A Neuroimaging Pattern-Recognition Approach To Mitochondrial Respiratory Chain Complex I Deficiency In The Genetic Era

Abstract

Background: Mitochondrial disorders are the most common congenital metabolic diseases. They are due to dysfunction of the mitochondria, the organelles that are responsible for energy (adenosine triphosphate) generation through the respiratory chain. Mitochondria are present in almost every body cells, therefore, their disorders cause various manifestations including encephalomyopathy, cardiomyopathy, and gastrointestinal symptoms. About 25% of mitochondrial disorders are secondary to mitochondrial DNA (mtDNA) genes mutations, and 75% are due to mutations in genes encoded in the nucleus (nuclear DNA or nDNA). Mitochondrial respiratory chain has five major complexes. Defect of each component can cause different clinical and imaging manifestations. Isolated complex I deficiency (OMIM: 252010) is the most common defect of respiratory chain in pediatrics. Complex I (NADH:ubiquinone oxidoreductase) is the largest component of the respiratory chain. It has 38 core subunits encoded by nDNA, and 7 core subunits encoded by mtDNA. Mutations of 17 nDNA genes (NDUFS1−4 and 6−8; NDUFA1, 2, 10, 11; NDUFB3, 9, 11; NDUFV1, 2; NDUFAF3; FOXRED1; ACAD9; MTFMT), and 7 mtDNA genes (MTND1−6; MTTS2) have been reported to cause complex I deficiency. Objectives: To investigate the neuroimaging patterns of pediatric mitochondrial respiratory chain complex I deficiency based on the affected gene. Methods: 16 genetically proven pediatric patients with complex I deficiency were found through searching the database of a genetics center and a pediatric neurology referral hospital. Of the included cases, conventional MRI of 14 patients were retrieved by calling the parents. The MR images were reviewed and reported by an expert radiologist blinded to the genetics results. The neuroimaging pattern of each gene mutation was determined by genotype-MRI correlation. Mann-Whitney U test and Fisher’s exact test were used for analyses. Results: Of 14 investigated patients, eight patients had nDNA genes mutation (NDUFS1 in four cases, NDUFS4 in two cases, NDUFA1 in one case, and NDUFV2 in one case) and six cases revealed mtDNA genes mutation (MTND3 in four cases, MTND4 in one case, and MTND6 in one case). 11 patients (78%) were male, and the rest were female. The mean age of the patients at the time of brain imaging was 3.1 years (range, 6 months−11 years). The mean age of the patients with nDNA mutations was significantly lower compared to the patients with mtDNA mutations (1.4 versus 5.3 years, p =0.03). Symmetrical brainstem lesions were present in all of the patients. Involvement of the basal ganglia was observed in 5/8 patients with nDNA and 5/6 cases of mtDNA mutations (p =0.58). Progressive cavitating leukoencephalopathy (periventricular and centrum semiovale white matter cavitary lesions with a rim of hyperintensity and subcortical sparing) was observed in three patients, all of whom had NDUFS1 mutation. All of these three patients revealed corpus callosal lesions. Corpus callosal involvement was absent in the rest of cases. Cortical hyperintensities were seen in 3/6 cases of mtDNA mutations (all with MTND3 mutation). Supratentorial cerebral atrophy was observed in 1/6 case of mtDNA mutation. Cerebellar signal abnormalities were present in 3/8 patients with nDNA and 3/6 cases of mtDNA mutations (p =1.00). Cerebellar atrophy was observed in 4/6 cases of mtDNA mutations (three cases with MTND3 and one case with MTND6 mutations), but none of nDNA mutations (p =0.01). Conclusions: In summary, neuroimaging abnormalities are manifested earlier in nDNA compared to mtDNA mutations. Brainstem involvement is a constant feature of complex I deficiencies. Cavitating leukoencephalopathy is highly suggestive of NDUFS1 mutation. Cortical signal abnormalities and cerebellar atrophy are present in mtDNA, but not nDNA, mutations. MRI pattern recognition can aid the physician and the geneticist to focus on a specific set of genes as the main cause of symptoms in a child.