琥珀酸半醛脱氢酶缺陷病一例

患儿女 ,2岁 3个月 ,主因“运动及语言发育迟缓 1年”来我科就诊。患儿为第 1胎 ,足月顺产出生。出生时一般情况好。 5个月抬头稳 ,10个月出牙 ,1岁能独坐 ,1岁多才会爬 ,至今独自站立不稳 ,行走时步态异常 ,极易摔跤。现只会叫“爸爸、妈妈” ,虽然不能表达 ,但能听懂别人的话 ,能正确完成一些简单的指定动作。会有意识的笑 ,不能自己穿衣 ,不会使用匙吃饭。近半年家属发现患儿有阵发性全身用劲 ,伴有头不自主抖动 ,持续数分钟自行缓解。并且在没有任何诱因的情况下时不时表现惊恐状。婴儿期无喂养困难。父母健康 ,非近亲婚配。家族中无类…     

琥珀酸半醛脱氢酶缺陷病

琥珀酸半醛脱氢酶（SSADH）缺陷病是一种少见的常染色体隐性遗传病。本研究总结3例SSADH缺陷病患儿的临床资料并复习相关文献。3例患儿均为婴幼儿,主要表现为智力运动、语言发育落后,抽搐和肌张力低下。3例患儿脑电图均表现异常;2例脑MRI检查异常,表现为大脑脚对称性长T2高信号和基底节损害;3例尿液的气相色谱-质谱（GC-MS）分析均显示4-羟基丁酸增高,根据临床表现及尿液GC-MS分析确诊为SSADH缺陷病。对不明原因发育迟缓、智力运动障碍和癫癎的患儿应早期进行尿液有机酸分析,对明确诊断具有重要意义。     

Selective involvement of the globus pallidus and dentate nucleus in succinic semialdehyde dehydrogenase deficiency

MRI findings in a 12-year-old boy with succinic semialdehyde dehydrogenase (SSADH) deficiency are described. SSADH deficiency is a rare neurometabolic disorder of GABA catabolism. The clinical diagnosis is difficult and the disease is underdiagnosed. MRI showed an unusual pattern with hyperintense signal in the globus pallidus and cerebellar dentate nucleus in T2-weighted images. The remaining basal ganglia and white matter were normal. This is the second report showing this particular pattern of pallidal-dentate nucleus involvement, which might be suggestive for SSADH deficiency.     

Defective succinic semialdehyde dehydrogenase activity in 4-hydroxybutyric aciduria

Succinic semialdehyde dehydrogenase deficiency has been demonstrated in a fourth patient with 4-hydroxybutyric aciduria. Lysates of freshly isolated lymphocytes and cultured lymphoblasts of the patient had much lower than control activity in the conversion of U-¹⁴C-4-aminobutyric acid to ¹⁴C-succinic acid in an assay designed to estimate succinic semialdehyde dehydrogenase utilizing endogenous 4-aminobutyrate transaminase. Lymphocyte and lymphoblast lysates of the patient accumulated U-¹⁴C-succinic semialdehyde when incubated with U-¹⁴C-4-aminobutyric acid and NAD⁺ whereas none could be detected in controls. Assays using U-¹⁴C-succinic semialdehyde as substrate for succinic semialdehyde dehydrogenase in lysates of cultured lymphoblasts characterized the patient as having a severe deficiency of succinic semialdehyde dehydrogenase. The data indicate that defective activity of succinic semialdehyde dehydrogenase is responsible for 4-hydroxybutyric aciduria.     

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.     

Oxidation of [U-14C]succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria

The oxidation of [U-14C]succinic semialdehyde to 14CO2 has been investigated in cultured lymphoblasts to develop a whole cell assay for succinic semialdehyde dehydrogenase. We have previously demonstrated deficiency of this enzyme in extracts of white cells derived from 13 patients with 4-hydroxybutyric aciduria. Major goals were the demonstration of greater residual succinic semialdehyde dehydrogenase activity in patient cell lines and the better representation of physiology in vivo. In 18 control lymphoblast lines, the conversion of [U-14C]succinic semialdehyde to 14CO2 was 1579 +/- 310 dpm. The mean value in lymphoblasts derived from 11 patients with deficiency of succinic semialdehyde dehydrogenase was 112 +/- 36 dpm approximating 7% of the mean control value. Analysis of organic acids produced from [U-14C]succinic semialdehyde in control lymphoblasts indicated that 14CO2 emanated from the tricarboxylic acid cycle; the major metabolic products were succinic and lactic acids. In the presence of 5mM malonic and 2-propylpentanoic (valproic) acids, 14CO2 production in a control lymphoblast line was decreased by 68 and 45%, respectively. The whole cell assay is less laborious than our previously described assay employing cell extracts, and the general trend was the demonstration of higher residual levels of activity for lymphoblasts derived from patients.     

ALDH5A1基因突变致琥珀酸半醛脱氢酶缺陷症1例报告并文献复习

目的探讨ALDH5A1基因突变致琥珀酸半醛脱氢酶缺陷症(SSADHD)的临床特征,基因突变及致病机制。方法回顾分析1例SSADHD患儿的临床资料和基因测序结果,并复习相关文献。结果患儿,女,3岁6个月,表现为反复发作的发作性肌张力障碍。头颅磁共振成像、视频脑电图、血液生化检查、血尿遗传代谢筛查均无异常。基因测序显示,ALDH5A1基因外显子区域有2处杂合突变,c.112GA(p.A38T)(致病性尚不明确)、c.1529CT(p.S510F)(已报道的致病突变);2处杂合突变分别来自其父母,为复合杂合突变,符合常染色体隐性遗传规律。确诊为ALDH5A1突变致SSADHD。检索到相关文献26篇,报道75种ALDH5A1突变,分别位于外显子1～11,涉及错义突变、缺失突变、插入突变、剪切突变和无义突变。结论 ALDH5A1基因突变与SSADHD发生密切相关,基因检测有助SSADHD确诊。     

Short-chain hydroxyacyl-coenzyme A dehydrogenase deficiency presenting as unexpected infant death: A family study

We describe a case of liver-specific short-chain hydroxyacyl-coenzyme A dehydrogenase deficiency. Enzymatic confirmation of heterozygosity was shown in family members, illustrating the recessive nature of this new disorder. Heterozygous carriers did not present with biochemical abnormalities when challenged by fasting.     

Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria).

Succinic semialdehyde dehydrogenase deficiency is one of the disorders of GABA metabolism, so it is not surprising that seizures occur as one of the symptoms in affected patients. Other features that are described include delayed development, hypotonia, myopathy with ragged red fibres, abnormal behaviour, and ocular abnormalities. Neonatal problems include prematurity, respiratory difficulties, and hypoglycaemia. The responsible gene has been identified on the short arm of chromosome 6. There are many mutations, and there is poor genotype-phenotype correlation resulting in difficulties in diagnosis. The pathogenesis of the condition is discussed, especially the results of the disturbed GABA catabolism, and the production of the gamma-hydroxybutyric acid. The many properties of this substance suggest it may act as a neurotransmitter or neuromodulator in the brain. The diagnosis may be difficult as the clinical picture is not really suggestive, but the MRI examination can help if it shows abnormalities in the globus pallidus. It will be confirmed by finding an excess of 4-hydroxybutyric acid in the body fluids; and the methods of estimation are discussed. Prenatal diagnosis is possible using a combination of methods. Treatment possibilities are limited. Vigabatrin should be of value as it is an inhibitor of GABA transaminase, but results have been disappointing. Symptomatic treatment may well be needed for control of seizures, abnormal behaviour and other disorders; and special educational needs must be served.     

Triose phosphate isomerase deficiency: report of a family

Triose phosphate isomerase (TPI) deficiency is associated with a syndrome of congenital non-spherocytic haemolytic anaemia, mental subnormality, motor impairment, growth failure and cardiac failure. The deficiency state is characterized by moderately reduced red cell TPI activity, and marked instability of the abnormal enzyme to heat. The clinical features of an affected child are described, and some problems in the laboratory diagnosis delineated.     

Glucose-6-phosphate dehydrogenase deficiency with recurrent infections: case report

OBJECTIVE: To report a case of rare neutrophil functional disorder with clinical and laboratory findings similar to those of chronic granulomatous disease. METHODS: Patient with extremely reduced level of glucose-6-phosphate dehydrogenase and recurrent infections that improved after continuous use of cotrimoxazole. The patient presented leukocytes with defective respiratory burst, similar to what occurs in chronic granulomatous disease. COMMENTS: The diagnosis of glucose-6-phosphate dehydrogenase deficiency in neutrophils should be considered in any patient with hemolytic anemia whose level of G6PD is extremely low or in any patient that presents recurrent infections as differential diagnosis of chronic granulomatous disease.     

Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy

Clinical course, diagnostic and therapeutic management, and neurodevelopmental outcome were evaluated in 11 patients with glutaryl-coenzyme A dehydrogenase deficiency. In 9 patients macrocephalus was present at or shortly after birth and preceded the neurological disease. In 7 children an acute illness resembling encephalitis appeared after a period of normal development; 2 had developmental delay and progressive "dystonic cerebral palsy." Later, all 9 displayed typical signs of a disorder of the basal ganglia. In 1 patient with macrocephalus the disorder was diagnosed before the onset of neurological disease; in another it was diagnosed prenatally. Computed tomography and magnetic resonance imaging scans revealed severe generalized cerebral atrophy, most striking in the frontal and temporal lobes in 10 patients. Further deterioration was halted after initiation of treatment consisting of low-protein diets, special formulas low in lysine and tryptophan, and supplements of riboflavin and L-carnitine. Only 1 patient showed a slight clinical improvement. Later, dietary therapy was discontinued in 2 older patients and relaxed in a third without observed adverse effects. Two patients in whom treatment could be initiated before the onset of neurological symptoms have developed normally. However, duration of follow-up (6 and 29 months) does not yet allow classification of glutaryl-coenzyme A dehydrogenase deficiency as a treatable disorder. Total body production of glutaric acid, reflected in the daily urinary output, was efficiently reduced by therapeutic measures. Levels of glutaric acid in plasma and cerebrospinal fluid remained unchanged, which may in part explain the overall unsatisfactory outcome. All patients presented with a severe secondary deficiency of carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency

A family is described in which the father and three (and probably all four) of his children had a decreased capacity for the oxidation of medium-chain fatty acids. One of the children suddenly died at the age of 16 months following an episode of a rapidly deteriorating Reye syndrome-like illness with hypoketotic hypoglycemia and dicarboxylic aciduria, but without any previous alarming symptoms. The eldest sibling had died at the age of 19 months under similar conditions. The other family members had always been healthy. On fasting, all affected family members accumulated in their plasma the medium-chain fatty acids octanoic, decanoic, and cis-4-decenoic acids. Their urinary organic acid excretion profile could be characterized as "dicarboxylic aciduria." A deficiency of medium-chain acyl-coenzyme A dehydrogenase was demonstrated in a postmortem liver sample of the index patient. Cultured fibroblasts from the father and the two healthy children had a decreased rate of [14C]octanoate oxidation. It is suggested that a deficiency of medium-chain acyl-coenzyme A dehydrogenase may lead to a life-threatening illness when other complicating factors such as diarrhea and vomiting result in an abnormal depletion of the body's glycogen stores. Careful monitoring of at-risk patients during a minor illness is necessary.     

Short-chain acyl-coenzyme A dehydrogenase deficiency in mice

A murine model for short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency has been identified and characterized in BALB/cByJ mice. These mice have undetectable SCAD activity, severe organic aciduria; excreting ethylmalonic and methylsuccinic acids and N-butyrylglycine, and develop a fatty liver upon fasting or dietary fat challenge. The mutant mice develop hypoglycemia after an 18-h fast, and have elevated urinary and muscle butyrylcarnitine concentrations. Most of these findings parallel those of human disorders associated with SCAD deficiency and other beta-oxidation defects. This mouse model presents important opportunities to investigate the biology of mammalian fatty acid metabolism and the related human diseases.     

Sleep in the family

Family systems are dynamic, with reciprocal interactions among family members. When children have sleep problems, they often awaken a parent, affecting parent sleep and subsequent parent daytime functioning. Child sleep patterns can also be disrupted by parent cognitions related to the child's sleep, as well as when parents are experiencing external stressors (eg, work or marital problems). This article focuses on sleep in a family context, reviewing the relationship between sleep among children and their parents from infancy to adolescence. Sleep in the family when a child has a chronic illness or development disorder is also reviewed.     

Hyperuricemia in medium-chain acyl-coenzyme A dehydrogenase deficiency.

Six infants and children with medium-chain acyl-coenzyme A dehydrogenase deficiency were found to have hyperuricemia during an acute episode. Hyperuricemia may be a clue to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency.     

2甲基3羟基丁酰辅酶A脱氢酶缺陷症一家系基因突变分析

目的 对一个2甲基3羟基丁酰辅酶A脱氢酶缺陷症(MHBDD)家系进行基因突变分析,为疾病的诊断及遗传咨询提供依据.方法 采集患儿及父母外周静脉血,分别提取总RNA及基因组DNA.应用RT-PCR方法扩增ACAT1基因全编码区序列.应用PCR方法扩增ACAT1基因启动子序列及HADH2基因全部外显子编码区及两侧内含子区域.所有扩增产物,均进行直接测序并与参考序列进行比对.结果 患儿1岁1个月,主要表现为精神运动发育迟缓,就诊时尚不能独站,生化检测血乳酸升高(3.19 mmol/L),头颅核磁提示髓鞘发育延迟,气相色谱质谱检测提示乙酰乙酰辅酶A硫解酶缺陷症.ACAT1基因全编码区及启动子区域未见异常突变位点,HADH2基因第4外显子发生c.388C ＞T(p.R130C)半合子改变,使编码的第130位精氨酸变成了半胱氨酸.患者母亲该位点为杂合改变,父亲正常.结论 通过基因突变分析确诊了1例2甲基3羟基丁酰辅酶A脱氢酶缺陷症患儿,p.R130C是该患儿的致病突变,为准确的遗传咨询提供了可能.