Objective To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies.
Design and subjects The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations.
Results All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients.
Conclusion A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.
- Mitochondrial disorders
- Leigh syndrome
- complex I deficiency
- metabolic disorders
- getting research into practice
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- Mitochondrial disorders
- Leigh syndrome
- complex I deficiency
- metabolic disorders
- getting research into practice
Isolated complex I deficiency, the most frequent cause of respiratory chain defects in childhood,1 accounts for various clinical presentations including Leigh syndrome, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and numerous other clinical presentations combining hypotonia, developmental delay, seizures, cardiomyopathy, optic atrophy or retinopathy and other organ involvement.2
Complex I (NADH:ubiquinone oxidoreductase; EC 18.104.22.168), the largest component of the respiratory chain, comprises seven core subunits encoded by mitochondrial DNA (mtDNA), 38 core subunits encoded by nuclear DNA (nDNA), and a few known (but many unknown) assembly factors.1 2 To date, disease-causing mutations have been identified in 19 core subunits, including 12 nuclear genes (NDUFS1-4, NDUFS6-8, NDUFV1-2, NDUFA1-2 and NDUFA11), seven mtDNA genes, and six assembly factors (NDUFAF1-4, C8orf38 and C20orf7).3
While MRI abnormalities have been reported in patients with respiratory chain disorders, including those presenting complex I deficiency, no correlation between genotypes and brain MRI phenotypes has been hitherto reported in a large series of patients.
We have retrospectively collected brain MRI and/or CT scans of 30 complex I deficient patients carrying known mutations and compared them with the brain MRIs of 11 patients with known mutations in pyruvate dehydrogenase (PDH) genes and 10 patients with MT-TL1 mutations. This retrospective study allows us to identify a consistent pattern of brain MRI imaging in primary complex I deficiency.
Patients and methods
A total of 30 patients with complex I deficiency (25 males, 5 females) were included in this study. Inclusion criteria were: (1) known mutation(s) in either mtDNA or nuclear genes; and (2) availability of brain imaging for review. The mean age at imaging ranged from to 2 months to 30 years (mean 6.8 years). Their brain MRIs were compared to those of 11 patients (8 males, 3 females) with known PDH mutation(s) and 10 patients (5 males, 5 females) with MT-TL1 mutation (m.3243A>G or m.3271T>C). Mean ages at imaging ranged from to 4 months to 9 years (mean 4.08 years) for PDH deficient patients, and from 4 years to 56 years (mean 21.9 years) for patients with MT-TL1 mutations. Clinical and biochemical features have been previously reported in 31 patients.4–14 Written informed consent was obtained from all patients participating in the study. All reported mutations are described in Mitomap (http://www.mitomap.org/MITOMAP) and HGMD (https://portal.biobase-international.com/) databases.
Brain imaging methods
The MRI examination consisted of sagittal spin echo (SE) T1, axial fast SE (FSE) T2 and coronal fluid attenuated inversion recovery (FLAIR) images. Additional imaging sequences were occasionally obtained, including three dimensional (3D) fast spoilt gradient recalled imaging (FSPGR), T2*, diffusion weighted images, 1H magnetic resonance spectroscopy (MRS) or one of the primary sequences in additional planes. MRS single voxel spectroscopy was most commonly performed using PRESS TR=1500 and TE=144; TE=288 was occasionally employed. The patients had one spectroscopy in their basal ganglia and eventually one in their brain anomalies. Exceptionally, brain MRI was performed with an injection of contrast. MRIs were acquired with a 1 or 1.5 Tesla Signa GE. For the majority of patients, scans were all collected on the same MRI scanner with the same protocol. For a few patients, brain MRIs had been performed many years ago or in other hospitals. Missing images or data were reported as non-available (na). CT scans were the only available brain images for two complex I deficient patients and for four patients with MT-TL1 mutations. The same paediatric neuroradiologist reviewed all the brain images.
Statistical calculations were performed with R version 2.8.0 (The R Foundation for Statistical Computing). Qualitative variables were compared by the χ2 or Fisher exact tests and quantitative variables were compared using the Students t test. Statistical significance was defined as p<0.05. All statistical tests were two sided.
Among our 30 complex I deficient patients, 20 carried an mtDNA mutation and 10 carried a nuclear gene mutation (tables 1 and 2). Brain MRI anomalies were consistently observed in the brainstem of all patients (tables 1 and 2). Hyperintensities in the brainstem were found on T2 and FLAIR sequences (figure 1) and appeared as hypointensities on T1. They were very important in size and generally symmetrical. Confluent areas of hyperintensitiy were occasionally seen. Substantia nigra, periaqueductal grey matter, mamillothalamic and spinothalamic tracts and/or medial lemniscus, and medial longitudinal fasciculus were occasionally involved. Subthalamic nuclei, periaqueductal grey matter and superior colliculus lesions were more frequently observed in patients carrying mtDNA than nuclear mutations (data not shown).
Brainstem lesions were associated with at least one striatal anomaly (putamen or caudate) in 27/30 patients. No patient presented thalamus anomalies without striatal lesions. Striatal anomalies were almost consistently present (27/30, 90%) independent of the mutated genome. Putamenal (23/30, 77%) and pallidal lesions (16/30, 53%) were frequent as well, regardless of the mutation. Caudate lesions were frequently present (11/30, 37%) and were more common in patients with mtDNA as opposed to nuclear mutations (10/20, 50%, and 1/10, 10%, respectively) (p<0.05).
Interestingly, stroke-like lesions predominantly affecting grey matter and not confined to arterial vascular territories were observed in 40% of patients carrying mtDNA mutations (8/20) but in none of the patients carrying nDNA mutations (p<0.05) (figure 2A–C).
A diffuse supratentorial leucoencephalopathy involving the deep lobar white matter was observed in 50% of patients with nDNA mutations (5/10) but in none of the patients carrying mtDNA mutations. The leucoencephalopathy was most likely necrotising in 4/5 patients, including 3/4 patients with NDUFS1 mutations. FLAIR sequences were available for 2/4 patients with abnormal white matter containing cysts (figure 2D). In the 2/4 others patients, lesions were notably hyperintense on T2 and very hypointense on T1 weighted images, suggesting cysts (figure 2E,F).
Cerebellar hyperintensities were present in 13/29 patients (45%) regardless of the mutated genome. Cerebellar atrophy was observed in 9/12 patients carrying mtDNA mutation aged 5 years (75%) but neither in patients below 5 years nor in patients carrying nDNA mutations.
Spinal cord was not usually explored but T2 hyperintensities were observed in all three cases studied. When MRS was performed and voxels placed over the brain lesions, important lactate peaks were consistently found in all patients (10/10), independent of the type of mutation (mtDNA or nDNA).
Patients with nDNA mutations presented significantly earlier brain anomalies than patients with mtDNA mutations (2.8 years and 8.9, respectively, p<0.05).
A group of 11 PDH deficient patients and 10 patients with MT-TL1 mutations was chosen as the control group (tables 3 and 4). MRI anomalies in complex I deficient patients were observed significantly earlier than in patients with MT-TL1 mutations (mean age 6.8 years vs 21.9 years, p<0.05). Similarly, brainstem lesions associated with at least one striatal anomaly were significantly more frequent in complex I deficient patients (27/30) than in PDH deficient patients (1/11, p<0.001) and were never observed in patients with MT-TL1 mutations (0/6, p<0.001). Interestingly, stroke-like lesions were equally frequent in patients carrying complex I mtDNA mutations (8/20) and in patients with MT-TL1 mutations (5/11), but were never observed in PDH deficient patients. Similarly, brainstem anomalies associated with stroke-like images or leucoencephalopathy were common in complex I deficiency but were never observed in PDH deficient patients or patients with MT-TL1 mutations.
Cerebellar hyperintensities were observed in all groups. Cerebellar atrophy before 5 years was observed in PDH deficient patients (3/7) but not in complex I deficient patients (0/16, p<0.05). Similarly, an anomaly of the corpus callosum was very frequent in PDH deficient patients (9/10) but never observed in complex I deficient children (0/30, p>0.001). When available, CT scans showed calcifications in the basal ganglia in patients with MT-TL1 mutations (6/6) but not in complex I deficient patients (0/3, p<0.05).
Based on a retrospective study of 30 cases, we report here on a common pattern of brain MRI imaging in patients with mitochondrial diseases and respiratory chain complex I deficiency. Bilateral and symmetric brainstem lesions were consistent features in complex I deficiency and most patients also presented at least one associated striatal anomaly. This association was significantly more frequent in complex I deficient patients (27/30) than in PDH deficient patients (1/11) or patients with MT-TL1 mutations (0/6) (p<0.001, tables 3 and 4).14 The almost consistent detection of a lactate peak in our series supports the view that MRS should be performed in all patients with suspected complex I deficiency.
Abnormal brain images were observed significantly earlier in patients with nDNA mutations than in patients with mtDNA mutations. The age at onset was not determined by the date of the brain imaging; however, this could suggest an earlier clinical presentation for patients with nDNA mutations. For mtDNA mutations, heteroplasmic load has been shown to correlate with age at onset.15 In this retrospective study, samples were not available anymore to quantify it. However, heteroplasmic load may help to explain the later diagnosis for patients with mtDNA mutation (compared to patients with nDNA mutations) and the differences in brain image findings in patients with the same mtDNA mutation.
Supratentorial stroke-like lesions, similar to that observed in MT-TL1,16 CABC117 or POLG18 mutations, were only observed in patients with mtDNA mutations. CT scans showed no evidence of calcifications in these patients with stroke-like lesions. As brainstem lesions are usually not observed in patients with mutations in MT-TL116 (table 3), CABC117 or POLG,18 the combination of brainstem anomalies with stroke-like images, but without calcifications, should help in focusing on the mtDNA encoded complex I genes. In contrast, stroke-like images with calcifications and without brainstem anomalies should prompt to screen for MT-TL1 mutations.19
In this study, necrotising leucoencephalopathy was found in patients carrying nuclear gene mutations as already described in NDUFA12L20 and C6ORF6621 mutations. This suggests that a necrotising leucoencephalopathy in patients with complex I deficiency should first prompt investigation of nuclear genes, including the NDUFS1, NDUFS3, NDUFS7, NDUFA12L and C6ORF66 genes. Brain MRIs also help in diagnosing other causes of necrotising leucoencephalopathy—namely, childhood ataxia with central nervous system hypomyelination (CACH), megalencephalic leucodystrophy with subcortical cysts (MLC), and Aicardi–Goutières syndrome (AGS).22
Apart from complex I deficiency, brain MRI involvement of brainstem and basal ganglia anomalies has also been reported in cases of Leigh syndrome ascribed to SURF1 and MT-ATP6 mutations.23–28 Similarly, brain MRI imaging of patients carrying RanBP2 mutations is relatively similar to that observed in patients with Leigh syndrome and reportedly includes brainstem and thalamus lesions.29 Yet, reported RanBP2 patients never presented the striatal anomalies that are constantly observed in our complex I deficient patients. Therefore, the presence of striatal anomalies may help to distinguish between the two diagnoses.
MRS data were obtained only in 10/30 patients and an important lactate peak was consistently found in all patients. MRS is usually regarded as a more sensitive tool than cerebrospinal fluid (CSF) lactate.30 For this reason, MRS should explore brainstem or white matter (in case of leucoencephalopathy) in complex I deficiency.
In conclusion, this retrospective study supports the view that mutations in complex I genes cause a common pattern of brain MRI imaging. We suggest giving consideration to the association of brainstem and basal ganglia anomalies with lactate peak but no corpus callosum dysmorphism as a clue to complex I deficiency. When associated with stroke-like lesions or cerebellar atrophy, these images should serve as prompt to screen for mtDNA mutations. Finally, a necrotising leucoencephalopathy should prompt investigators to look for nuclear gene mutations.
Hence, brain imaging may assist in focusing on specific genes and contribute to faster gene identification in respiratory chain deficiency.
We thank Dr Michèle Brivet (Hôpital Bicêtre, Service de Biochimie France) for providing us information on PDH patients. We are grateful to all patients, doctors, nurses, and other people who were involved with the series studies.
Funding Mitocircle contract from the European commission [grant No 005260].
Competing interests None.
Patient consent Obtained. Details have been removed from these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Provenance and peer review Not commissioned; externally peer reviewed.
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