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.     

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 phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia

Eight children (5 living, 3 deceased) with severe hereditary nonspherocytic hemolytic anemia caused by glucose phosphate isomerase deficiency have been observed in two Kentucky and Indiana families. All affected children were severely anemic in early life. Three deaths occurred in young patients who did not receive adequate transfusions of blood or whose parents refused to permit splenectomy. Splenectomy generally abolishes the requirement for blood transfusion. No patient has required regular transfusion of blood after puberty. Growth and development have been surprisingly normal and no patient has died of infection. The anemia is expressed as an autosomal recessive trait, but the enzyme variant can be detected in hematologically normal heterozygotes. The abnormal isomerase molecule is heat labile and is contained in neutrophils and lymphocytes as well as in erythrocytes.     

GLUCOSEPHOSPHATE ISOMERASE DEFICIENCY IN A DUTCH FAMILY

ABSTRACT: Van Biervliet, J. P. G. M. (University Children's Hospital, Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands). Glucosephosphate isomerase deficiency in a Dutch family. Acta Paediatr Scand, 64: 868, 1975.–A mentally retarded girl with severe hemolytic anemia due to glucosephosphate isomerase deficiency is described. The deficiency was detected in erythrocytes, leukocytes, thrombocytes, liver and muscle tissues. Besides the glucosephosphate isomerase deficiency, a glutathione instability of unknown origin was found in the erythrocytes of the propositus.     

Triosephosphate isomerase deficiency. Familial survey and prenatal detection

Triose phosphate isomerase catalyses dihydroxyacetone phosphate to glyceraldehyde 3 phosphate isomerism. Its deficiency associates hemolytic anemia, neurologic abnormalities, relapsing infections and results in encephalopathy or early death. On the occasion of 2 new cases, we report one of the most important familial surveys as 93 subjects were studied, confirming the autosomal recessive transmission of the deficiency and the first results of antenatal diagnosis which could be performed in one of the families.     

Myopathy and growth failure in debrancher enzyme deficiency: improvement with high-protein nocturnal enteral therapy

Seven patients with debrancher enzyme deficiency and childhood or adolescent onset myopathy, four of whom also had growth failure, received long-term treatment consisting of high-protein enteral infusion overnight and high-protein feeds during the day for periods varying from 8 to 42 months. All patients demonstrated improvement in physical activity and endurance. Improvement in muscle strength was documented in five patients, with reversal of myopathic EMG patterns to normal in two patients and reversal of abnormal ECG findings to normal in one patient. All four patients with growth failure showed dramatic improvement in growth rates. This positive response to high-protein enteral therapy supports the concept that myopathy in debrancher enzyme deficiency is at least partly the result of reversible muscle amino acid depletion.     

Glucose phosphate isomerase (GPI) Tadikonda: Characterization of a novel Pro340Ser mutation

After a thirty-year lag, we serendipitously reestablished contact with a patient with glucose phosphate isomerase deficiency and hydrops fetalis first reported in 1987. We now provide a clinical update and provide results of mutation analysis in this patient, from Southern India. The patient now an adult female of 36 years of age has moderate anemia but requires no transfusions except with some intercurrent illnesses. Exome sequencing studies showed a homozygous c.1018C>T (Pro340Ser) mutation in exon 12 of the glucose phosphate isomerase gene and later confirmed by direct sequencing. This mutation has not been previously described. To our knowledge, this is also the first known homozygous mutation in the hydrophobic core of the protein and is a highly deleterious mutation by in silico analysis and by clinical history in the family. Flow cytometry studies of band 3 content with eosin maleimide showed a unique tail of red cells on histograms, reflecting the dense red cells (presumably ATP depleted) seen on blood smears; similar findings were seen in patients with pyruvate kinase and phosphoglycerate kinase deficiency.     

Successful long-term phenobarbital therapy of hyperbilirubinemia in congenital hemolytic anemia due to glucose phosphate isomerase deficiency

Long-term phenobarbital treatment (2 mg/kg body weight/day) permanently reduced hyperbilirubinemia in a patient with congenital non-spherocytic hemolytic anemia due to erythrocyte glucose phosphate isomerase deficiency. Phenobarbital treatment is recommended in patients with congenital hemolytic anemia in whom hyperbilirubinemia is not improved by splenectomy or in whom splenectomy is not indicated. Early phenobarbital treatment may prevent the development of cholelithiasis in patients with chronic hemolysis.With support of the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Schr 86/13     

Glucosephosphate isomerase deficiency in a Dutch family.

A mentally retarded girl with severe hemolytic anemia due to glucosephosphate isomerase deficiency is described. The deficiency was detected in erythrocytes, leukocytes, thrombocytes, liver and muscle tissues. Besides the glucosephosphate isomerase deficiency, a glutathione instability of unknown origin was found in the erythrocytes of the propositus.     

Relationship of vitamin A (retinol) status to lung disease in the preterm infant

Plasma concentrations of retinol and retinol-binding protein were measured at birth in 91 preterm infants. In 64% of these babies retinol values were less than 20 micrograms/dl, suggestive of vitamin A deficiency. Forty-seven of these infants were observed with sequential measurements of retinol and retinol binding protein through 21 days of age. In babies with respiratory distress syndrome retinol values were similar to those in babies without respiratory distress syndrome. The retinol binding protein levels were lower on the third day of life in babies with respiratory distress syndrome. Babies who developed bronchopulmonary dysplasia had lower concentrations of retinol at birth (P less than 0.05) and on day 21 (P less than 0.05) than did babies who did not develop bronchopulmonary dysplasia, despite receiving recommended intakes of vitamin A. Many preterm infants are deficient in vitamin A at birth, and failure to correct this deficiency may contribute to the development of chronic lung disease.     

Malabsorption of iron in children with iron deficiency.

Inability to absorb oral iron is believed to be an extremely rare cause of therapeutic failure in the treatment of iron deficiency anemia. Six patients who had failed to respond to oral iron therapy were studied by a simple oral absorption test and contrasted with 25 patients with untreated iron deficiency anemia and 10 normal subjects. All six of the patients who were therapeutic failures demonstrated impaired iron absorption in the absence of other clinical evidence of gastrointestinal disease. In the 25 newly diagnosed patients with iron deficiency. 24 demonstrated elevated iron absorptions while 10 ironreplete normal subjects had minimal elevations in their serum iron values following the administration of the test dose of 1 mg of elemental iron per kilogram. When the therapeutic failures were treated with parenteral iron, all had a therapeutic response. In addition, after treatment the impaired absorption of iron improved transiently. All children who absorbed iron readily responded to oral iron therapy.     

Acute myeloblastic leukemia following non-hodgkin lymphoma in an adolescent. A report of a case with preleukemic syndrome,and review of the literature

Reports of acute nonlymphoblastic leukemia occurring after successful treatment of Hodgkin and non-Hodgkin lymphoma (NHL) are appearing with increasing frequency. Two years after completion of LSA²-L² therapy for stage III, poorly differentiated lymphocytic lymphoma, a 16-year-old boy developed a preleukemic state characterized by a refractory macrocytic anemia with excess blasts, dyshematopoiesis, abnormal cluster:colony ratio on in vitro bone marrow culture, and acquired deficiencies of erythrocyte pyruvate kinase, triose phosphate isomerase, and adenylate kinase. Four months later acute myeloblastic leukemia was evident. The RNA index determined by flow cytofluorometry was increased. Four marker chromosomes were found and involved complex translocation of chromosomes 11 and 17 (t11;17) in 100% of the cells, and chromosome 4 (t4q;4) in 10% of the cells. A thorough literature search uncovered four other reports of acute nonlymphoblastic leukemia occurring in children treated for NHL and a total of 58 cases in the adult and pediatric age groups. Over 50% of the patients had AML, were men over 50 years of age, and were treated with radiotherapy and chemotherapy. It is anticipated that additional cases of second malignancies will be reported in this population of patients whose outlook for the curability of the primary malignancy is 75%.     

Hyperreactivity to cow milk in young children with pulmonary hemosiderosis and cor pulmonale secondary to nasopharyngeal obstruction.

Six black infants and young children with high titers of milk precipitins were identified by screening the sera of 160 children with idiopathic chronic lung disease. None of the six had immunoglobulin deficiency, elevation of sweat chlorides, SS hemoglobin, or recurrent aspiration. All six children had typical manifestations of milk-induced pulmonary hemosiderosis: recurrent pulmonary infiltrates (6/6), hemosiderin-laden pulmonary macrophages (5/6), intermittent wheezing (5/6), eosinophilia (4/6), anemia (4/6), iron deficiency (4/4), failure to thrive (4/6), and elevated levels of serum IgE (4/4). Three children also had chronic rhinitis and eventually developed large adenoids, hypercapnia and acidosis during sleep, and right heart failure. Elimination of cow milk from the diet, symptomatic therapy, and adenoidectomy when indicated resulted in improvement of all six patients. Pulmonary hemosiderosis and some cases of upper airway obstruction with pulmonary hypertension appear to be two stages, early and delayed, of the same immunophysiologic process. Early dietary intervention may prevent the cardiovascular complications of this process.     

人羊水细胞中SLC25A13基因转录产物的克隆和序列分析

目的：克隆分析citrin蛋白编码基因SLC25A13在人羊水细胞中的mRNA编码区全长,并分析其转录子的序列特征,为从mRNA水平开展 Citrin 缺陷导致的新生儿肝内胆汁淤积症（NICCD）产前诊断提供实验依据。方法：选取1例接受 citrin 缺陷病产前诊断并已证实胎儿为851del4突变携带者的羊水标本;另1例取自无 citrin 缺陷病史患者的羊水细胞标本作为正常对照。抽提体外培养的羊水细胞总RNA,逆转录合成cDNA,通过巢式PCR扩增SLC25A13 cDNA编码区全长。PCR产物克隆后测序分析。结果：从2例羊水细胞标本中成功克隆到SLC25A13 cDNA编码区全长,并发现SLCA型转录子（正常型转录子mRNA）;在正常对照样本中发现 SLCB型转录子（外显子9和10之间CAG插入）;在851del4突变携带者标本中发现SLCC 型转录子（外显子5~11缺失）,未发现含851del4突变等位基因转录产物。结论：SLC25A13 cDNA编码区全长可以从羊水细胞中扩增获得,而外显子5~11缺失型转录子是SLC25A13基因一种新的转录子。在正常对照和包含851del4突变的杂合子胎儿SLC25A13基因转录产物中正常mRNA占据优势,提示胎儿无罹患NICCD风险。这些转录特征可以为NICCD产前诊断提供实验依据。     

Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI

Molybdenum cofactor deficiency type A (MoCD-A) is an inborn error of metabolism presenting early after birth with severe seizures. Recently, experimental substitution treatment with cyclic pyranopterin monophosphate (cPMP) has become available. Because prenatal data is scarce, we report data of prenatal Magnetic Resonance Imaging (MRI) in two cases with MoCD-A demonstrating signs of possible early brain injury. Prenatal MRI can be used for monitoring in MoCD-A to guide decision-making in timing of delivery.     

Hypothalamic failure as a sequela of heterozygous protein C deficiency?

Protein C deficiency can lead to cerebrovascular occlusive disease. We describe a patient in whom heterozygous protein C deficiency (type 1) is suspected on the grounds of reduced protein C activity and who suffered from multiple thrombo-embolic events involving the brain and peripheral organs. The patient developed hypothalamic failure with hypernatraemia, hypodipsia, hypersomnolence and hyperkapnia, obesity, hyperprolactinaemia, hypogonadotropic hypogonadism and growth hormone deficiency. We hypothesize that protein C deficiency caused cerebrovascular occlusions which eventually led to hypothalamic insufficiency in this patient. Disorders of the anticoagulant system should be looked for in patients with unexplained hypothalamic disease.     

Diagnosis and treatment of a newborn with homozygous protein C deficiency

The case is reported of a seriously affected newborn with homozygous protein C deficiency who developed neonatal purpura fulminans. Foetal ultrasound at 33 wk of gestation revealed ventriculomegaly. The first lesions appeared on the scalp 48 h after birth. She was initially treated with fresh-frozen plasma and, after the diagnosis was confirmed, with purified protein C concentrate. After skin necrosis had healed, therapy was continued with oral warfarin. The infant was homozygous for protein C W380G mutation. Diagnosis at the DNA level gave the parents an option of reliable prenatal diagnosis in their subsequent pregnancy. CONCLUSION: Difficulties in reaching an accurate diagnosis are discussed since early diagnosis and urgent therapy with protein C replacement are crucial to avoid further damage after delivery.     

Liver disease associated with alpha1-antitrypsin deficiency in childhood.

Liver disease in children with alpha1-antitrypsin deficiency and protease inhibitor type ZZ does not necessarily carry a bad prognosis. Fourteen of our 18 patients presented with the neonatal hepatitis syndrome and four had hepatomegaly without jaundice. Although four patients have died of cirrhosis and its complications, and three have severe liver disease, most of the 11 others, of whom four are over 13 years of age, have relatively little clinical, biochemical, or histologic evidence of liver disease. Persistent elevation of SGOT during the third year of life and renal or pulmonary problems were associated with a poor prognosis. Liver biopsy early in the course of the disease was not helpful prognostically but was useful in assessment of the severity of liver disease and demonstration of alpha1AT storage, alpha1AT deficiency was found in 29% of our patients who presented with the neonatal hepatitis syndrome. One of seven apparently healthy Pi type ZZ sibs of our patients had significant liver disease which had not been suspected previously.     

Pyruvate-Carboxylase Deficiency with Urea Cycle Impairment

ABSTRACT. We report a case of pyruvate-carboxylase deficiency (EC 6.4.1.1, McKusick 26615) with neonatal onset of lactic acidosis, hyperammonemia, and citrullinemia. The patient developed signs of severe liver damage and died at 13 days of age after increasing metabolic acidosis and severe bleedings. The pyruvate-carboxylase activity in fibroblasts was less than 1% of controls, but normal activities of propionyl-CoA carboxylase (EC 6.4.1.3) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) were found. To prepare for early prenatal diagnosis of pyruvate-carboxylase deficiency, the activity of the enzyme has been measured in chorionic villus samples     

Infantile Refsum disease: deficiency of catalase-containing particles (peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal β-oxidation enzyme proteins

In recent years a number of biochemical abnormalities have been described in patients with the infantile form of Refsum disease, including the accumulation of very long chain fatty acids, trihydroxycoprostanoic acid and pipecolic acid. In this paper we show that catalase-containing particles (peroxisomes), alkyl dihydroxyacetone phosphate synthase and acyl-CoA oxidase protein are deficient in patients with infantile Refsum disease. These findings suggest that in the infantile form of Refsum disease, as in the cerebro-hepato-renal (Zellweger) syndrome the multiplicity of biochemical abnormalities is due to a deficiency of peroxisomes and hence to a generalized loss of peroxisomal functions. As a consequence the infantile form of Refsum disease can be diagnozed biochemically by methods already available for the prenatal and postnatal diagnosis of the cerebro-hepato-renal (Zellweger) syndrome.