A Rare Pitfall in Bone Mineral Densitometry: Gaucher Disease.

ABSTRACT: We report a rare case of type 3 Gaucher disease presenting with calcified mesenteric lymph nodes that interfere with bone mineral densitometric measurements.

Genotype-Phenotype Correlation of the Childhood-Onset Bethlem Myopathy in the Mediterranean Region of Turkey.

OBJECTIVES: Collagen-VI-related myopathies are caused by both dominant and recessive mutations in the three collagen-VI-related genes (COL6A1, COL6A2, and COL6A3) and present as two different major clinical entities; Bethlem myopathy and Ullrich congenital muscular dystrophy. METHODS: In this study, we evaluated the clinical, pathologic, and genetic features of 8 patients with Bethlem myopathy from 3 families. RESULTS: We inspected disease course differences with age and mutations. Different variants in COL6A1 and COL6A2 genes were detected. Muscle MRI of the lower limbs showed a specific pattern of muscle involvement with variable severity of fatty infiltration. One family had essential hypertension. CONCLUSION: Genotype-phenotype correlation studies are critical in determining gene or mutation-targeted therapies, patient follow-up, severity and progression prediction, and genetic counselling.

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.

The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations.

Familial hypobetalipoproteinemia is a codominant disorder characterized by low plasma levels of low-density lipoprotein cholesterol and apolipoprotein B (apoB), which in ∼50% of the cases is due to mutations in APOB gene. In most cases, these mutations cause the formation of truncated apoBs of various sizes, which have a reduced capacity to bind lipids and form lipoprotein particles. Here, we describe 2 children with severe hypobetalipoproteinemia found to be homozygous for novel APOB gene mutations. The first case (HBL-201) was an asymptomatic 13-year-old boy incidentally found to have slightly elevated serum transaminases associated with hepatic steatosis. He was homozygous for a truncated apoB (2211 amino acids, apoB-48.74) whose size is similar to that of wild-type apoB-48 (2152 amino acids) produced by the intestine. ApoB-48.74 is expected to be incorporated into chylomicrons in the intestine but might have a reduced capacity to form secretion-competent very low-density lipoprotein in the liver. The second patient (HBL-96) was a 6-month-old girl suspected to have abetalipoproteinemia, for the presence of chronic diarrhea, failure to thrive, extremely severe hypobetalipoproteinemia, and low plasma levels of vitamin E and vitamin A. She was homozygous for a nonsense mutation (Gln513*) resulting in a short truncated apoB (apoB-11.30), which is not secreted into the plasma. In this patient, the impaired chylomicron formation is responsible for the severe clinical manifestations and growth retardation. In homozygous familial hypobetalipoproteinemia, the capacity of truncated apoBs to form chylomicrons is the major factor, which affects the severity of the clinical manifestations.

A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2.

Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase.

Transient neonatal hyperparathyroidism: a presenting feature of sialidosis type II.

Sialidosis is a lysosomal storage disease caused by deficiency of α-N-acetyl neuraminidase-1. Sialidosis is classified into two main clinical variants: type I, the milder form of the disease, and type II, which can in turn be subdivided into three forms: congenital, infantile, and juvenile. We report a female patient with sialidosis type II, presenting with the congenital form of the disease with thrombocytopenia, pulmonary interstitial thickening, and transient secondary neonatal hyperparathyroidism.

Quality of life in children treated with restrictive diet for inherited metabolic disease.

BACKGROUND: The aim of this study was to investigate the quality of life (QoL) of a group of patients with inherited metabolic diseases (IMD) who were treated with restrictive diet. METHOD: A total of 68 patients (35 boys, 51.5%; 33 girls, 48.5%) with IMD (organic acidemia [OA], n = 14; disorder of carbohydrate metabolism [CMD], n = 33; and disorder of amino acid metabolism [AMD], n = 21) and their parents were inteviewed. Both parents completed a QoL Scale for Metabolic Diseases-Parent Form, a KINDL parent questionnaire, and a depression form. All patients aged ≥4 years completed a questionnaire themselves, including the KINDL-Kid and KINDL-Kiddo self-reports. The semi-standardized interviews were carried out with patients and their parents in a clinical setting. RESULTS: The patients with bad diet compliance had lower scores for school labeling and perception of disease on both the parent and child questionnaire forms (P < 0.05). The patients were then divided into three groups (OA, CMD, AMD) for further analysis. Differences were seen between groups with regard to scores of physical function and school performance according to QoL Scale for Metabolic Diseases-Parent Form (P < 0.01). According to parent perceptions, the CMD patients had better QoL with regard to emotional wellbeing. CONCLUSION: As negative effects of the disease increased, the QoL of IMD patients and their parents decreased in terms of emotional, physical, and cognitive function. Application of expanded newborn scanning programs, early diagnosis, regular follow up, and family education would lessen the effects of the disease and improve the QoL of both families and children.

Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray.

Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by mutations in the G6PC gene encoding glucose-6-phosphatase (G6Pase), a key enzyme for the maintenance of glucose homeostasis. Molecular analysis is a reliable and accurate way of diagnosing GSD Ia without to need for invasive liver biopsies for enzyme tests. In some ethnic groups and geographic regions, allelic homogeneity was detected in GSD Ia. In the present study, the most common 12 mutations in the world were searched by microelectronic array technology, a new method, in 27 Turkish patients diagnosed for GSD Ia and the relation between detected mutations and clinical and laboratory findings was investigated. Mutations causing the disease were detected in 45 (83.3%) of 54 alleles screened in the cases with GSD Ia. Allelic frequency of mutations (p.R83C, p.G270V, p.G188R, p.W77R) looked for were found as 68.5%, 7.4%, 3.7%, and 3.7%, respectively. p.G188R mutation was detected for the first time in a patient of Turkish origin. Eight (p.R170Q, p.Q347X, c.79delC, c.380_381insTA, p.D38V, p.W63X, c.648G>T, c.979_981delTTC) of 12 mutations looked for were coincided in none of the patients. The patient with homozygous p.W77R mutation seemed to present milder clinical and laboratory findings, compared to other patients. In conclusion, we suggest that microarray technology, which allows rapid analysis of frequently detected mutations and has considerably lower costs than other methods, can be successfully used in diagnosis of GSD Ia in populations with allelic homogeneity, such as patients of Turkish origin, instead of screening the whole gene.

Cystic fibrosis presenting with neonatal cholestasis simulating biliary atresia in a patient with a novel mutation.

Neonatal cholestasis is a rare presenting feature of cystic fibrosis which usually cannot be differentiated from other types of cholestasis. Herein, the authors report a 63 d-old boy with cystic fibrosis presenting with neonatal cholestasis mimicking biliary atresia. A new mutation in CFTR gene resulting in severe phenotype has been described. The cystic fibrosis patients with c.3871 G > T mutation may have acholic gaita mimicking biliary atresia in the absence of insipissated bile with minimal histologic findings in the liver.

Hypercalcemia in glycogen storage disease type I patients of Turkish origin.

Glycogen storage disease type I (GSD I) is an autosomal recessive disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-a (G6Pase) catalytic unit characterizes GSD IA and defects in the glucose-6-phosphate transporter protein (G6PC) characterize GSD IB. The main clinical characteristics involve fasting hypoglycemia, hyperuricemia, hyperlactatemia, and hyperlipidemia. Hypercalcemia arose as an unknown problem in GSD I patients, especially in those with insufficient metabolic control. The aim of the present study was to obtain the prevalence of hypercalcemia and to draw attention to the metabolic complications of GSD I patients, including hypercalcemia in poor metabolic control. Hypercalcemia frequency and the affecting factors were studied cross-sectionally in 23 GSD I pediatric subjects. Clinical diagnosis of GSD I was confirmed in all patients either through documentation of deficient G6Pase enzyme activity levels on liver biopsy samples or through G6PC gene sequencing of DNA. Hypercalcemia was detected in 78.3% of patients with GSD I. Different from the previous report about hypercalcemia in a GSD IA patient who had R83H and 341delG mutations, we could not identify any genotype-phenotype correlation in our GSD I patients. Hyperlactatemia and hypertriglyceridemia correlated significantly with hypercalcemia. Furthermore, no differences in serum calcium concentrations could be demonstrated between patients with optimal metabolic control. We observed hypercalcemia in our series of GSD I patients during acute metabolic decompensation. Therefore, we speculate that hypercalcemia should be considered as one of the problems of GSD I patients during acute attacks. It may be related with prolonged lactic acidosis or may be a pseudohypercalcemia due to hyperlipidemia that can be seen in GSD I patients with poor metabolic control.

Very long-chain acyl CoA dehydrogenase deficiency which was accepted as infanticide.

Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) (OMIM #201475) is an autosomal recessive disorder of fatty acid oxidation. Major phenotypic expressions are hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, myopathy, rhabdomyolysis, elevated creatinine kinase, and lipid infiltration of liver and muscle. At the same time, it is a rare cause of Sudden Infant Death Syndrome (SIDS) or unexplained death in the neonatal period [1-4]. We report a patient with VLCADD whose parents were investigated for infanticide because her three previous siblings had suddenly died after normal deliveries.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation.

INTRODUCTION: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder characterized by severe gastrointestinal dysmotility and leads to cachexia, ptosis, external ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy. RESULTS AND DISCUSSION: It is often misdiagnosed as anorexia nervosa or intestinal pseudoobstuctions and are unnecessarily treated with surgery. It has been established that MNGIE is caused by mutations in the gene encoding thymidine phosphorylase, which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine and deoxyuridine. CONCLUSION: We present herein the clinical, neuroimaging, and molecular findings of a patient with MNGIE caused by a novel homozygous TYMP gene mutation (c.112G>T which convert codon 38 from glutamate to a stop codon [p.38E>X]).

Factors related to non-alcoholic fatty liver disease in obese children.

BACKGROUND/AIMS: The incidence of non-alcoholic fatty liver disease has been increasing parallel to obesity in the pediatric age group. This study aimed to analyze the factors that are related to non-alcoholic fatty liver disease in obese children. METHODS: 101 obese children and 68 non-obese controls were included in the study. Liver steatosis was investigated by ultrasonography. The subjects were divided into three groups: 53 obese patients with fatty liver (Group I), 48 obese patients without steatosis (Group II), and 68 controls without steatosis (Group III). Group I was further divided into those with Grade 1 steatosis (44 patients, Group Ia) and higher grades of steatosis (9 patients, Group Ib). The relationships of body mass index, serum ALT, lipids, leptin, and insulin resistance index with steatosis were analyzed. RESULTS: 52.4% of obese children had fatty liver and 13.8% had high ALT levels. Additionally, all patients with elevated ALT levels were seen to have liver steatosis by ultrasonography. Leptin and insulin resistance index levels were higher in obese groups than controls; however, the difference disappeared when these levels were adjusted for body mass index. ALT levels were higher in Group I (31.5+/-30.2) than Group II (18.0+/-7.1) and Group III (14.5+/-5.2) (p<0.05). Group Ib showed higher VLDL and ALT levels than Group Ia (p<0.05). Multiple regression analysis revealed that body mass index was the most important determinant of liver steatosis, while body mass index and VLDL were the determinants of higher ALT levels. CONCLUSIONS: We suggest that body mass index and VLDL are the most important determinants of non-alcoholic fatty liver disease and elevated ALT levels in obese children. The contribution of leptin to this process could not be determined in our findings.

Lipid apheresis applications in childhood: experience in the University Hospital of Gazi.

The most commonly encountered complications in familial hypercholesterolemia (FH) are mainly cardiovascular in origin and the majority of cases unfortunately die due to this problem. LDL-apheresis is a proven therapeutic method in lowering this mortal risk. In this study we aimed to demonstrate the efficiency of LDL-apheresis performed by DALI or Cascade filtration on four pediatric patients with the diagnosis of homozygous FH. Applied LDL-apheresis techniques, side effects, laboratory results and cardiovascular follow-up are discussed in the light of current literature. Our study has shown once again that lipid apheresis treatment in children with homozygous FH is the most effective treatment. The number of childhood subjects in whom lipid apheresis is performed is quite insufficient. There are no studies that compare DALI with cascade filtration in childhood subjects in our knowledge. The view of this aspect, this study will contribute to literature.