Clinical,Neuroimaging,and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations

Background: Leigh syndrome(LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity.We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA(mtDNA) mutations.Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging(MRI)were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid(CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography–mass spectrometry and tandem mass spectrometry.The histopathological traits of skeletal muscles were analyzed under microscope.Results: Among 13 patients, mutations of MT?NDs(n = 8) and MT?ATP6(n = 4) genes were most common. Strabismus(8/13), muscle weakness(8/13), and ataxia(5/13) were also common, especially for the patients with late?onset age after 2 years old. However, respiratory distress was common in patients with early?onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem(12/13), particularly the dorsal part of midbrain, followed by basal ganglia(6/13), thalamus(6/13), cerebellum(5/13),and supratentorial white matter(2/13). Besides, the elevated lactate levels in CSF(6/6) were more common than those in serum(7/13).However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results(0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late?onset patients but not in the early?onset ones.Conclusions: Noninvasive genetic screening is recommended for mtDNA mutations in MT?NDs and MT?ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.

Late-onset mitochondrial disease in a patient with MELAS and mitochondrial DNA T14487C mutation

To the Editor: Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS) is one of the most common multisystem mitochondrial disorders with broad clinical manifestations.[1] It is usually caused by point mutations in the mitochondrial MT-TL1 gene, which accounts for approximately 80% of mutations in individuals with MELAS syndrome.[2] Pathogenic mitochondrial DNA (mtDNA) mutations were first described in 1980[3] and m.l4487T>C is a known pathogenic mtDNA mutation,[4] which has been reported in patients with Leigh syndrome, optic neuropathy, ptosis, dystonia, and encephalomyopathy. We herein report a patient with late-onset MELAS syndrome with the m.l4487T>C mutation for the first time.

Activated mTOR signaling pathway in myofibers with inherited metabolic defect might be an evidence for mTOR inhibition therapies

Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscles from patients are still unknown.This study aimed to analyze the activity of mTOR pathway in IMMs muscles.Methods:We collected muscle samples from 25 patients with mitochondrial myopathy(MM),lipid storage disease(LSD)or Pompe disease(PD).To evaluate the activity of mTOR pathway in muscle specimens,phosphorylation of S6 ribosomal protein(p-S6)and p70S6 kinase(p-p70S6K)were analyzed by Western blotting and immunohistochemistry.Results:Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls(NC)(NC vs.LSD,U=2.000,P=0.024;NC vs.MM:U=6.000,P=0.043).Likewise,p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs(NC vs.LSD,U=0.000,P=0.006;NC vs.PD,[7=0.000,P=0.006;NC vs.MM,U=1.000,P=0.007).Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect.In MM muscles,most p-S6 positive fibers showed cytochrome C oxidase(COX)deficiency(U=5.000,P=0.001).In LSD and PD muscles,p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets(17=0.000,P=0.002)or basophilic materials(U=0.000,P=0.002).Conclusion:The mTOR pathway might be activated in myofibers with various metabolic defects,which might provide evidence for mTOR inhibition therapy in human IMMs.