Neonatal muscular manifestations in mitochondrial disorders

During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation.     

COA6基因新发变异致婴儿细胞色素c氧化酶缺陷致心脑肌病4型1例报告并文献复习

目的 提高对婴儿细胞色素c氧化酶缺陷致心脑肌病4型(CEMCOX 4)临床表型及基因型的认识.方法 回顾分析1例婴儿CEMCOX 4患儿的临床资料并复习相关文献.结果 女性患儿,5日龄,出生后即出现呼吸困难;多次血气分析示乳酸增高;心脏彩超示肥厚型心肌病,双侧心室流出道梗阻.全外显子测序发现患儿COA 6基因存在c.4...     

Congenital hypertrophic cardiomyopathy,cataract, mitochondrial myopathy and defective oxidative phosphorylation in two siblings with Sengers-like syndrome

We describe two siblings with a Sengers-like syndrome, who presented with congenital hypertrophic cardiomyopathy, infantile cataract, mitochondrial myopathy, lactic acidosis and normal mental development. A mitochondrial adenine nucleotide translocator 1 (ANT1) defect was detected since the ANT1 protein was not detectable by immmunoblotting in muscle samples of the patients. Additionally to these features of classical Sengers syndrome (OMIM 212350), we found that the mitochondrial oxidative phosphorylation, measured by biochemical analysis, was severely compromised in skeletal muscle in both children. Biochemical and morphological analysis of the fibroblasts revealed normal results. The association of significantly decreased pyruvate oxidation rates, deficient energy production and decreased multiple mitochondrial enzyme-complex activities in the muscle samples of our patients is a new finding which differs from previous results in patients with Sengers syndrome. Conclusion:we recommend a muscle biopsy and the biochemical analysis of the oxidative phosphorylation system in patients with muscle hypotonia, cardiomyopathy and congenital or infantile cataract.Abbreviations ANT1 adenine nucleotide translocator 1 - COX cytochrome c oxidase - SDH succinate dehydrogenase     

Cytochrome c oxidase deficiency in a child with isolated myopathy

Cytochrome c oxidase (COX) deficiency is the most commonly recognized respiratory chain defect in childhood. The disease is clinically heterogeneous with phenotypes including Leigh syndrome, hepatic failure and myopathies. COX deficiency has been associated with mitochondrial DNA mutations in COX I, II, and III with large-scale deletions of the mitochondrial genome and with point mutations in mitochondrial tRNA genes. Here we report on a 3.5-year-old girl with a rare type of isolated myopathy due to COX deficiency.     

Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.     

Fatal combined defects in mitochondrial multienzyme complexes in two siblings

A female child suffering from intrauterine growth retardation was born by caesarean section at 32 weeks. In the immediate newborn period there was a metabolic acidosis but this resolved. Hypotonia, muscular weakness and poor respiratory effort were evident and the child died at 6 days of age. A previous male sibling had died at 3 months of age after similar symptoms with seizures and a dysmyelination disorder. Post-mortem examination of both children showed damage to the basal ganglia. Defects in the activities of the pyruvate dehydrogenase complex, cytochrome oxidase and succinate cytochrome c reductase were found in cultured skin fibroblasts. Similar defects were found in isolated muscle mitochondria but not in isolated liver mitochondria from the patient. Immunoblotting for cytochrome oxidase showed that the multienzyme complex was not assembled in muscle and skin fibroblast mitochondria, but was assembled in liver mitochondria. Similar results were obtained in cultured skin fibroblast mitochondria for complex I of the mitochondrial respiratory chain. This is the first occasion that multiple defects have been demonstrated both in tissue and in culture skin fibroblasts in mitochondrial respiratory chain complexes.     

Early-onset fatal encephalomyopathy associated with severe mtDNA depletion

Abstract We studied a 3-month-old girl who was admitted to hospital because of respiratory distress. The clinical course was characterized by a rapidly progressive generalized hypotonia with lactic acidosis and she died at 4 months of age. A muscle biopsy showed few ragged-red fibres and lack of histochemical cytochrome c oxidase reaction in all fibres. Enzyme activities of the respiratory chain complexes containing subunits encoded by the mitochondrial DNA (mtDNA) were markedly decreased. A quantitative Southern blot analysis revealed 99% depletion of mtDNA in muscle and normal amounts in blood. There was no family history and the dizygotic twin sister of the patient was no symptomatic.Conclusion This new case confirms the rapidly fatal evolution associated with severe depletion of muscle mtDNA     

Fatal infantile liver failure associated with mitochondrial DNA depletion.

A 3-month-old girl was admitted to the hospital because of hypotonia and frequent vomiting. She had severe metabolic acidosis and her liver function was abnormal. Hepatomegaly and rapidly progressive liver failure developed, and she died at 4 months of age. Two half-siblings from a different mother had died in infancy of an undiagnosed myopathy. The liver was fatty and hepatocytes were filled with large and small lipid droplets. Other tissues were morphologically normal. The respiratory chain enzymes containing subunits encoded by mitochondrial DNA were markedly decreased in liver, partially decreased in muscle, but normal in other tissues. Southern blot analysis showed 90% depletion of mitochondrial DNA in liver, 53% depletion in muscle, and normal amounts in other tissues. This is the second case of fatal infantile liver failure associated with mitochondrial DNA depletion. This pathogenetic mechanism should be considered in infants with multiple respiratory chain defects and variable tissue expression.     

Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review

Barth syndrome presents in infancy with hypotonia, dilated cardiomyopathy, and neutropenia. We report a patient whose family history included two males who had died suddenly at the age of 15 days and 2 years, respectively. The index case presented with acute metabolic decompensation at 13 days of age. Within 8 h of presenting with metabolic acidosis (pH 7.13), lactic acidemia (18.5 mmol/l), hyperammonemia (375 mug/dl), hypoglycemia (25 mg/dl), and coagulopathy, the patient developed respiratory failure and required intubation. The diagnosis was established by the presence of left ventricular noncompaction and molecular analysis (c.C153G or Y51X mutation of the TAZ gene). The gene product, taffazin, is a homologue of the glycerolipid transferases involved in the phospholipid metabolism as tetralinoleoyl-cardiolipin, a component of the mitochondrial inner membrane. In conclusion, mutations in taffazin impair mitochondrial respiratory chain complexes, which may results in the acute metabolic decompensation and sudden death; cardiac transplantation is the only possibility at the present time.     

The use of skin fibroblast cultures in the detection of respiratory chain defects in patients with lacticacidemia

Cultured skin fibroblasts from patients with lacticacidemia were incubated with glucose for 1 h and the lactate and pyruvate production measured. Those patients with increased lactate to pyruvate ratios were further analyzed for the cause of the abnormal redox state. Two categories of patients are described. The first contains patients with either severe or partial cytochrome oxidase deficiency; this group can be broken down further into patients with Leigh's disease, Kearns-Sayre syndrome, and liver-specific cytochrome oxidase deficiency. In this group, the rise in lactate to pyruvate ratio roughly correlated with the severity of the defect. The second patient category had defects located in complex I of the mitochondrial respiratory chain. This is easily demonstrated in the most severely affected patients with the fatal infantile form of the disease. Patients with severe defects in either complex I or cytochrome oxidase had complexes that were only partially assembled. Patients with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes demonstrated only minor changes in redox state and in the behavior of the mitochondrial respiratory chain.     

Infantile form of muscle phosphofructokinase deficiency in a premature neonate

Muscle phosphofructokinase (PFK) deficiency is a rare autosomal recessive disease. We report the case of a preterm female infant who was diagnosed with the infantile form of phosphofructokinase deficiency due to a lack of PFK activity in her muscles, manifesting at a corrected age of 1 month as floppy infant syndrome, congenital joint contracture, cleft palate and duplication of the pelvicalyceal system. She died at a corrected age of 6 months due to respiratory failure. We further reviewed other infantile cases in the literature. Congenital hypotonia (78.6%), arthrogryposis (64.3%) and other systemic involvement including encephalopathy (35.7%) and cardiomyopathy (21.4%) are common presentations of the infantile form of PFK deficiency. The overall survival rate of the infantile form is low. The early recognition of multiple system involvement is essential to provide better clinical care for infants with the infantile form of PFK deficiency.     

Encephalomyelopathy, cardiomyopathy, cataract and changes in the retinal pigment epithelium resulting from a cytochrome c oxidase deficiency

A 4 1/2 months old female baby was admitted to our hospital after an unexpected heart attack. Birth was in the 37th gestational week after an uneventful pregnancy and delivery by sectio, birth weight 1650 g, Apgar 9/10/10. In the following weeks the baby showed general muscle hypotonia, failure to thrive and sometimes an uncharacteristic heart murmur. Besides a chronic lactic acidemia we found a hypertrophic cardiomyopathy, cataract and small defects of the pigment epithelium of the retina. The CT-scan of the brain showed hypodense areas of both thalami and the mid-brain. Metabolic examination of two muscle specimens showed a deficiency of cytochrome-c-oxidase activity (I: 30, II: 20, normal: 73-284 mU/mg protein). So our patient may be the first case with an established defect in the respiratory chain suffering from cardiomyopathy, cataract and mitochondrial dysfunction. There is also a strong similarity to other encephalomyopathies especially to the Leigh-Syndrome.     

Clinical, biochemical and molecular analyses of six patients with isolated cytochrome c oxidase deficiency due to mutations in the SCO2 gene

BACKGROUND AND AIM: Cytochrome c oxidase (COX) deficiency represents a heterogeneous group of disorders. Numerous proteins are required for efficient COX assembly and maintenance. In 26 children with isolated COX deficiency, we studied mutations in the SCO2 gene, which is involved in the copper transport into the inner mitochondrial membrane, and we analysed the clinical and biochemical consequences of SCO2 mutations. METHODS: The activities of respiratory chain complexes were measured spectrophotometrically in isolated mitochondria and/or crude cell extracts in all available tissues. Two-dimensional polyacrylamide electrophoresis (2D-PAGE) was used to separate the complexes and their subunits. The mutations were detected by sequencing and RFLP analysis. RESULTS: Mutations in the SCO2 gene were found in six children. Early neonatal onset of hypertrophic cardiomyopathy and encephalopathy were observed in one boy with compound heterozygous mutations C1280T and G1541A. In all five children with homozygous mutation G1541A, progressive encephalopathy developed between 2 and 6 mo of age. Isolated COX deficiency was found in the skeletal muscle, heart, liver and brain but not in fibroblasts. 2D-PAGE in the skeletal muscle showed markedly decreased amounts of all COX subunits. CONCLUSION: Our results suggest that mutations in the SCO2 gene are not rare, at least in our population. Although clinical symptoms may rely on the type of SCO2 mutation, the prognosis is unfavourable in all patients.     

SURF1基因突变导致Leigh综合征家系1例

Leigh综合征是一种由于线粒体氧化磷酸化障碍所导致的严重退行性脑病。常染色体SURF1基因突变所致细胞色素C氧化酶缺乏是导致Leigh综合征的常见原因,国外已报道多种突变类型。该研究回顾了1例SURF1基因604G>C杂合性错义突变所致中国人Leigh综合征患者及其家系的临床与遗传学特点。患者,女, 9个月起病,表现为喂养困难,营养不良,进行性运动倒退,肌张力低下,眼震。17个月时来院就诊, 23个月时死于呼吸衰竭。脑MRI显示双侧基底节对称性损害,脑干、小脑萎缩。聚合酶链式反应扩增SURF1基因的全部外显子,进行序列测定及限制性片断长度多态性分析均显示患者及其母亲、舅舅的SURF1基因的外显子7存在一个604G>C杂合性错义突变,其父亲及正常对照的相关外显子序列未发现异常。该研究首次报道了1例中国人群中由于SURF1基因604G>C杂合性错义突变导致的Leigh综合征及其家系,不仅明确了病因,亦将有助于今后对患者家系的遗传咨询。     

线粒体心肌病研究进展

心肌细胞线粒体结构和功能的异常导致心肌能量代谢异常,临床表现为心肌病,称为线粒体心肌病.线粒体心肌病患儿具有肥厚型心肌病或扩张型心肌病的临床特征,常伴多系统损害,如身材矮小、感音性重听、肌张力低下、小脑共济失调、智力低下、视网膜色素变性、白内障等.该病主要由线粒体DNA突变所致.目前尚无特效治疗方法,治疗措施主要包括心肌病的一般治疗及并发症的对症治疗,可应用辅酶Q10、大剂量B族维生素等.目前开始探讨基因治疗的可能性.     

Clinical presentation of mitochondrial respiratory chain defects in NADH-coenzyme Q reductase and cytochrome oxidase: clues to pathogenesis of Leigh disease

Measurement of pyruvate and lactate produced from glucose by confluent skin fibroblast cultures from 95 patients with lactic acidemia revealed 10 in whom the lactate/pyruvate ratio (L/P) was increased (L/P = 57 to 232) compared with that observed in control cell lines (L/P = 18 to 35). Mitochondria prepared from these cells revealed two types of respiratory chain defect. In four patients the deficient activity was present in NADH-coenzyme Q reductase (14% to 21% of controls), and in six the deficiency was in cytochrome c oxidase (21% to 28% of controls). The four patients with NADH-coQ reductase deficiency presented early with lactic acidosis, respiratory failure, anorexia, and hypotonia; all four died within 7 months. The group with cytochrome oxidase deficiency had a somewhat later (18 months to 2 years of age) presentation with milder lactic acidemia, but also with hypotonia and anorexia. They had delayed development, beginning to walk and talk at 18 to 24 months, and then slowly regressed. Although an investigation of central nervous system disorders in this latter group has not been possible, the clinical progression fits into the broad category of Leigh disease. We conclude that in these two groups respiratory chain defects can be detected and localized by the use of skin fibroblast cultures.     

Infantile cardiomyopathy and neuromyopathy with β-galactosidase deficiency

We observed an infant with congenital cardiomyopathy, muscular weakness and hypotonia, who developed hepatosplenomegaly and died from heart failure at the age of 8 months. His condition (including electromyographic findings) resembled infantile Pompe disease but was different by echocardiography, morphology of lymphocyte inclusions, and enzymatic studies demonstrating an almost total deficiency of -galactosidase activity towards methylumbelliferyl substrate in leucocytes, plasma and fibroblasts. His parents had about half the normal activities in leucocytes and plasma. Whilst -galactosidase deficiency in an infantile storage disorder is characteristic of generalized (type 1) GM₁-gangliosidosis, this patient differed by the striking involvement of the cardiac and skeletal muscles and the lack of facial and osseous changes. This case and a similar one reported underlines the necessity to consider storage disorders apart from glycogenosis in congenital cardiomyopathy.     

Autosomal recessive lethal infantile cytochrome C oxidase deficiency.

Three bedouin children with mitochondrial myopathy due to cytochrome c oxidase deficiency presented with progressive muscle weakness, failure to thrive, proximal renal tubular acidosis, and lactic acidemia leading to death. Two died by age 5 months and one by age 16 months. Cytochrome c oxidase was markedly reduced in skeletal muscle extracts of all three. Three other children of the same family with most probably the same metabolic aberration are also described. We suggest an autosomal recessive inheritance for this lethal mitochondrial myopathy.