Brain Imaging in Mitochondrial Respiratory Chain Deficiency
Brain Imaging in Mitochondrial Respiratory Chain Deficiency
MELAS is a neurodegenerative syndrome caused by an A-to-G point mutation at position 3243 of the mitochondrial tRNA 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 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). At variance with complex I mutations, brainstem lesions associated with only one striatal anomaly were never observed in MELAS patients. 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).
(Enlarge Image)
Figure 5.
(A–D) Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) mutation (m.3243A>G). Brain MRI and CT scan of a 10-year-old child with the MELAS mutation. CT scan demonstrates calcifications in basal ganglia (A). Sagittal T2 images (B) show a cerebellar atrophy and the coronal FLAIR images (C) and diffusion-weighted images (D) show a stroke-like lesion in the parieto-occiptal cortex.
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.
Mutation in the mitochondrial arginyl tRNA synthetase gene (RARS2) was consistently 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).
(Enlarge Image)
Figure 6.
DARS2 mutation. Brain MRI of a 9-year-old child carrying a mutation in the aspartate aminoacyl-tRNA synthetase gene (DARS2). Axial T2-weighted FSE images show periventricular leucoencephalopathy and bilateral involvement of the posterior limb of the internal capsule.
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 mutations showed severe cortical atrophy with bilateral hyperintensity in the putamen (Figure 7).
(Enlarge Image)
Figure 7.
FARS2 mutation. Brain MRI of a 14-year-old child carrying a mutation in the mitochondrial phenylalanyl tRNA synthetase gene (FARS2). Axial T2-weighted FSE images (A) show severe cortical atrophy with bilateral hyperintensity of putamens. The two abnormal peaks centred at 1.33 ppm represent lactate (B).
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 white matter. Proton magnetic resonance spectroscopy showed increased lactate in the cerebral white matter (Figure 8).
(Enlarge Image)
Figure 8.
EARS2 mutation. Brain MRI of a 14-year-old child carrying a EARS2 mutation. Axial T2-weighted FSE image hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim (arrow).
Melas Syndrome and Others Translation Deficiency
MELAS is a neurodegenerative syndrome caused by an A-to-G point mutation at position 3243 of the mitochondrial tRNA 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 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). At variance with complex I mutations, brainstem lesions associated with only one striatal anomaly were never observed in MELAS patients. 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).
(Enlarge Image)
Figure 5.
(A–D) Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) mutation (m.3243A>G). Brain MRI and CT scan of a 10-year-old child with the MELAS mutation. CT scan demonstrates calcifications in basal ganglia (A). Sagittal T2 images (B) show a cerebellar atrophy and the coronal FLAIR images (C) and diffusion-weighted images (D) show a stroke-like lesion in the parieto-occiptal cortex.
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.
Mutation in the mitochondrial arginyl tRNA synthetase gene (RARS2) was consistently 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).
(Enlarge Image)
Figure 6.
DARS2 mutation. Brain MRI of a 9-year-old child carrying a mutation in the aspartate aminoacyl-tRNA synthetase gene (DARS2). Axial T2-weighted FSE images show periventricular leucoencephalopathy and bilateral involvement of the posterior limb of the internal capsule.
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 mutations showed severe cortical atrophy with bilateral hyperintensity in the putamen (Figure 7).
(Enlarge Image)
Figure 7.
FARS2 mutation. Brain MRI of a 14-year-old child carrying a mutation in the mitochondrial phenylalanyl tRNA synthetase gene (FARS2). Axial T2-weighted FSE images (A) show severe cortical atrophy with bilateral hyperintensity of putamens. The two abnormal peaks centred at 1.33 ppm represent lactate (B).
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 white matter. Proton magnetic resonance spectroscopy showed increased lactate in the cerebral white matter (Figure 8).
(Enlarge Image)
Figure 8.
EARS2 mutation. Brain MRI of a 14-year-old child carrying a EARS2 mutation. Axial T2-weighted FSE image hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim (arrow).