Intractable secretory diarrhea in a Japanese boy with mitochondrial respiratory chain complex I deficiency

The etiology of secretory diarrhea in early life is often unclear. We report a Japanese boy who survived until 3 years of age, despite intractable diarrhea commencing soon after birth. The fecal sodium content was strikingly high (109 mmol/L [normal range, 27–35 mmol/L]) and the osmotic gap was decreased (15 mOsm/kg), consistent with the findings of congenital sodium diarrhea. We examined the mitochondrial respiratory chain function by blue native polyacrylamide gel electrophoresis (BN-PAGE) in-gel enzyme staining, BN-PAGE western blotting, respiratory chain enzyme activity assay, and immunohistochemistry. Liver respiratory chain complex (Co) I activity was undetectable, while other respiratory chain complex activities were increased (Co II, 138%; Co III, 153%; Co IV, 126% versus respective control activities). Liver BN-PAGE in-gel enzyme staining and western blotting showed an extremely weak complex I band, while immunohistochemistry showed extremely weak staining for the 30-kDa subunit of complex I, but normal staining for the 70-kDa subunit of complex II. The patient was, therefore, diagnosed with complex I deficiency. The overall complex I activity of the jejunum was substantially decreased (63% of the control activity). The immunohistochemistry displayed apparently decreased staining of the 30-kDa complex I subunit, together with a slightly enhanced staining of the 70-kDa complex II subunit in intestinal epithelial cells. These data imply that intestinal epithelial cells are also complex I-deficient in this patient. Complex I deficiency is a novel cause of secretory diarrhea and may act via disrupting the supply of adenosine triphosphate (ATP) needed for the maintenance of ion gradients across membranes.     

线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症1例并文献复习

目的探讨线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症的临床表现及基因突变特点。方法回顾分析1例确诊为可逆性婴幼儿呼吸链缺乏症患儿的临床资料,并复习相关文献。结果男性患儿,2个月23天,入院时消瘦,呼吸急促,双肺可闻及痰鸣音及喘鸣音;肌力IV级,肌张力减弱。有一胞姐生后不久因重症肺炎去世。入院时肌酸激酶同工酶123 U/L,肌酸激酶890 U/L;血乳酸8.9 mmol/L;病原学检查均为阴性。头颅MRI无异常。入院后患儿持续高乳酸血症、肌酶异常升高,伴呼吸困难,放弃治疗后死亡。基因检查示线粒体MT-TE基因存在14674TC突变,来源于母亲。国外文献报道线粒体MT-TE 14674TC突变患儿早期临床表现与进展型线粒体病类似,呼吸肌无力、喂养困难,运动发育里程碑延迟,肌酶及乳酸升高。予补充能量,维持内环境稳定等治疗,约1岁左右逐渐好转。结论线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症早期表现与进展型线粒体病类似,积极治疗预后良好。早期进行基因检测可明确预后,增强治疗的信心。     

Mitochondrial respiratory chain complex IV deficiency complicated with chronic intestinal pseudo‐obstruction in a neonate

A female infant born at 36 weeks gestational age with birthweight 2135 g, and who developed respiratory disorder, hyperlactacidemia and hypertrophic cardiomyopathy after birth, was admitted to hospital at 3 days of age. After admission, bilious emesis, abdominal distention, and passage disorder of the gastrointestinal tract were resistant to various drugs. Exploratory laparotomy was performed at 93 days of age, but no organic lesions were identified and normal Meissner/Auerbach nerve plexus was confirmed, which led to a clinical diagnosis of chronic intestinal pseudo‐obstruction (CIPO). She was diagnosed with mitochondrial respiratory chain complex IV deficiency on histopathology of the abdominal rectus muscle and enzyme activity measurement. This is the first report of a neonate with mitochondrial respiratory chain complex deficiency with intractable CIPO. CIPO can occur in neonates with mitochondrial respiratory chain disorder, necessitating differential diagnosis from Hirschsprung disease.     

线粒体呼吸链复合物Ⅰ缺陷导致幼儿肝内胆汁淤积症

线粒体呼吸链复合物缺陷是导致儿童线粒体病的主要原因。本文就1例线粒体呼吸链复合物Ⅰ缺陷导致的幼儿胆汁淤积症患者的临床经过、生化特点、线粒体呼吸链复合物活性分析及基因突变进行回顾性研究。患儿,男,自1岁1个月起腹泻,体重下降,伴无力、进行性黄疸、肝损害。经多种检查、尿液有机酸分析及血液氨基酸、酯酰肉碱谱分析未见特异性改变。外周血白细胞线粒体呼吸链复合物Ⅰ活性降低,线粒体基因分析发现患儿及其母亲tRNA 5821G>A突变,证实患儿存在线粒体呼吸链复合物Ⅰ缺陷。患儿疾病进展迅速,治疗无效,于1岁5个月时夭折。复合物Ⅰ缺陷是线粒体呼吸链缺陷中最常见的类型,本研究首次诊断了1例线粒体呼吸链复合物Ⅰ缺陷所导致的中国儿童患者,其临床表现为胆汁淤积症。线粒体肝病是导致儿童代谢性肝病的主要原因之一,生化分析、线粒体呼吸链复合物活性测定及基因分析是病因诊断的关键。     

Mitochondrial respiratory chain complex I deficiency causes intractable gastrointestinal symptoms

We report the case of a 13‐month‐old girl with frequent vomiting, intractable diarrhea, hyperlactatemia, and liver dysfunction. Although the symptoms were treatment resistant, enteral nutrition formula containing medium‐chain triglycerides reduced the weight loss, vomiting, and diarrhea. Immunostaining of mitochondrial respiratory chain (MRC) complexes of the colonic mucosa confirmed the diagnosis of MRC complex I deficiency. This case shows that this disease should be included in the differential diagnosis of hyperlactatemia and intractable, cryptogenic gastrointestinal symptoms. In addition, the mucosa of the affected gastrointestinal organ should be analyzed on immunostaining or electron microscopy for MRC complexes.     

End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation

The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed. Conclusion The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded. Received: 12 October 1999 and in revised form: 26 January 2000 / Accepted: 26 January 2000     

线粒体基因13513G>A突变导致呼吸链酶复合物I缺陷Leigh综合征

Leigh综合征是由于线粒体呼吸链能量代谢障碍所导致的遗传性疾病,呼吸链酶复合物I缺陷是导致Leigh综合征的常见原因之一。该研究通过线粒体基因13513G>A突变分析首次确诊了1例中国人Leigh综合征患者。患儿为第一胎,12岁时出现抽搐,13岁时先后出现双眼视力下降,13岁来院就诊左眼颞侧视野缺损,痉挛步态,血液乳酸、丙酮酸增高,腓肠肌活检肌纤维内脂滴轻度增多;心电图检查显示不完全右束支传导阻滞;脑MRI显示双侧基底节对称性损害,符合Leigh综合征诊断,合并继发性癫癎。经基因分析证实患者存在线粒体基因13513G>A突变,导致线粒体呼吸链酶复合物I活性下降。治疗以多种维生素为主,补充左旋肉碱、辅酶Q10,同时给予卡马西平、苯巴比妥、丙戊酸等抗癫癎治疗。现在患儿16岁,休学,智力无明显倒退,体力、体重显著减退。Leigh综合征病因复杂,临床表现多种多样,该患儿以抽搐起病,合并视力减退,经基因分析明确了病因,有助于相关家庭的遗传咨询 。［中国当代儿科杂志,2009,11（5）：333-336］     

线粒体tRNA变异致儿童罕见线粒体心肌病合并癫痫1例报告

目的探讨线粒体心肌病的临床特点及诊治。方法回顾分析1例罕见的线粒体tRNA变异致心肌病合并癫痫患儿的临床资料,并进行文献复习。结果患儿,男,15月龄,因反复抽搐入院,临床表现为发育迟缓,左心房室扩大、心肌肥厚、左心室收缩功能减低,血乳酸增高,视频脑电图异常;基因检测发现患儿携带tRNA基因4300AG变异。诊断为线粒体心肌病,予强心、利尿、辅酶Q_(10)和左卡尼汀改善代谢及抗癫痫治疗。目前随访3月余,患儿左心房室较前缩小,心功能明显好转。结论儿童心肌病合并神经系统功能障碍、高乳酸血症等多系统官功能障碍时,需注意线粒体心肌病可能。     

Liver cirrhosis in an infant with Chanarin–Dorfman syndrome caused by a novel splice‐site mutation in ABHD5

We described a Turkish girl with Chanarin–Dorfman syndrome who developed liver cirrhosis in the early infancy. She had all the clinical features of Chanarin–Dorfman syndrome such as ichthyosis, Jordan’s anomaly, fatty liver disease and mild ectropion. The diagnosis was confirmed with a novel ABHD5 mutation. Liver steatosis or steatohepatitis with or without hepatomegaly is the predominant finding of Chanarin–Dorfman syndrome. Cirrhosis has been reported in patients with long‐duration disease. Conclusion: Local factors or dysfunction of local proteins such as mutations or polymorphisms in hepatic microsomal lipase and arylacetamide deacetylase may contribute the severity of liver involvement, and steatosis may progress to cirrhosis in the early infancy in Chanarin–Dorfman syndrome.     

Risk of hepatocellular carcinoma in liver mitochondrial respiratory chain disorders

Mitochondrial respiratory chain disorders (MRCD) are a large group of disorders that can affect any organ besides muscles or the central nervous system. We report two children who presented with neonatal cholestasis and progressive cirrhosis, who subsequently developed hepatocellular carcinoma (HCC). This suggests a particular risk of degeneration in these patients and the importance of a regular screening for secondary liver cancer. Suggestion of HCC should lead to early liver transplantation, which was successful without tumor recurrence in the two patients.     

A Chinese girl with Leigh syndrome: Effect of botulinum toxin on dystonia

Leigh syndrome is a form of neurodegenerative disease which is associated with intracranial infarcts. The diagnosis is made by finding hyperlactacidaemia together with cerebral infarcts on neuroimaging. We report a 4-year-old Chinese girl with Leigh syndrome who had several atypical features. She presented with generalized dystonia and developmental regression. In addition, she suffered from an unusual feature of bladder dystonia. This patient appeared to be suffering from respiratory chain complex I deficiency from studies on cultured skin fibroblasts. Assays for respiratory chain enzymes as well as mitochondrial DNA point mutations and major deletions in muscle were normal. Dystonia persisted despite treatments with muscle relaxants and a ketogenic diet. Intramuscular botulinum toxin resulted in significant relief of dystonia.     

Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor

Shigeta T, Kasahara M, Kimura T, Fukuda A, Sasaki K, Arai K, Nakagawa A, Nakagawa S, Kobayashi K, Soneda S, Kitagawa H. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor.
Pediatr Transplantation 2010: 14:E86–E88. © 2009 John Wiley Sons & A/S. Abstract: NICCD is an autosomal recessive genetic disorder, characterized by cholestasis, coagulopathy, hypoglycemia, fatty liver and multiple amino acidemia. NICCD develops in the neonatal/infantile period and has been reported as a “naturally curable” disease within one yr of life. Recently, we experienced an infantile NICCD who developed progressive liver failure, and required subsequent LT using a heterozygote living donor at eight months of age. Diagnosis of NICCD was established before transplantation, and donor evaluation included mutation in the SLC25A13 gene for exclusion of individuals with citrin deficiency citrullinemia. LDLT, from blood type identical mother using a left lateral segment graft, was performed without serious complication. Plasma amino acid concentration was normalized rapidly, and the patient was discharged 30 days after transplant. During one yr follow up, the recipient has been doing well without additional medication for NICCD. NICCD should be considered in the differential diagnosis as a cause of neonatal/infantile cholestatic disease. LT using a heterozygote living donor is an effective alternative in countries where a deceased donor is not available.     

Favourable clinical course in an infant with severe deficiency of complex III of the respiratory chain combined with less severe deficiencies of complexes I, II and IV

An infant with severe deficiency of complex III combined with less severe deficiencies of complexes I, II and IV of the mitochondrial respiratory chain in skeletal muscle tissue presented with intra-uterine growth retardation, generalized hypotonia and delayed motor development. In the following 3.5 years muscle tone and motor development gradually normalized whereas the lactic acidosis and enzyme activities did not improve. Conclusion This report documents a favourable clinical course in a child with combined respiratory chain deficiency despite persistent biochemical abnor-malities. Received: 4 February 1997 / Accepted in revised form: 20 June 1997     

Severe encephalopathy with epilepsy in an infant caused by subclinical maternal pernicious anaemia: case report and review of the literature

Vitamin B₁₂ deficiency is one of the major causes of megaloblastic anaemia with or without neurological symptoms. We report on a patient manifesting acute encephalopathy, epilepsy, microcephaly and megaloblastic anaemia at the age of 4 months. Vitamin B₁₂ deficiency in the patient was due to subclinical pernicious anaemia of the mother who exhibited neither haematological nor neurological symptoms. Mother and child both had elevated methylmalonic acid in their urine which is a sensitive parameter of vitamin B₁₂ deficiency. Vitamin B₁₂ therapy resulted in arrest of convulsions within 24 h. There were no further seizures although the patient showed moderate mental retardation at the age of 7 years but a normal head circumference. Long-term MRI follow-up, performed at the age of 7 years, showed moderate enlargement of the ventricles with reduction of myelin and hypoplasia of the corpus callosum. Conclusion:vitamin B₁₂ deficiency due to maternal pernicious anaemia should always be considered in the differential diagnosis of neurological symptoms in infants and especially in combination with megaloblastic anaemia. Since the age of onset and the duration of neurological symptoms may contribute to the development of long-term symptoms, early diagnosis and treatment is important for vitamin B₁₂ deficient children.