Combination of Brain MRI Features As a Useful Tool for Genotype/Phe

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

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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 cortical 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 cytochrome 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 associated 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 involvement. Abnormal white matter may contain small cysts and basal ganglia, thalamus, subthalamic nucleus and dentate nucleus could be involved. Hence, brain MRI features in COX mutations usually involved brainstem±basal ganglia ±leucoencephalopathy.

Figure 1 NUBPL mutation. Brain MRI of a 7-year-old child carrying a MELASSYNDROMEANDOTHERSTRANSLATION NUBPL mutation. Axial T2-weighted FSE images (A) show striking T2 DEFICIENCY hyperintensity of the entire cerebellum. Cerebellar proton-MR MELAS is a neurodegenerative syndrome caused by an A-to-G spectroscopy showed a marked cerebellar lactate peak (B). point mutation at position 3243 of the mitochondrial tRNALeu

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MELAS patients). MRI inconsistently detected calcifications (even in T2*weighted imaging) but showed cerebellar atrophy (8/10), cortical atrophy (5/10) and stroke-like episodes (5/10) in our study of young MELAS patients (mean age 6.8 years).2 At variance with complex I mutations, brainstem lesions associated with only one – striatal anomaly were never observed in MELAS patients.21114 Hence, brain MRI features in MELAS mutation involved basal ganglia ± cerebellar and cortical atrophy and stroke-like lesions. Brainstem anomalies are unlikely in the MELAS syndrome, but a normal MRI does not exclude this diagnosis (figure 5). Two features were commonly found on brain MRI of other translation deficiencies, namely, cortical atrophy (RARS2 or FARS2) and leucoencephalopathy with major white matter – abnormalities.15 19 Mutation in the mitochondrial arginyl tRNA synthetase gene (RARS2)wasconsistently associated with pontocerebellar hypoplasia type 6 with a progressive supra-tentorial cortical atrophy. Mutation in aspartate aminoacyl-tRNA synthetase gene (DARS2) was consistently associated with periventricular leucoencephalopathy with cerebellar, brainstem and pyramidal tract and spinal cord involvement and lactate elevation (figure 6). Mutation in the phenylalanyl tRNA synthetase gene (FARS2) was associated with catastrophic epilepsy and lactic academia of postnatal onset. The neuropathology is consistent with Alpers syndrome. Neuroimaging findings of the patients with FARS2

Figure 2 Complex I deﬁciency: NDUFS1 mutation. Brain MRI of a 7-month-old baby carrying a nDNA mutation (NDUFS1 mutation). Axial T2-weighted FSE (A) and axial T1 (B) images demonstrate the necrotising leucoencephalopathy. gene. Classical neurological features include encephalopathy, seizures and stroke-like episodes. MELAS mutations can be associated with cardiac conduction defects, diabetes mellitus, short stature, myopathy and gastrointestinal disturbances. Calciﬁcations of basal ganglia are frequently observed on CT scan (6/6 of our

Figure 4 Complex V deﬁciency. Neuropathy, ataxia and retinitis Figure 3 Complex I deﬁciency: mt-ND3 mutation (m.13514A>G). pigmentosa (NARP) mutation 8993 T.G. Brain MRI of an 11-month-old Brain MRI of a 1-year-old baby carrying a mtDNA mutation (mt-ND3 baby carrying the m.8993T>G mutation. Axial T2-weighted images show mutation). Axial T2-weighted FSE images demonstrate bilateral important hyperintensities in the bilateral putamen (A). A lactate peak is substantia nigra hyperintensities. seen at 1.33 ppm in the striatum in MRS spectroscopy (TE 144) (B).

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white matter. Proton magnetic resonance spectroscopy showed increased lactate in the cerebral white matter (ﬁgure 8).19

MITOCHONDRIAL DNA DELETION Kearns–Sayre syndrome (KSS) is caused by mtDNA deletions of various sizes. Patients present with ophthalmoplegia, myopathy, progressive ptosis, pigmentary degeneration of the retina, deafness, small stature, cardiomyopathy, ataxia and absent deep tendon reflexes. CT scan in KSS often revealed calcium deposits in the globus pallidus and caudate nuclei.20 MRI often displayed a characteristic pattern of symmetrical lesions of the globus pallidus and thalamus with supra-cortical white matter anomalies. Other central nucleus involvement often included caudate nucleus, substantia nigra and red nuclei. The white matter abnormalities were symmetrical and tended to involve all supra- cortical white matter in a patchy or confluent manner, sparing the periventricular white matter. The cerebellar white matter may also be involved and stroke-like lesions and extensive brain- – stem abnormalities have been reported. Cerebellar and, to a Figure 5 (A D) Mitochondrial encephalomyopathy with lactic acidosis 21 and stroke-like episodes (MELAS) mutation (m.3243A>G). Brain MRI lesser extent, cerebral atrophy may occur. In summary, KSS and CT scan of a 10-year-old child with the MELAS mutation. CT scan should be considered in patients showing a combination of basal demonstrates calcifications in basal ganglia (A). Sagittal T2 images (B) ganglia involvement ± leucoencephalopathy and brainstem show a cerebellar atrophy and the coronal FLAIR images (C) and involvement, cortical atrophy and stroke-like lesions. diffusion-weighted images (D) show a stroke-like lesion in the parieto-occiptal cortex. mutations showed severe cortical atrophy with bilateral hyperintensity in the putamen (figure 7).16 Mutation in the mitochondrial glutamyl-tRNA synthetase gene (EARS2) was associated with early-onset leucoencephalopathy. The brain MRI of EARS2 patients revealed extensive symmetrical and specific cerebral white matter abnormalities sparing the periventricular rim with symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar

Figure 7 FARS2 mutation. Brain MRI of a 14-year-old child carrying a Figure 6 DARS2 mutation. Brain MRI of a 9-year-old child carrying a mutation in the mitochondrial phenylalanyl tRNA synthetase gene mutation in the aspartate aminoacyl-tRNA synthetase gene (DARS2). (FARS2). Axial T2-weighted FSE images (A) show severe cortical Axial T2-weighted FSE images show periventricular leucoencephalopathy atrophy with bilateral hyperintensity of putamens. The two abnormal and bilateral involvement of the posterior limb of the internal capsule. peaks centred at 1.33 ppm represent lactate (B).

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The diagnosis of Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) disease is based on severe gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoplegia, sensorimotor neuropathy and asymptomatic leucoencephalopathy on brain MRI. Onset is usually between the first and fifth decade, but symptoms begin before age 20 years in 60% of patients. MNGIE is inherited as an autosomal-recessive trait and results from mutations in the thymidine phosphorylase (TP) gene, encoding a cytosolic enzyme involved in dNTP synthe- – sis.29 32 MRI showed diffuse high-signal intensity of cerebral and cerebellar white matter on T2-weighted and FLAIR images, usually sparing of the U fibres and corpus callosum. Thalami and basal ganglia may display patchy signal abnormalities but are spared in other patients. The internal capsule, external capsule, brainstem and middle cerebellar peduncles may be involved as well. In some patients, the white matter MRI abnormalities were more limited and mostly involved the periventricular white matter.33 Hence, the main brain MRI features in patients with MNGIE deficiency were leucoencephalopathy ± basal ganglia and cerebellar and brainstem involvement. Patients with SUCLA2/SUCLG1 mutations have a characteristic metabolic profile, namely urinary methylmalonic acid and Figure 8 EARS2 mutation. Brain MRI of a 14-year-old child carrying a C4-DC carnitine accumulation. As mtDNA depletion in muscle EARS2 mutation. Axial T2-weighted FSE image hallmarked by extensive is not a constant finding in SUCLG1 patients, brain MRI is symmetrical cerebral white matter abnormalities sparing the important as it may provide a hint in support of this metabolic periventricular rim (arrow). defect. Bilateral striatal necrosis (BSN) has been reported in – patients with SUCLG1/SUCLA2 mutations.34 37 Brain MRI in MITOCHONDRIAL DNA MAINTENANCE DEFICIENCY three patients carrying SUCLG1 mutations of our series Maintenance of mtDNA is under the control of many nuclear detected similar bilateral hyperintensities of the caudate and genes including those involved in mtDNA replication (POLG, putamen nuclei with a lactate peak.38 Reported patients also dis- PEO1) and dNTP synthesis (POLG, PEO1, DGUOK, TK2, TP, played moderate cortical atrophy, caudate atrophy and ventricu- RRM2B, SUCLA2, SUCLG1). Mutations of these genes result in lar dilatation. To summarise, brain MRI features in patients with either quantitative (mtDNA depletion) or qualitative anomalies SUCLA2/SUCLG1 mutations included basal ganglia involve- of the mitochondrial genome (multiple mtDNA deletions). The ment ± cerebral atrophy. SUCLA2/SUCLG1 mutation is unlikely mtDNA depletion syndromes (MDS) are characterised by severe if no basal ganglia involvement is noted. reduction of mtDNA copy number and are tissue-specific. MDS is usually passed as an autosomal-recessive trait and appears in UBIQUINONE DEFICIENCY early childhood. Multiple mtDNA deletions can be tissue- Cerebellar ataxia, epilepsy and muscle weakness are frequently specific and sometimes occur as an autosomal-dominant trait in observed in patients with ubiquinone deficiency. Spasticity, dys- – adulthood.22 26 tonia, tremor, migraine and epilepsy are occasionally present, Polymerase gamma (POLG)-related disorders comprise a con- and severe cognitive impairment is constant in early childhood. tinuum of overlapping phenotypes that were clinically defined MRI revealed important cerebellar atrophy and stroke-like long before their molecular bases were known. One of the most lesions in patients with ADCK3 mutations.39 40 Therefore, ubi- severe phenotypes, Alpers–Huttenlocher syndrome (AHS), is quinone deficiency should be considered in patients presenting characterised by childhood-onset progressive and ultimately cerebellar atrophy ± stroke-like lesions (figure 9). Ubiquinone severe encephalopathy with intractable epilepsy and hepatic deficiency is unlikely in patients with normal cerebellum. failure. Childhood myo-cerebro-hepatopathy spectrum (MCHS) presents as a developmental delay with dementia, lactic acidosis, LACTATE PEAK WITH MRS SPECTROSCOPY myopathy and failure to thrive in the first few months of life. CNS lactate can be measured using proton MRS (1H MRS). Other findings include liver failure, renal tubular acidosis, pan- Because MRS allows cerebral lactate to be measured non- creatitis, cyclic vomiting and hearing loss. The myoclonic epi- invasively, brain lactate may be a better marker of cerebral lepsy myopathy sensory ataxia syndrome (MEMSA) now metabolism than blood lactate.41 42 Yet neither normal brain delineates this spectrum of disorders with epilepsy, myopathy MRI nor normal MRS can exclude the diagnosis of respiratory and ataxia (without ophthalmoplegia) including spinocerebellar chain deficiency. ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes sensory ataxia, neuropathy, dysarthria and oph- Representative key findings thalmoplegia (SANDO). MRI analysis in adult patients occasion- For example, stroke-like episodes should prompt one to con- ally detected stroke-like lesions and cerebellar atrophy with sider mitochondrial complex I DNA mutation, MELAS, POLG occasional signal anomalies of basal ganglia.27 28 To summarise, and ubiquinone deficiency. Leucoencephalopathy are suggestive brain MRI features in patients carrying POLG mutations include of nuclear complex I DNA mutation. Focal bilateral lesions con- stroke-like lesions ± cerebellar and cerebral atrophy. Basal fined to the brainstem are suggestive of complex I or SURF1 ganglia involvement has been observed in adult patients while mutations. Periaqueductal hyperintensity are suggestive of most children with depletion mutation had a normal brain MRI complex I mtDNA mutation (mt-ND5 mutation). Major abnor- (unpublished data). malities of the entire cerebellum with a lactate peak could point

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literature, we believe that combining MRI features could be helpful for diagnosis. Thanks to genotype–radiological phenotype correlations, MRI could direct the genetic diagnosis. Furthermore, MRI could also rectify spurious biochemical findings. In particular, the absence of brain MRI anomalies in a patient with apparent complex I deficiency should prompt one to question the primary nature of this enzyme deficiency. Yet, we do not claim that any of these features, isolated or in associ- ation, are specific. Ongoing analyses of brain MRI of novel genetic entities will help in describing the phenotypic spectrum of mitochondrial respiratory chain deficiency. Improving those correlations will hopefully make accurate diagnosis of respiratory chain deficiency easier and faster.

Collaborators DG, FB: paediatric radiology unit. ASL, MR, AR, AM: genetic unit. ID, PDL, VV: neurology unit. NB: paediatric radiology unit, paediatric radiology, neurology and genetic units, Hôpital Necker-Enfants Malades and Inserm U781 and U1000, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris F-75015 France. Contributors All authors made a signiﬁcant contribution to the conception and design of experimental studies or the analysis and interpretation of data; participated in drafting the manuscript or reviewing and/or revising it for intellectual content; and approved the ﬁnal version of the manuscript. MB, DG and NB were in charge of the acquisition of funding for the research. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.

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Bricout M, et al. J Med Genet 2014;0:1–7. doi:10.1136/jmedgenet-2013-102256 7 Downloaded from jmg.bmj.com on June 17, 2014 - Published by group.bmj.com

Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations

M Bricout, D Grévent, A S Lebre, et al.

J Med Genet published online May 1, 2014 doi: 10.1136/jmedgenet-2013-102256

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