Downloaded from jmg.bmj.com on June 17, 2014 - Published by group.bmj.com JMG Online First, published on May 1, 2014 as 10.1136/jmedgenet-2013-102256 Review Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations M Bricout,1 D Grévent,1 A S Lebre,2 M Rio,2 I Desguerre,3 P De Lonlay,3 V Valayannopoulos,3 F Brunelle,1 A Rötig,2 A Munnich,2 N Boddaert1 1Department of Pediatric ABSTRACT COMPLEX I DEFICIENCY Radiology, Hôpital Necker- Mitochondrial diseases are characterised by a broad Isolated complex I deficiency, the most frequent Enfants Malades and Inserm U781 and U1000, Université clinical and genetic heterogeneity that makes diagnosis cause of respiratory chain defects in childhood, Paris Descartes-Sorbonne Paris difficult. Owing to the wide pattern of symptoms in accounts for various clinical presentations combin- Cité, Institut Imagine, Paris, mitochondrial disorders and the constantly growing ing hypotonia, developmental delay, seizures, car- France 2 number of disease genes, their genetic diagnosis is diomyopathy, optic atrophy or retinopathy and Department of Genetic Units, difficult and genotype/phenotype correlations remain other organ involvement. It includes Leigh syn- Hôpital Necker-Enfants Malades and Inserm U781 and elusive. Brain MRI appears as a useful tool for genotype/ drome, Leber hereditary optic neuropathy (LHON), U1000, Université Paris phenotype correlations. Here, we summarise the various mitochondrial encephalomyopathy, lactic acidosis Descartes-Sorbonne Paris Cité, combinations of MRI lesions observed in the most and stroke-like episodes (MELAS) and numerous Institut Imagine, Paris, France frequent mitochondrial respiratory chain deficiencies so other clinical presentations. Leigh syndrome is an 3Department of Neurology, Hôpital Necker-Enfants as to direct molecular genetic test in patients at risk of early-onset progressive neurodegenerative disorder Malades and Inserm U781 and such diseases. We believe that the combination of brain causing various symptoms, including hypotonia, U1000, Université Paris MRI features is of value to support respiratory chain psychomotor regression, ataxia, ocular movement Descartes-Sorbonne Paris Cité, deficiency and direct molecular genetic tests. abnormalities, seizures, dystonia, swallowing dys- Institut Imagine, Paris, France function and respiratory disturbances. Characteristic Correspondence to neuropathological features consist of spongiform Dr M Bricout, Department of Mitochondrial diseases are due to deficiency of the necrosis, myelin degeneration, vascular proliferation Pediatric radiology, Hôpital respiratory chain, which is made up of five com- and gliosis in one or more areas of the central Necker-Enfants Malades and plexes and consists of more than 80 different pro- nervous system (CNS), including thalamus, basal Inserm U781 and U1000, 1 Université Paris Descartes- teins. These diseases are characterised by a broad ganglia, brainstem and spinal cord. Sorbonne Paris Cité, Institut clinical and genetic heterogeneity that makes diag- Complex I (NADH:ubiquinone oxidoreductase), Imagine, 149 rue de sèvres, nosis difficult. Some clinical presentations are highly the largest component of the respiratory chain, Paris 75015, France; marine. suggestive of given gene mutations, allowing rapid comprises seven core subunits encoded by mitochon- [email protected] genetic diagnosis. However, owing to the wide drial DNA (mtDNA), 38 nuclearly encoded core Received 17 January 2014 pattern of symptoms in mitochondrial disorders and subunits and few known (but many unknown) assem- Revised 17 March 2014 the constantly growing number of disease genes, bly factors. To date, disease causing mutations have Accepted 6 April 2014 their genetic diagnosis is frequently difficult and been identified in 19 core subunits comprising 16 genotype/phenotype correlations remain elusive. nuclear genes (NDUFS1-4, NDUFS6-8, NDUFV1-2, Here, based on brain MRI features in known NDUFA1-2, NDUFA9-11, NDUFB3,9), 7 mtDNA nuclear/mitochondrial DNA mutations, we have genes and at least 6 assembly factors (NDUFAF1-4, tried to provide physicians with valuable informa- NUBPL, C8orf38 and C20orf7). Our retrospective tion so as to help them in interpreting the growing study of brain MRI and/or CT-scan in 30 complex amount of data derived from exome sequencing I-deficient patients carrying known mutations have and targeted gene resequencing in mitochondrial helped us identify a consistent pattern of brain MRI diseases. imaging in primary complex I deficiency.2 Indeed, we Based on the current review of published litera- observed a common and uniform pattern of bilateral ture, we have focused our MRI analysis for the and symmetrical brainstem lesions in 30/30 complex genotype/phenotype correlations on five brain areas I-deficient patients (table 1). Putaminal anomalies known as targets of mitochondrial dysfunction: (1) were very frequent (23/30). Supra-tentorial stroke- basal ganglia (hyperintensities on T2-weighted like lesions were only observed in patients carrying imaging or calcifications); (2) cerebellum (hyperin- mtDNA mutations (8/19) while necrotising leucoen- tensities on T2 or atrophy); (3) brainstem (hyperin- cephalopathy was constantly found in patients carry- tensities on T2 or atrophy); (4) white matter ing nDNA mutations (4/5). Cerebellar atrophy was (leucoencephalopathy); (5) cortex (supra-tentorial observed in 9/12 patients older than 5 years and car- atrophy). Stroke-like episodes were also considered. rying mtDNA mutation (75%) but neither below The combination of some features and absence of 5 years nor in patients carrying nDNA mutations.2 others are sometimes suggestive of a particular Interestingly, hyperintensity of coliculli was often To cite: Bricout M, respiratory chain deficiency or gene mutation. We encountered in patients in mt-ND5 mutation.3 Grévent D, Lebre AS, et al. J NUBPL Med Genet Published Online believe that the combination of brain MRI anomal- mutations caused major abnormalities of First: [please include Day ies is of value to support respiratory chain defi- the cerebellum and inconstant supra-tentorial leu- Month Year] doi:10.1136/ ciency and interpret next-generation sequencing coencephalopathy involvement but no anomalies of jmedgenet-2013-102256 data in respiratory chain deficiency. the basal ganglia45(figure 1). BricoutCopyright M, et al. J MedArticle Genet 2014;author0:1–7. (or doi:10.1136/jmedgenet-2013-102256 their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. 1 Downloaded from jmg.bmj.com on June 17, 2014 - Published by group.bmj.com Review Table 1 Various combinations of MRI abnormalities observed in the most frequent mitochondrial respiratory chain deficiencies Respiratory chain deficiency Basal ganglia Cerebellum Brainstem Leucoencephalopathy Cortical atrophy Stroke-like episodes Complex I mitochondrial DNA ± ± + −−± Complex I nuclear DNA ± ± + ± −− NUBPL − +±± −− SURF1 ± ± ± ± −− Complex V + ± ± −−− PDH deficiency ± ± ± −−− SUCLG1/SUCLA2 + −−− ± − Ubiquinone deficiency − + −− − ± MELAS ± ± −− ±± POLG ± ± −− ±± Kearns–Sayre syndrome ± ± ± ± ± ± RARS2 − ++− + − FARS2 + −−− + − DARS2 − ±++ −− EARS2 ± ± ± + −− MNGIE ± ± ± + −− MEALS, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MNGIE, Mitochondrial Neurogastrointestinal Encephalopathy. Hence, complex I mtDNA mutations consistently caused COMPLEX V DEFICIENCY brainstem±basal ganglia involvement±stroke-like episodes Complex V deficiency is a rare cause of respiratory chain defi- ±cerebellar atrophy involvement while nuclear complex I muta- ciency. Clinical presentations include neuropathy, ataxia and retin- tions caused brainstem±basal ganglia involvement±leucoence- itis pigmentosa (NARP) and Leigh syndrome. The most frequent phalopathy (figures 2 and 3). Complex I deficiency is unlikely if known cause of complex V deficiency is the MT-ATP6 gene muta- no brainstem involvement is observed. tion. Those patients present MRI lesions involving basal ganglia frequently associated with cerebellar atrophy (table 1).67 Associated brainstem lesions are observed in largely 25% of cases. No stroke-like lesions, delayed myelination or corpus callosum abnormalities were noted in patients carrying MT-ATP6 mutations. Few patients carrying mutant genotypes other than MT- ATP6-ATP8 mutation have been reported. Jonckheere et al8 reported no brain lesion but a cisterna magna in a patient carrying a MT-ATP8 mutation. Finally, brain MRI of TMEM70 patients showed prominent cerebellar and pontine atrophy, generalised cor- tical atrophy, hypoplastic corpus callosum and relative white matter deficiency.9 Hence, brain MRI features in MT-ATP6 mutations involved basal ganglia±brainstem and cerebellar atrophy (figure 4). CYTOCHROME C OXIDASE DEFICIENCY SURF1 is the first assembly factor gene reported to cause cyto- chrome c oxidase (COX) deficiency. Leigh syndrome is the most common clinical manifestation of SURF1 mutation, but milder neurological involvement with a malabsorption syndrome or leucoencephalopathy has been described.10 Mutations in three other COX assembly genes, COX10, SCO1 and SCO2, are asso- ciated with hypertrophic cardiomyopathy and encephalopathy combined with hepatic failure. Hitherto, two major brain MRI features were observed in COX deficiency, namely, diffuse leucoencephalopathy (corpus callosum, internal capsule, cerebellar white matter and U fibres) and/or brainstem involve- ment. Abnormal white