Analysis of retinal sublayer thickness in Leber hereditary optic neuropathy and G11778A mutation carriers / 中华眼底病杂志

Objective:To analyze the thickness of peripapillary retinal nerve fiber layer (pRNFL) and photoreceptor (PR) sublayer in Leber hereditary optic neuropathy (LHON) and G11778A mutation carriers. Methods:A cross sectional study. From September 2020 to October 2021, 68 LHON patients (136 eyes) (patient group) and 40 G11778A mutation carriers (80 eyes) of LHON patients' families (carrier group) were included in the study. All patients were found to have G11778A mutation by Genetic testing. Forty healthy volunteers with 80 eyes matched to the age and gender of the patient group were recruited as a normal control group. All eyes were examined by optical coherence tomography (OCT). The pRNFL thickness was automatically measured by the built-in software of the OCT device. The total retinal thickness (MT) and the thickness of the outer bundle layer (OPL), outer nuclear layer (ONL), external limiting membrane to retinal pigment epithelium (ELM-RPE) in macular OCT images were measured by Image J software. Linear mixed model was used to analyze and compare the thickness of pRNFL, macular fovea and four layers above the nasal and temporal paracentral retina in patients, carriers and normal controls. The correlation between pRNFL and macular retinal sublayer thickness and the course of disease was also analyzed. Results:The thickness of the upper and lower pRNFL, temporal pRNFL and average pRNFL of the patients were smaller than those of the carriers and the normal control group ( P<0.01), and the nasal pRNFL thickness of the patients was smaller than that of the carriers ( P<0.01). Fovea: compared with the normal control group, the thickness of MT and ONT in the patient group was decreased, ONL thickness decreased in carrier group, with the significant different ( P<0.05). Parafovea: compared with normal control group, the thickness of MT and temporal ONL decreased and temporal OPL increased in the patients group, with the significant different ( P<0.05). In the carrier group, the thickness of MT and temporal, nasal ONL decreased, and the thickness of nasal OPL increased, with the significant different ( P<0.05). Compared with the carrier group, the MT thickness of the patient group was decreased, and the nasal ONL and nasal ELM-RPE thickness were increased, with the significant different ( P<0.05). Correlation analysis results showed that the thinning of pRNFL in the superior, nasal, temporal and average ( r=-0.22, -0.21, -0.25, -0.22), and the thickening of ELM-RPE in foveo-temporal ( r=0.19) were correlated with the course of disease ( P<0.05). Conclusions:The pRNFL of LHON patients with G11778A mutation becomes thinner and is related to the course of the disease. There were significant differences in the thickness of MT and PR sublayers between patients and carriers compared to the normal control group.

Approach to the diagnosis of metabolic myopathies

Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.

Neonatal mitochondrial disease / 中国小儿急救医学

Mitochondrial disease refers to an energy metabolic disorder caused by dysfunction of oxidative phosphorylation system or pyruvate dehydrogenase complex as a result of mitochondrial DNA or nuclear DNA mutation.It can occur at any age arranging from newborn to adult, which is often presented as clinical syndromes.Common clinical manifestations in neonatal period include premature delivery, intrauterine growth restriction, hypotonia, dyspnea, convulsions, feeding difficulties, hyperlactic acid, etc, lacking of specificity.Neonatal onset syndromes include Leigh syndrome, mitochondrial encephalomyopathy-lactic acidosis and stroke-like episodes syndrome, Alpers syndrome, myocerebrohepatopathy spectrum disorder, Barth syndrome and Pearson syndrome.The diagnosis depends on the comprehensive analysis of clinical symptoms, biochemical tests, neuroimaging, histological tests and genetic tests.In most cases, there are few effective drugs.Gene therapy and exogenous mitochondrial transplantation are the directions of future exploration.

Valoración ética de las nuevas opciones reproductivas en las enfermedades mitocondriales / Ethical value of new reproductive choices in mitochondrial diseases / Valoração ética das novas opções reprodutivas nas enfermidades mitocondriais

Las enfermedades mitocondriales son un grupo de desórdenes clínicamente heterogéneo con manifestaciones clínicas muy variables y alta tasa de morbi-mortalidad. Tienen complejas implicancias en la reproducción, ya que los riesgos de repetición en la familia son variables, 25% en las formas autosómicas recesivas, alrededor de 4% en los casos de mutaciones mitocondriales de novo, y un riesgo incierto pero elevado si la madre es portadora de las mutaciones mitocondriales. Por ello, se proponen distintas técnicas de diagnóstico preimplantacional, prenatal o de reproducción asistida a fin de evitar el nacimiento de niños con esta patología. En el presente trabajo se describen y analizan las implicancias científicas y éticas de las nuevas técnicas de reproducción asistida que se proponen a las familias con alto riesgo.

Mitochondrial diseases are a clinically heterogeneous group of disorders with variable clinical features and high morbidity and mortality. As there are different hereditary patterns, complex implications in reproduction are expected; the recurrence risk may be about 25% in autosomal recessive inheritance, 4% in de novo mitochondrial mutations, and an uncertain, but high risk, when the mother is carrier of mitochondrial mutations. Thus, different preimplantation and prenatal diagnosis or assisted reproductive techniques are proposed to avoid the birth of children with these diseases. In this paper scientific and ethical implications of new assisted reproductive techniques offer to high risk families are describe and analyzed.

As enfermidades mitocondriais são um grupo de desordens clinicamente heterogêneos com manifestações clínicas muito variáveis e alta taxa de morbi-mortalidade. Têm complexas implicações na reprodução, já que os riscos de repetição na família são variáveis, 25% nas formas autossômicas recessivas, ao redor de 4% nos casos de mutações mitocondriais de novo, e um risco incerto porém elevado se a mãe é portadora das mutações mitocondriais. Por isso, se propõem distintas técnicas de diagnóstico pré-implantacional, pré-natal ou de reprodução assistida a fim de evitar o nascimento de crianças com esta patologia. No presente trabalho se descrevem e analisam as implicações científicas e éticas das novas técnicas de reprodução assistida que se propõem às famílias com alto risco.

Lactic Acidosis in Children: Clinical and Laboratory Evaluation / 대한소아신경학회지

PURPOSE: Lactic acidosis is one of the most common forms of metabolic acidosis. It is hard to fine the cause of lactic acidosis, because in many cases the clinical features of this disorder are non-specific and overlap with those of other metabolic or non-metabolic diseases. In this report, we tried to identify the causes of lactic acidosis and classified them into four groups:primary and secondary lactic acidosis, neurodegenerative disorders and others. METHODS: We analyzed the clinical characteristics of 22 patients who had arterial blood lactate levels over 2.5 mmol/L. They visited Ilsan Hospital because of seizures or delayed development. Clinical characteristics include laboratory findings, EEG, brain imaging study, chromosomal study and metabolic enzymatic evaluation. RESULTS: The mean age of the patients was 3.4 years. Most of them complained of delayed development(21 cases) and seizures(14 cases). One of the patients was revealed as primary lactic acidosis, and the other one secondary lactic acidosis. Also, there was a case of neurodegenerative disease. Furthermore, the other ten patients were affected by other causes of lactic acidosis:7 cases of epilepsy, a case of Rett syndrome, a case of 4p deletion syndrome, and a case of cerebral palsy. However, the causes of lactic acidosis of the remaining 9 patients were unknown. But 5 of them were thought to be affected by respiratory chain disorders diagnosed by modified Walker's criteria. CONCLUSION: There are numerous disorders in children which can produce lactic acidosis. Although metabolic work-ups of these patients are very complex and require coordinated efforts of clinicians and laboratory works, early diagnosis of the etiologic nature of the disease is essential to minimize the progression and the complications of the disease.

A Case of Leigh Syndrome with Typical MRI and MRS Findings

Leigh syndrome (LS) is a genetically and clinically heterogeneous disorder caused by metabolic defects affecting lactate/pyruvate metabolism. The consequence of the metabolic defects are decreased amounts of APT and basic cell energy productions of the nervous system. In LS, several mutations have been reported in both the nuclear and the mitochondrial genome. Here, we report a 26-year-old woman clinically diagnosed with LS having characteristic brain MR and MRS abnormalities but without known definite pathogenetic mitochondrial DNA mutations.