Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report.

BACKGROUND: Mitochondrial encephalomyopathy caused by bi-allelic deleterious variants in TARS2 is rare. To date, only two pedigrees were reported in the literature and the connection between the gene and disease needs further study. CASE PRESENTATION: We report one infant who presented with limb hypertonia, epilepsy, developmental delay, and increased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed to help to underlie the cause. We identified compound heterozygous variants c.470C > G, p.Thr157Arg and c.2143G > A, p.Glu715Lys in TARS2 and the variants were confirmed by Sanger sequencing. The patient was diagnosed with combined oxidative phosphorylation deficiency 21 according to the Online Mendelian Inheritance in Man (OMIM) database based on the clinical data and the deleterious effect of the two variants in TARS2 predicted by in silico tools. CONCLUSIONS: We presented one case diagnosed with combined oxidative phosphorylation deficiency 21 based on clinical characteristics and genetic analysis. This is the first case in China and the fourth case in the world based on our document retrieval. This study facilitates the understanding of combined oxidative phosphorylation deficiency disease and demonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphorylation deficiency.

Evaluation of a mitochondrial disease criteria scoring system on mitochondrial encephalomyopathy in Chinese patients.

Due to the complicated clinical features of mitochondrial encephalomyopathy, simplified mitochondrial disease criteria (MDC) have recently been established in Europe. This study evaluated the sensitivity and specificity of this scoring system in Chinese patients. Seventy-eight patients with suspected mitochondrial encephalomyopathy were recruited to be scored by the simplified MDC and were further classified into "possible" (2-4), "probable" (5-7), or "definite" categories (≥8). Significant differences were observed between the total scores in the mitochondrial encephalomyopathy group and the other myopathy group. In the mitochondrial encephalomyopathy group, 73.5% of patients had a score above 8, whereas in the other myopathy group, the "definite" percentage was only 3.2%, suggesting the proposed MDC scoring system has a high sensitivity for diagnosis of mitochondrial encephalomyopathy in China. Moreover, there were significant differences in the clinical scores and imaging portions of the MDC, suggesting that the simplified MDC may distinguish mitochondrial disorder from other multisystem disorders to aid in early diagnosis prior to a muscle biopsy.

Mitochondrial neurogastrointestinal encephalopathy in an Indian family with possible manifesting carriers of heterozygous TYMP mutation.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a distinctive autosomal recessive disorder with mitochondrial alterations due to mutations TYMP gene encoding thymidine phosphorylase. MATERIALS AND METHODS: Study of clinical and biochemical characteristics of a family with MNGIE. RESULTS: Index case was a 32 year old man presenting with recurrent vomiting, early satiety and progressive weight loss. He had ptosis, restricted eye movements, generalized muscle wasting, and absent tendon reflexes. Lactate levels were elevated in venous blood and CSF lactate. MRI brain showed diffuse leucoencephalopathy. Barium swallow showed near total obstruction at mid portion of vertical limb of duodenum with ileus. Esophageal manometry suggested myopathy. Muscle biopsy revealed moderate numbers of ragged blue and ragged red fibers as well as cytochrome c oxidase deficient fibers. An elder brother had similar symptoms and expired after a surgical procedure and a 28 year old brother has similar illness. The father had asymptomatic bilateral ptosis with mild ophthalmoparesis. The paternal grandfather and paternal aunt also had bilateral ptosis. Clinical diagnosis of MNGIE was confirmed in the two living brothers by demonstrating severe defects of thymidine phosphorylase activity in buffy coat, elevated thymidine and deoxyuridine in plasma, and a homozygous TYMP c.893G>A mutation. CONCLUSIONS: This family with biochemically and genetically confirmed mitochondrial neurogastrointestinal encephalopathy syndrome uncharacteristically included heterozygous TYMP mutation carriers manifesting extra-ocular weakness. It is important to identify MNGIE patients early because therapeutic options are emerging.

An overview of a cohort of South African patients with mitochondrial disorders.

Mitochondrial disorders are frequently encountered inherited diseases characterized by unexplained multisystem involvement with a chronic, intermittent, or progressive nature. The objective of this paper is to describe the profile of patients with mitochondrial disorders in South Africa. Patients with possible mitochondrial disorders were accessed over 10 years. Analyses for respiratory chain and pyruvate dehydrogenase complex enzymes were performed on muscle. A diagnosis of a mitochondrial disorder was accepted only if an enzyme activity was deficient. Sixty-three patients were diagnosed with a mitochondrial disorder, including 40 African, 20 Caucasian, one mixed ancestry, and two Indian patients. The most important findings were the difference between African patients and other ethnicities: respiratory chain enzyme complexes CI+III or CII+III deficiencies were found in 52.5% of African patients, being of statistical significance (p value = 0.0061). They also presented predominantly with myopathy (p value = 0.0018); the male:female ratio was 1:1.2. Twenty-five (62.5%) African patients presented with varying degrees of a myopathy accompanied by a myopathic face, high palate, and scoliosis. Fourteen of these 25 also had ptosis and/or progressive external ophthalmoplegia. No patients of other ethnicities presented with this specific myopathic phenotype. Caucasian patients (16/20) presented predominantly with central nervous system involvement. Of the South African pediatric neurology patients, Africans are more likely to present with myopathy and CII+III deficiency, and Caucasian patients are more likely to present with encephalopathy or encephalomyopathy.

[Mitochondrial DNA mutation analysis in 97 Chinese patients with mitochondrial cephalomyopathy].

OBJECTIVE: To investigate the characteristics of mitochondrial DNA mutations and genotype-phenotype correlations in mitochondrial encephalomyopathies. METHODS: Biopsy of skeletal muscle and collection of peripheral blood samples were conducted among 97 patients with mitochondrial encephalomyopathies. Southern blotting, PCR-RFLP and direct sequencing of PCR products were performed to search large scale deletions, and common and uncommon pathological point mutations in the muscle and/or blood mtDNA. RESULTS: Seventy-seven patients were identified to be with mitochondrial DNA mutations, including single large deletion (n = 21), multiple large-scale deletions (n = 4), A3243G point mutation (n = 43), A8344G point mutation (n = 6), T8993G mutation (n = 1), T8993C mutation (n = 1), and T3271C mutation (n = 1). Total mtDNA sequencing revealed 4 different novel point mutations in four unrelated patients with isolated mitochondrial myopathy. CONCLUSION: The type and frequency of mtDNA mutations in this series of Chinese mitochondrial encephalopathies are consistent with those reported abroad, Although there is some association between the genotype and phenotype, heterogeneity in phenotype and genotype is also a prominent feature seen in this series of patients, especially those with A3243G mutation.