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.

Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population.

BACKGROUND: Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs. METHODS: We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines. RESULTS: Sixty-six patients with pre-biopsy MDC scores of 3-8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC. CONCLUSIONS: We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

[Analysis of NFU1 gene mutation in a Chinese family affected with multiple mitochondrial dysfunction syndrome].

OBJECTIVE: To detect potential mutation of NFU1 gene in a Chinese family affected with multiple mitochondrial dysfunction syndrome (MMDS). METHODS: For a mother with two children died of MMDS, next-generation sequencing (NGS) was used to scan her exome. Suspected mutation was validated with PCR and Sanger sequencing. Potential mutation of exons 1 to 8 and flanking regions of the NFU1 gene was also detected in the father by PCR and Sanger sequencing. RESULTS: A novel deletional mutation c.90delC(p.Tyr30Ter) of the NFU1 gene was found in the mother, while the father was found to have carried a heterozygous c.572A>T (p.Asp191Val) mutation. The same mutations were not found among 100 healthy controls. CONCLUSION: The novel mutations c.90delC (p.Tyr30Ter) and c.572A>T (p.Asp191Val) of the NFU1 gene probably underlie the pathogenesis of MMDS in our case. Combined NGS and Sanger sequencing may provide efficient and accurate diagnosis for this disease.

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.

Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting.

Experience with new-born screening (NBS) for disorders of fatty-acid oxidation (FAOD) is now becoming available from an increasing number of programs worldwide. The spectrum of FAOD differs widely between ethnic groups. Incidence calculations from reports from Australia, Germany, and the USA of a total of 5,256,999 newborns give a combined incidence of all FAOD of approximately 1:9,300. However, it appears to be much lower in Asians. Consequently, a significant prevalence and evidence for a clear benefit of NBS is proven for medium-chain acyl-CoA dehydrogenase deficiency (MCAD) only in countries with a high percentage of Caucasians, with very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) and long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHAD) being additional candidates. The long-term benefit for many disorders has still to be evaluated and will require international collaboration, especially for the rarest disorders. Short-chain acyl-CoA dehydrogenase deficiency (SCAD) [as well as Systemic carnitine transporter deficiency (CTD) and dienoyl-CoA reductase deficiency (DE-RED)] are conditions of uncertain clinical significance, but most FAOD have a spectrum of clinical presentations (healthy-death). Confirmatory diagnostic procedures should be agreed upon to ensure international comparability of results and evidence-based modifications. The case of short-chain acyl-CoA dehydrogenase deficiency (SCAD) deficiency shows that even inclusion of conditions without a clearly known natural course may prove useful with respect to gain of knowledge and consecutive exclusion of a biochemical abnormality without clinical significance, although this line of argument implies the existence of structured follow-up programs and bears ethical controversies. As a final conclusion, the accumulated evidence suggests all FAOD should to be included into tandem mass spectrometry (MS/MS)-based NBS programs provided sufficient laboratory performance is guaranteed.

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.

Minimum birth prevalence of mitochondrial respiratory chain disorders in children.

Mitochondrial respiratory chain disorders comprise a group of perhaps several hundred different genetic diseases. Each individual disorder is rare, but collectively they account for substantial use of health care resources. However, few accurate data on prevalence are available due to problems such as variation in clinical presentation, age of onset, referral practices and limitations of diagnostic methodologies. With this retrospective study, we aimed to determine the minimum birth prevalence of respiratory chain disorders that have onset in childhood, that is the proportion of births that will have onset of symptoms caused by a respiratory chain defect by 16 years of age. Of the 1 706 694 children born in the three south-eastern states of Australia (New South Wales, Victoria and South Australia) between January 1st 1987 and December 31st 1996, samples from 430 were referred for investigation of a respiratory chain disorder. Definite diagnosis of a respiratory chain disorder was made in 86 cases based on defined clinical, pathological, enzyme and molecular criteria. Age at presentation ranged from 0 to 129 months (median 4 months). The total data set predicts a minimum birth prevalence for respiratory chain disorders in children of 5.0/100 000 [95% confidence interval (CI) 4.0-6.2]. A significantly higher figure of 58.6/100 000 (95% CI 34.7-92.6) was noted for Australian families of Lebanese origin. Clinical awareness of respiratory chain disorders and investigation methods have improved since 1987, but not all affected children would have been recognized as such from the more recent years. The minimum birth prevalence of 6.2/100 000 (95% CI 4.5-8.4) for the 43 patients born between 1991 and 1994 is thought to be a more accurate estimate for respiratory chain disorders presenting in childhood. Combining our data with a previous study on prevalence of adult-onset respiratory chain disorders predicts a minimum birth prevalence of 13.1/100 000 or 1/7634 for respiratory chain disorders with onset at any age.