Humans ; Leigh Disease/therapy* ; Consensus ; Brain ; DNA, Mitochondrial

Introduction: Leigh disease and Leigh-like syndrome are a heterogenous group of neurodegenerative disorders involving any level of the neuraxis and may present with a variety of clinical presentations, prominent among them is psychomotor regression. Despite the remarkable number of established disease genes and novel mutations being discovered, many cases of Leigh syndrome remain without a genetic diagnosis, indicating that there are still more disease genes to be identified. Case: Here we present a case of a two and a half-year-old girl who presented with delayed acquisition of developmental milestones with subsequent regression, ataxia, and dyskinesia. Her work-up showed raised blood lactate levels and lactate peak in MR spectroscopy. Mitochondria genome showed absence of mitochondrial DNA mutation, while whole exome sequence analysis revealed a novel dynein gene variant, p.A1577S. Her parents underwent genetic testing as well, and her father also had the same dynein mutation, however, is non-symptomatic. She had an older brother who initially presented with ophthalmoplegia and eventually developed psychomotor regression. He subsequently expired from respiratory failure after almost 2 years from initial presentation. Both siblings were diagnosed with Leigh syndrome. Conclusion The diagnosis of Leigh syndrome remains based on characteristic clinical and radiologic findings. However, a specific defect must be identified if reliable genetic counseling is to be provided.
Neurodegenerative Diseases|leigh Disease

OBJECTIVE: To explore the clinical and genetic characteristics of a child with MEGDEL syndrome. METHODS: Clinical data of the child was reviewed. Peripheral blood samples of the child and his parents were collected. Mitochondrial genome and the whole exome of the child were analyzed by next-generation sequencing. Candidate variants and its origin were verified by Sanger sequencing and fluorescence quantitative PCR. RESULTS: The patient, a 2-year-and-6-month-old male, has featured hypoglycemia, mental and motor retardation with regression. Cranial MRI showed bilateral putamen damage suggestive of Leigh syndrome. Testing of urine organic acid indicated that the level of 3-methylpentenoic acid was slightly increased. Whole exome sequencing revealed that the child has harbored heterozygous deletion of exons 6 to 17 and c.307A>T nonsense variant of the SERAC1 gene, which were respectively inherited from his parents who were asymptomatic. Treatment with Levocarnitine, vitamin B1, vitamin B2, coenzyme Q10, baclofen and glucuronolactone resulted in improvement of sleep and mental state. CONCLUSION A case of MEGDEL syndrome without deafness was diagnosed. Discovery of the nonsense mutation and large fragment deletion have enriched the spectrum of SERAC1 gene variants.
Child, Preschool ; Hearing Loss, Sensorineural/genetics* ; Humans ; Leigh Disease ; Male ; Metabolism, Inborn Errors/genetics* ; Molecular Biology ; Mutation

OBJECTIVE: To explore the genetic basis for a child with Leigh syndrome. METHODS: Clinical features and laboratory test of the patient were analyzed. Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of the mitochondrial genome were carried out. Next generation sequencing (NGS) was used to capture and sequence nuclear genes related to mitochondrial structure and function. RESULTS: The child presented with developmental delay, unsteady gait, falling episodes, bilateral upper extremity tremor, muscle hypertonia, convulsions, and mouth angle asymmetry. Serum lactic acid was significantly increased. Cranial MRI showed abnormal signal in bilateral cerebellar hemispheres, bilateral basal ganglia, left thalamus, and corona radiata. Her mother and brother did not show any anomalies. Sanger sequencing revealed the child, her mother and brother all carried the MT-ND3 m.10191 T>C mutation, with heterogeneous rates respectively being 74.34%, 9.73%, and 6.28%. MLPA revealed heterogeneity of (MT-ND6, MTCYB-390nt)] deletion in all three individuals. No significant mutation was found by NGS sequencing of the children, their parents and brother. CONCLUSION Leigh syndrome can be caused by the simultaneous existence of multiple mitochondrial genes, and multiple mutations may play a synergic role in the occurrence of the disease.
Child ; DNA, Mitochondrial ; Female ; Genes, Mitochondrial ; High-Throughput Nucleotide Sequencing ; Humans ; Leigh Disease ; genetics ; Male ; Mutation

Asian Continental Ancestry Group ; Genotype ; Humans ; Leigh Disease ; genetics ; pathology ; Phenotype ; Retrospective Studies

PURPOSE: Leigh syndrome (LS) is a rare, progressive neurodegenerative disorder with characteristic abnormalities in the central nervous system. Such patients present with heterogeneous clinical symptoms and genetic abnormalities; thus, prognosis is difficult to anticipate. The present study investigates whether distinct patient characteristics are associated with mitochondrial DNA (mtDNA) mutation in LS patients. METHODS: We retrospectively analyzed data from patients diagnosed with LS at our hospital who were assessed using genomic sequencing of mtDNA. A subgroup analysis was performed to divide patients according to the mtDNA sequencing results. RESULTS: Among the 85 patients enrolled, 18 had mtDNA mutations. Most patients had lactic acidosis and a lactate/pyruvate ratio above 20, indicating respiratory chain abnormalities. In the subgroup analysis, the mutation group had a significantly higher female-to-male ratio, alanine level, ocular involvement, and midbrain and medulla abnormalities on magnetic resonance imaging (MRI). CONCLUSION: The subgroup analysis indicates that mtDNA sequencing is recommended for female patients, or those who exhibit ocular involvement, high alanine levels, or MRI findings with lesions in the midbrain and medulla.
Acidosis, Lactic ; Alanine ; Brain Stem ; Central Nervous System ; DNA, Mitochondrial* ; Electron Transport ; Female ; Humans ; Leigh Disease* ; Magnetic Resonance Imaging ; Mesencephalon ; Mitochondria ; Neurodegenerative Diseases ; Prognosis ; Retrospective Studies

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.
Child ; Child, Preschool ; Creatine Kinase ; blood ; Cytochrome-c Oxidase Deficiency ; DNA, Mitochondrial ; genetics ; Fasting ; blood ; cerebrospinal fluid ; Female ; Humans ; Infant ; Lactic Acid ; blood ; cerebrospinal fluid ; Leigh Disease ; diagnostic imaging ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; genetics ; Neuroimaging ; methods

BACKGROUND AND PURPOSE: Few studies have analyzed the clinical course and functional outcome in Leigh syndrome (LS). The aim of this study was to determine the clinical, radiological, biochemical, and genetic features of patients with LS, and identify prognostic indicators of the disease progression and neurological outcome. METHODS: Thirty-nine patients who had been diagnosed with LS at the Seoul National University Children's Hospital were included. Their medical records, neuroimaging findings, and histological/biochemical findings of skeletal muscle specimens were reviewed. Targeted sequencing of mitochondrial DNA was performed based on mitochondrial respiratory chain (MRC) enzyme defects. RESULTS: Isolated complex I deficiency was the most frequently observed MRC defect (in 42% of 38 investigated patients). Mitochondrial DNA mutations were identified in 11 patients, of which 81.8% were MT-ND genes. The clinical outcome varied widely, from independent daily activity to severe disability. Poor functional outcomes and neurological deterioration were significantly associated with early onset (before an age of 1 year) and the presence of other lesions additional to basal ganglia involvement in the initial neuroimaging. CONCLUSIONS: The neurological severity and outcome of LS may vary widely and be better than those predicted based on previous studies. We suggest that age at onset and initial neuroimaging findings are prognostic indicators in LS.
Basal Ganglia ; Disease Progression ; DNA, Mitochondrial ; Electron Transport ; Humans ; Leigh Disease* ; Medical Records ; Muscle, Skeletal ; Neuroimaging ; Seoul

OBJECTIVETo explore the application value of next generation sequencing (NGS) in the diagnosis of mitochondrial disorders.

METHODAccording to mitochondrial disease criteria, genomic DNA was extracted using standard procedure from peripheral venous blood of patients with suspected mitochondrial disease collected from neurological department of Beijing Children's Hospital Affiliated to Capital Medical University between October 2012 and February 2014. Targeted NGS to capture and sequence the entire mtDNA and exons of the 1 000 nuclear genes related to mitochondrial structure and function. Clinical data were collected from patients diagnosed at a molecular level, then clinical features and the relationship between genotype and phenotype were analyzed.

RESULTMutation was detected in 21 of 70 patients with suspected mitochondrial disease, in whom 10 harbored mtDNA mutation, while 11 nuclear DNA (nDNA) mutation. In 21 patients, 1 was diagnosed congenital myasthenic syndrome with episodic apnea due to CHAT gene p.I187T homozygous mutation, and 20 were diagnosed mitochondrial disease, in which 10 were Leigh syndrome, 4 were mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes syndrome, 3 were Leber hereditary optic neuropathy (LHON) and LHON plus, 2 were mitochondrial DNA depletion syndrome and 1 was unknown. All the mtDNA mutations were point mutations, which contained A3243G, G3460A, G11778A, T14484C, T14502C and T14487C. Ten mitochondrial disease patients harbored homozygous or compound heterozygous mutations in 5 genes previously shown to cause disease: SURF1, PDHA1, NDUFV1, SUCLA2 and SUCLG1, which had 14 mutations, and 7 of the 14 mutations have not been reported.

CONCLUSIONNGS has a certain application value in the diagnosis of mitochondrial diseases, especially in Leigh syndrome atypical mitochondrial syndrome and rare mitochondrial disorders.

Child ; DNA, Mitochondrial ; genetics ; High-Throughput Nucleotide Sequencing ; Homozygote ; Humans ; Leigh Disease ; Mitochondrial Diseases ; diagnosis ; Mitochondrial Encephalomyopathies ; Mutation ; Optic Atrophy, Hereditary, Leber ; Phenotype ; Point Mutation ; Sequence Analysis, DNA

OBJECTIVETo investigate the clinical features and genetic characteristics of patients with 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) gene mutations.

METHODThe clinical data of a patient with novel HIBCH mutations were collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center for Biotechnology Information and PubMed (up to December 2014) by using search terms" HIBCH", "3-hydroxy-isobutyryl-CoA hydrolase" or "beta-Hydroxyisobutyryl CoA Deacylase Deficiency". The clinical features, neuroimage and treatment of the patients with HIBCH gene mutations were studied.

RESULTThe patient was a girl who was born at term after an uneventful pregnancy to non-consanguineous healthy parents, she was hospitalized at 5 years and 5 months of age because of development delay for 5 years and 5 months and abnormal posture on the left of body for more than 10 days. The family history was unremarkable. Her psychomotor development was significantly delayed. Three times brain MRI between 2. 5 years and 5 years of age revealed bilateral symmetrical lesions in basal ganglia. At the age of 5 years and 5 months, she presented with acute encephalopathy and severe extrapyramidal symptoms preceded by fever. At that time, her brain MRI revealed aggravated lesions in bilateral basal ganglia, new lesions in the midbrain cerebral peduncle and pons, and cerebellar atrophy. The results of biochemical tests were normal. A novel compound heterozygous mutation of HIBCH gene, c. 1027C > G, p. H343D and c. 79-1G > T, splicing, were found in the parent. Further study showed that c. 1027 C > G mutation was inherited from her father and c. 79-1 G > T from her mother. Her symptoms were mitigated after "cocktail" therapy and symptomatic treatment. Repeated brain MRI revealed that the lesion in basal ganglia got better, the lesions in brain stem disappeared. Literature relevant to HIBCH published all around the world was reviewed, no Chinese cases with HIBCH gene mutations had been reported, 6 foreign cases with HIBCH gene mutations were reported. Among them, 5 patients were diagnosed as Leigh-like syndrome, with progressive neurodegenerative course, and symmetrical basal ganglia lesions on brain MRI. Another case was reported in 1982, with developmental delay and various physical malformations without data on his brain MRI. HIBCH gene mutational analysis showed that 4 cases had homozygous mutations, which were c. 950G > A (p. G317E) in two brothers, c. 219 _220insTTGAATAG (p. K73fsX86) and c. 1128_1129insT (p. K377X) respectively. Three of them died before 3 years old. Two cases had compound heterozygous mutations: c. 365A > G (p. Y122C) and IVS2-3C > G (p. R27fsX50); c. 517 + 1G > A and c. 410C > T (p. A137V). They were alive at the time of the report.

CONCLUSIONPatients with HIBCH gene mutation mainly presented as Leigh-like syndrome both in clinical manifestation and in neuroimage. HIBCH gene mutational analysis should be performed on children with Leigh-like syndrome, if the mutations of known genes of Leigh syndrome were negative.

Abnormalities, Multiple ; diagnosis ; genetics ; Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Female ; Heterozygote ; Homozygote ; Humans ; Infant ; Leigh Disease ; diagnosis ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; Siblings ; Thiolester Hydrolases ; deficiency ; genetics