscle samples showed decreased CoQ10 lev- aprataxin (APTX) gene causing ataxia and oculomotor 20,26,27,29 els. In contrast, fibroblast CoQ10 levels have varied and apraxia, the electron-transferring-flavoprotein de- were normal in 1 patient with encephalomyopathy but hydrogenase gene (ETFDH) causing isolated myopathy,7 low in 1 of 2 patients with the myopathic form and in 7 and the BRAF gene causing cardiofaciocutaneous syn- 35 of 8 patients with the infantile multisystemic form. drome. Moreover, CoQ10 deficiency has been reported in 1 In 2 patients with isolated nephropathy,CoQ10 levels and association with mitochondrial DNA mutations. respiratory chain enzyme activities were reduced in either In most cases, family history suggests autosomal re- fibroblasts or muscle. Ragged-red–like fibers were observed cessive inheritance. Pathogenic mutations have been re- in the only patient who underwent muscle biopsy.12 ported in 63 patients (Table 1). Muscle biopsies revealed mitochondrial prolifera- No mutations have been described among the en- tion, cytochrome c oxidase–negative fibers, or lipid ac- cephalomyopathic patients.

ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 981

©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Except for the patients reported by Gempel and col- ment, a patient with PDSS2 mutations developed intrac- leagues in 2007,7 we did not find other mutations in table seizures and died at age 8 months,8 and a patient ETFDH in our cohort of patients with isolated myopa- with infantile-onset Leigh syndrome, hepatopathy, and thy, indicating that other genes may be responsible for hypertrophic cardiomyopathy after initial clinical im- this phenotype. provement died at age 3 years. Published data for 2 pa- Most patients with the infantile-onset multisystemic vari- tients with mutations in the COQ6 gene noted de- ant have genetically confirmed primary CoQ10 deficiency. creased proteinuria in both patients after CoQ10 treatment, Mutations have been described in COQ2 (3 patients),11,12,16 but hearing improved in only 1 patient.14 8 9 16 PDSS2 (1 patient), COQ9 (1 patient), PDSS1 (2 patients), Response to CoQ10 supplementation in patients with and COQ6 (3 patients).14 Interestingly, 2 patients with iso- cerebellar ataxia is also variable. Three patients with mu- lated nephrotic syndrome had COQ2 mutations.11,12 Thus, tations in the ADCK3 gene showed mild clinical improve- patients with COQ2 mutations have presented with either ment after treatment,17,30,31 but 7 patients carrying mu- infantile multisystemic syndrome or isolated nephropa- tations in the same gene did not improve24,32 and another thy. There are 3 potential explanations for the divergent patient, despite dramatic muscle improvement, devel- phenotypes. First, variations in the phenotypes may be due oped tremor, myoclonic jerks, and cerebellar atro- to genetic or environmental modifiers. Second, patients with phy.23,24 In 3 siblings with mutations in the APTX gene, isolated nephropathies may develop multisystemic dis- CoQ10 supplementation was associated with clear im- ease later in life. Third, CoQ10 treatment may have altered proved ambulation as well as resolution of seizures in 1 the clinical course of the disease by preventing neurologic patient.20 Nevertheless, another patient with APTX mu- complications in both patients with only renal disease. In tations did not improve after therapy.27 Improvement in contrast, in 9 patients, mutations in the COQ6 gene have muscle but not neurologic signs and symptoms has been been associated with kidney involvement (nephrotic syn- noted in 1 new and 2 reported patients.18,19 Reductions drome and nephrolithiasis) and sensorineural hearing loss.14 in International Cooperative Rating Scale scores in 9 pa- A subgroup of patients with juvenile-onset cerebel- tients with an unknown genetic defect and in 1 patient lar ataxia have primary CoQ10 deficiency owing to mu- with ADCK3 gene mutations have been docu- tations in the ADCK3 gene (22 patients).17,24,28,30-32 Sec- mented.22,25,30 Eleven patients with undefined molecu- ondary forms have been described in association with lar defect did not respond to therapy.21,31 mutations in the APTX gene (12 patients) including 4 af- Among the clinically atypical cases of CoQ10 defi- fected members of 1 family that we studied.20,26,27,29 Most ciency, 2 sisters with Leigh syndrome and 1 patient with patients with cerebellar ataxia and CoQ10 deficiency still cardiofaciocutaneous syndrome improved after CoQ10 lack molecular diagnosis. supplementation.34,35 One patient with neonatal hypotonia and infantile spasm showed no improvement.36 THERAPY CONCLUSIONS Patients with CoQ deficiency showed variable re- 10 It is important to identify CoQ deficiency as this con- sponses to CoQ treatment (Table 3). We recommend 10 10 dition often responds to supplementation. The diagno- oral supplementation doses up to 2400 mg daily in adult sis can be made by direct measurement of CoQ in muscle patients and up to 30 mg/kg daily in pediatric patients, 10 and reinforced by the presence of reduced biochemical divided into 3 doses per day. activities of respiratory chain complexes, in particular In patients with encephalomyopathy, muscle symp- complexes IϩIII and IIϩIII. Molecular genetic testing has toms improved after therapy.2-4 In 1 of our patients, muscle revealed causative mutations in a small proportion of pa- symptoms and seizures resolved, creatine kinase and lac- tients, indicating that screening for DNA mutations is not tic acid levels normalized, and a muscle biopsy showed yet effective for diagnosing CoQ deficiency. Our ob- CoQ level normalization.4 In contrast, another patient 10 10 servations not only highlight the clinical heterogeneity developed cerebellar ataxia.3 of CoQ deficiency but also the genetic heterogeneity that Six patients with pure myopathy4-7 (including 1 un- 10 is likely related to the large number of proteins involved reported) improved after CoQ supplementation, while 10 in ubiquinone biosynthesis and regulation and of sec- 2 patients with ETFDH mutations improved only after ondary CoQ deficiencies. Clinical improvement after addition of treatment with riboflavin, 100 mg daily.7 10 CoQ supplementation was documented in many pa- In some patients with the infantile multisystemic form, 10 tients, but treatment protocols have not been standard- CoQ supplementation has halted progression of the en- 10 ized and results have not been uniform. Progress in our cephalopathy and improved the myopathy.15 One pa- knowledge of the genetic bases of CoQ deficiencies may tient with a homozygous COQ2 mutation during therapy 10 help researchers develop a more accurate molecular clas- showed neurologic but not renal improvement and un- sification of this syndrome, while additional studies of derwent kidney transplant; however, his sister with iso- the pathogenesis of CoQ deficiency may lead to more lated nephropathy received CoQ and has had progres- 10 10 effective therapies. sive recovery of renal function, reduced proteinuria, and no neurologic manifestations.11-13 In contrast, a patient with a homozygous COQ9 mutation during therapy had Accepted for Publication: February 6, 2012. a reduction of blood lactate but neurologic and cardiac Published Online: April 9, 2012. doi:10.1001 worsening and died at age 2 years.9 Similarly, despite treat- /archneurol.2012.206. Corrected on May 2, 2012.

ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 982

©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Correspondence: Michio Hirano, MD, H. Houston Mer- 10. Leshinsky-Silver E, Levine A, Nissenkorn A, et al. Neonatal liver failure and Leigh ritt Clinical Research Center, Department of Neurol- syndrome possibly due to CoQ-responsive OXPHOS deficiency. Mol Genet Metab. 2003;79(4):288-293. ogy, Columbia University Medical Center, 630 W 168th 11. Quinzii C, Naini A, Salviati L, et al. A mutation in para-hydroxybenzoate- St, P&S 4-423, New York, NY 10032 (mh29@columbia polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J .edu). Hum Genet. 2006;78(2):345-349. Author Contributions: All authors contributed equally 12. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, et al. COQ2 nephropa- to this article. Study concept and design: Emmanuele, Di- thy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol. 2007;18(10):2773-2780. Mauro, Quinzii, and Hirano. Acquisition of data: Em- 13. Montini G, Malaventura C, Salviati L. Early coenzyme Q10 supplementation in manuele, Lo´pez, Berardo, Naini, Tadesse, Wen, primary coenzyme Q10 deficiency. N Engl J Med. 2008;358(26):2849-2850. D’Agostino, Solomon, Quinzii, and Hirano. Analysis and 14. Heeringa SF, Chernin G, Chaki M, et al. COQ6 mutations in human patients pro- interpretation of data: Emmanuele, Lo´pez, Berardo, Di- duce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011; Mauro, Quinzii, and Hirano. Drafting of the manuscript: 121(5):2013-2024. 15. Ro¨tig A, Appelkvist EL, Geromel V, et al. Quinone-responsive multiple respiratory- Emmanuele, Lo´pez, Solomon, Quinzii, and Hirano. Criti- chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet. 2000; cal revision of the manuscript for important intellectual con- 356(9227):391-395. tent: Emmanuele, Berardo, Naini, Tadesse, Wen, 16. Mollet J, Giurgea I, Schlemmer D, et al. Prenyldiphosphate synthase, subunit 1 D’Agostino, DiMauro, Quinzii, and Hirano. Statistical (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiqui- analysis: Emmanuele and Solomon. Obtained funding: none deficiency and oxidative phosphorylation disorders. J Clin Invest. 2007; 117(3):765-772. Quinzii and Hirano. Administrative, technical, and mate- 17. Lagier-Tourenne C, Tazir M, Lo´pez LC, et al. ADCK3, an ancestral kinase, is mu- rial support: Emmanuele, Lo´pez, Naini, Tadesse, Wen, tated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am and Hirano. Study supervision: Emmanuele, DiMauro, and J Hum Genet. 2008;82(3):661-672. Quinzii. 18. Boitier E, Degoul F, Desguerre I, et al. A case of mitochondrial encephalomy- Financial Disclosure: None reported. opathy associated with a muscle coenzyme Q10 deficiency. J Neurol Sci. 1998; 156(1):41-46. Funding/Support: This study was supported by grants 19. Musumeci O, Naini A, Slonim AE, et al. Familial cerebellar ataxia with muscle K23HD065871 (Dr Quinzii) and 1R01HD057543 (Dr Hi- coenzyme Q10 deficiency. Neurology. 2001;56(7):849-855. rano) from the Eunice Kennedy Shriver National Insti- 20. Quinzii CM, Kattah AG, Naini A, et al. Coenzyme Q deficiency and cerebellar ataxia tute of Child Health and Human Development. Dr Hi- associated with an aprataxin mutation. Neurology. 2005;64(3):539-541. rano’s work is supported by grants R01HD056103 and 21. Lamperti C, Naini A, Hirano M, et al. Cerebellar ataxia and coenzyme Q10 deficiency. Neurology. 2003;60(7):1206-1208. 1RC1NS070232 from the National Institutes of Health, 22. Gironi M, Lamperti C, Nemni R, et al. Late-onset cerebellar ataxia with hypogo- as well as grants from the Muscular Dystrophy Associa- nadism and muscle coenzyme Q10 deficiency. Neurology. 2004;62(5):818- tion and the Marriott Mitochondrial Disorder Clinical Re- 820. search Fund. 23. Aure´ K, Benoist JF, Ogier de Baulny H, Romero NB, Rigal O, Lombès A. Progres- Online-Only Material: The eTables are available at http: sion despite replacement of a myopathic form of coenzyme Q10 defect. Neurology. 2004;63(4):727-729. //www.archneurol.com. 24. Mollet J, Delahodde A, Serre V, et al. CABC1 gene mutations cause ubiquinone Additional Contributions: We are grateful to all of the pa- deficiency with cerebellar ataxia and seizures. Am J Hum Genet. 2008;82(3): tients and relatives for their participation. We thank all of 623-630. the clinicians who referred patients and samples to us. 25. Artuch R, Brea-Calvo G, Briones P, et al. Cerebellar ataxia with coenzyme Q10 deficiency: diagnosis and follow-up after coenzyme Q10 supplementation. J Neu- rol Sci. 2006;246(1-2):153-158. REFERENCES 26. Le Ber I, Dubourg O, Benoist JF, et al. Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology. 2007;68(4):295-297. 1. Quinzii CM, Hirano M. Primary and secondary CoQ(10) deficiencies in humans. 27. D’Arrigo S, Riva D, Bulgheroni S, et al. Ataxia with oculomotor apraxia type 1 Biofactors. 2011;37(5):361-365. (AOA1): clinical and neuropsychological features in 2 new patients and differ- 2. Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency in fa- ential diagnosis. J Child Neurol. 2008;23(8):895-900. milial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A. 1989;86 28. Gerards M, van den Bosch B, Calis C, et al. Nonsense mutations in CABC1/ (7):2379-2382. ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion. 2010; 3. Sobreira C, Hirano M, Shanske S, et al. Mitochondrial encephalomyopathy with 10(5):510-515. coenzyme Q10 deficiency. Neurology. 1997;48(5):1238-1243. 29. Castellotti B, Mariotti C, Rimoldi M, et al. Ataxia with oculomotor apraxia type1 4. Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q10 reverses patho- (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and logical phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology. clinical findings in Italian patients. Neurogenetics. 2011;12(3):193-201. 2001;57(3):515-518. 30. Pineda M, Montero R, Aracil A, et al. Coenzyme Q(10)-responsive ataxia: 2-year- 5. Lalani SR, Vladutiu GD, Plunkett K, Lotze TE, Adesina AM, Scaglia F. Isolated treatment follow-up. Mov Disord. 2010;25(9):1262-1268. mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch 31. Terracciano A, Renaldo F, Zanni G, et al. The use of muscle biopsy in the diag- Neurol. 2005;62(2):317-320. nosis of undefined ataxia with cerebellar atrophy in children [published online 6. Horvath R, Schneiderat P, Schoser BG, et al. Coenzyme Q10 deficiency and iso- August 26, 2011]. Eur J Paediatr Neurol. doi:10.1016/j.ejpn.2011.07.016. lated myopathy. Neurology. 2006;66(2):253-255. 32. Horvath R, Czermin B, Gulati S, et al. Adult-onset cerebellar ataxia due to muta- 7. Gempel K, Topaloglu H, Talim B, et al. The myopathic form of coenzyme Q10 tions in CABC1/ADCK3. J Neurol Neurosurg Psychiatry. 2011;83(2):174-178. deficiency is caused by mutations in the electron-transferring-flavoprotein de- 33. Rahman S, Hargreaves I, Clayton P, Heales S. Neonatal presentation of coen- hydrogenase (ETFDH) gene. Brain. 2007;130(pt 8):2037-2044. zyme Q10 deficiency. J Pediatr. 2001;139(3):456-458. 8. Lo´pez LC, Schuelke M, Quinzii CM, et al. Leigh syndrome with nephropathy and 34. Van Maldergem L, Trijbels F, DiMauro S, et al. Coenzyme Q-responsive Leigh’s CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) encephalopathy in two sisters. Ann Neurol. 2002;52(6):750-754. mutations. Am J Hum Genet. 2006;79(6):1125-1129. 35. Aeby A, Sznajer Y, Cave´ H, et al. Cardiofaciocutaneous (CFC) syndrome associ- 9. Duncan AJ, Bitner-Glindzicz M, Meunier B, et al. A nonsense mutation in COQ9 ated with muscular coenzyme Q10 deficiency. J Inherit Metab Dis. 2007;30 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: (5):827. a potentially treatable form of mitochondrial disease. Am J Hum Genet. 2009; 36. Huntsman RJ, Lemire EG, Dunham CP. Hypotonia and infantile spasms: a new phe- 84(5):558-566. notype of coenzyme Q10 deficiency? Can J Neurol Sci. 2009;36(1):105-108.

ARCH NEUROL / VOL 69 (NO. 8), AUG 2012 WWW.ARCHNEUROL.COM 983