High incidence of co-existing factors significantly modifying the phenotype in patients with Fabry disease.

Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ±â€¯12,1 Range 8-46) and 16 males (Age 24,56 ±â€¯15,04 Range 2-48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co-existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.

Hematologic Findings of Inherited Metabolic Disease: They are More Than Expected.

Inherited metabolic diseases are pathologic conditions that generally develop as a result of impairment of the production or breakdown of protein, carbohydrate, and fatty acids. Early determination of hematological findings has a positive effect on the prognosis of metabolic diseases. Three hundred eighteen patients who were being followed-up within the previous 6 months at Department of Pediatric Nutrition and Metabolism, Gazi University, Turkey, were included in the study. The hematological findings were classified under 7 main groups: anemia of chronic disease, iron deficiency anemia, vitamin B12 deficiency anemia, hemophagocytosis, leukocytosis, and thrombocytosis. Nine hundred twenty-two hematological examinations of the 319 patients were included in the study, and 283 hematological findings were determined, 127 anemia of chronic disease, 81 iron deficiency anemia, 56 cytopenia, and 4 vitamin B12 deficiency anemia. Leukocytosis (n=1), thrombocytosis (n=5), and hemophagocytosis (n=9) were also observed. It was determined that, although anemia of chronic disease and nutritional anemia are the most common hematological findings, these may be diagnosed late, whereas neutropenia, thrombocytopenia, pancytopenia, and hemostasis disorders may be diagnosed earlier. Our study is the most comprehensive one in the literature, and we think it would positively contribute to the monitoring and prognosis of congenital metabolic diseases.

Diagnostic dilemma: osteopetrosis with superimposed rickets causing neonatal hypocalcemia.

Osteopetrosis is a rare genetic condition of reduced osteoclastic bone resorption which causes defective bone remodeling and skeletal sclerosis during growth, having effects on many organs and tissues. Mutation of T-cell immune regulator 1 (TCRG1) gene is the most common genetic defect leading to osteopetrosis, with poor prognosis. The autosomal recessive form presents in the infantile period (also known as malignant infantile osteopetrosis--MIOP), and is characterized by fractures, short stature, hepatosplenomegaly, compressive neuropathies, hypocalcemia and pancytopenia. Being a rare disease with non-specific clinical manifestations, the diagnosis is difficult and usually delayed. Rickets is a characteristic feature of MIOP which results from the defect in osteoclasts to provide a normal Ca/P balance resulting in the poor mineralization of the osteoid. Various treatment options have been suggested for osteopetrosis, but hematopoietic stem cell transplantation still remains the only curative treatment option presently. The authors report the case of a 46-day-old girl with late-onset neonatal hypocalcemia and rickets that was later diagnosed as osteopetrosis. This case report emphasizes that infantile osteopetrosis is an important cause of neonatal hypocalcemia. As irreversible complications develop within the first months of life, immediate diagnosis and early intervention are crucial and may be life-saving.

Serum dipeptidyl peptidase-IV: a better screening test for early detection of mucopolysaccharidosis?

We aimed to investigate the diagnostic utility of serum DPP-IV enzyme activity, urinary GAG/Cre ratio, chitotriosidase activity, total adenosine deaminase (ADA) and ADA-1 isoenzyme activity in the diagnosis of MPS. 31 MPS patients which were previously diagnosed by clinical and enzymatic analysis and 31 healthy controls matched with age and gender were included in this study. Serum DPP-IV enzyme activity, urinary GAG/Cre ratio, total ADA and ADA-1 isoenzyme activity were significantly higher in patients than in controls (p<0.001, p<0.001, p=0.038 and p=0.006, respectively). There were significant correlations between serum DPP-IV enzyme activity and urinary GAG/Cre ratios, ADA-1 activity, ADA-1/total ADA (r=0.498, p<0.001; r=0.348, p=0.006; r=0.270, p=0.034, respectively). Area under ROC curve for DPP-IV enzyme activity was 0.988, p<0.001 and for urinary GAG/Cre ratio was 0.986, p<0.001. DPP-IV enzyme activity and urinary GAG/Cre ratio were the most significant parameters according to the univariate logistic regression analysis (p=0.001 and p<0.001, respectively). The measurement of serum DPP-IV enzyme activity can be used complementary to the urinary GAG/Cre ratio for first-line MPS screening, since it is more less prone to age and hydration related interferences.

Rapid molecular diagnosis of genetic diseases by high resolution melting analysis: fabry and glycogen storage 1A diseases.

For inborn errors of metabolism, high resolution melting analysis (HRMA) is a rapid, efficient, simple, and inexpensive method for mutation/rare variant screening. HRMA is a recent molecular technique for genotyping single-nucleotide polymorphisms without using probes. Here we apply HRMA to the α-galactosidase a (GLA) and glucose-6-phosphatase-alpha (G6PC) genes for mutation detection of patients with Fabry disease (MIM 301500) and glycogen storage disease type 1A (GSD1A; MIM 232200), respectively. To evaluate the procedure, genomic DNAs were blindly tested for known GLA mutations (c.658C>T, c. 679C>T, c.772G>A, c.796G>A, or c.718-719delAA) in three affected males and two obligate heterozygotes with Fabry disease, a G6PC mutation (c.247C>T) in a patient homozygous for that lesion, and 10 healthy control Turkish individuals. HRMA clearly detected the mutant amplicons and discriminated them from all wild-type GLA or G6PC amplicons. HRMA proved to be a sensitive, specific, and cost-effective mutation screening method for the rapid molecular diagnosis of these inborn errors of metabolism, indicating that the technique can be readily adapted to other genetic diseases.

Home sleep study characteristics in patients with mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction may result from multiple causative factors which may impact severely upon morbidity and mortality. METHODS: We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Metabolic Unit. Patients underwent home-based sleep measurements, and sleep respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index (AHI), hypopnea index, oxygen desaturation index, and minimal oxygen saturation were obtained through home sleep study. RESULTS: For 19 children, the disorder was normal in 1, mild (AHI=1.5-5/h) in 5, moderate (AHI=5-10/h) in 2, and severe (AHI>10/h) in 11. The prevalence of OSA was 94.7 % (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients. CONCLUSION: Home sleep study is a quick and accessible screening test to determine the abnormalities of breathing during sleep and enables clinicians to take necessary action for patients with severe manifestations.

Severe renal tubulopathy in a newborn due to BCS1L gene mutation: effects of different treatment modalities on the clinical course.

Very early onset Toni-Debré-Fanconi Syndrome, a disorder of proximal renal tubules of the kidney which results in the increased urinary excretion of glucose, amino acids, uric acid, phosphate and bicarbonate, could be the manifestation of various inborn errors. Defects of oxidative phosphorylation are a heterogeneous group of disorders with various clinical presentations. Recently, patients with early liver failure, renal tubulopathy and encephalopathy due to the mutations in the BCS1L gene coding for a structural protein in mitochondrial complex III have been described. Ten-day-old female newborn was referred to our clinic because of intractable acidosis. Physical examination revealed severe hypotonia, and hepatomegaly. The laboratory examinations revealed lactic acidosis, increased blood alanine, alanine aminotransferase and aspartate aminotransferase levels, generalized aminoaciduria and glucosuria. The tubular reabsorption of phosphate was reduced. Because of multisystem involvement, mitochondrial disease was suspected and the mutational analysis of the BCS1L gene revealed homozygous P99L mutation. As the patient was unresponsive to bicarbonate replacement, oral dichloroacetate and peritoneal dialysis, continuous high dose intravenous sodium bicarbonate therapy with a dose up to 1.25 mEq/kg/h was started. The patient got on well until the age of 9 months when she died of sepsis. It was stressed that high dose intravenous continuous sodium bicarbonate therapy could be an alternative treatment option in patients with severe acidosis and renal tubulopathy resistant to dichloroacetate and peritoneal dialysis. Patients with BCS1L mutations should be considered in the differential diagnosis of severe tubulopathy in the newborn period.

Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: identification of new case with novel mutation.

BACKGROUND: Chronic renal failure (CRF) is a serious complication of Fabry disease (FD). The aims of the present study were to determine the prevalence of unrecognized FD in Turkish hemodialysis population and to investigate the molecular background. METHOD: Primarily, α-galactosidase A (α-Gal A) activity was investigated on DBS in 1136 patients of both sexes who underwent dialysis for CRF in Turkey. The disease was confirmed by analyzing enzyme activity in leukocyte and GLA gene sequencing in all patients in whom α-Gal A level was 40% of normal or less. RESULTS: Mean age of the patients (44.5% female, 52.5% male) was 56.46±15.85 years. Enzyme activity was found low with DBS method in 12 patients (four males, eight females). Two men, but no women, were diagnosed with FD by enzymatic and molecular analysis. In consequence of genetic analysis of a case, a new mutation [hemizygote c.638C>T (p.P214S) missense mutation in exon 5] was identified, which was not described in literature. Family screening of cases identified six additional cases. CONCLUSION: As a result of this initial screening study performed on hemodialysis patients for the first time with DBS method in Turkey, the prevalence of FD was detected as 0.17%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members.

Apheresis-inducible cytokine pattern change in children with homozygous familial hypercholesterolemia.

Familial hypercholesterolemia is a genetic disorder that leads to severe atherosclerosis related cardiovascular complications in young adults. Extracorporeal elimination is a method of LDL-lowering procedures effective in patients with homozygous or severe heterozygous FH utilized in cases. The recruitment of leucocytes into the arterial intima is dependent on a cascade of events mediated through a diverse family of adhesion molecules. Several pro-inflammatory adhesion molecules are cleared by various lipid apheresis methods. This study showed that, LDL-apheresis led to several changes in circulating inflammatory factors which induced antiinflammatory and antiatherogenic changes in the plasma profile in homozygous familial hypercholesterolemic patients.

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]).

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.

Cholesterol screening in school children: is family history reliable to choose the ones to screen?

AIM: Hyperlipidemia is a major factor accompanying atherosclerosis. As the basis of atherosclerotic heart disease begins at early childhood, we aim to find out which children should be tested for hypercholesterolemia, what the high cholesterol level in children is and what cautions should be taken to avoid atherosclerosis. METHODS: The study was carried on 2096 school children (1043 male, 1053 female) in Ankara. Their mean age was 9.03 years. Demographic properties of the study group and their families were determined and the serum lipid levels of the subjects were obtained. The relation between these demographic properties and lipid levels were investigated. RESULTS: In 135 of the subjects' serum cholesterol level was >or=200 mg/dL and in 83 subjects serum LDL-cholesterol level was >or=130 mg/dL. Despite 64.4% of the subjects reported a family history of hyperlipidemia, no relations between family history and serum lipid levels were found. CONCLUSION: We suggest that regardless of family history, all children over 5 years should be screened for hyperlipidemia. Education about hyperlipidemia and precautions for its complications should be given to both children and families. The best and easiest way to reach children is to screen them at schools. School is also a good place for education of children about hyperlipidemia and risk factors.

Serum leptin, oxidized low density lipoprotein and plasma asymmetric dimethylarginine levels and their relationship with dyslipidaemia in adolescent girls with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate serum leptin, oxidized low density lipoprotein (ox-LDL) and asymmetric dimethylarginine (ADMA) levels and their interaction with dyslipidaemia in adolescents with polycystic ovary syndrome (PCOS). PATIENTS AND DESIGN: The study group consisted of 23 obese (obPCOS) and 21 nonobese girls with PCOS (nPCOS), and 31 lean healthy controls. PCOS was defined by the National Institutes of Health (NIH) criteria as the presence of chronic oligoanovulation and hyperandrogenism. Fasting leptin, ox-LDL, ADMA and detailed lipid-lipoprotein profile were determined. Atherogenic index (AI) was calculated as [Total cholesterol - HDL cholesterol/HDL cholesterol]. Logarithmic transformations were made for ox-LDL. RESULTS: Total cholesterol, triglycerides, LDL cholesterol, very low density lipoprotein (VLDL) cholesterol, apolipoprotein B, lipoprotein A levels and AI were higher and apolipoprotein AI was lower in obPCOS compared to those in controls (P < 0.05). LDL cholesterol, apolipoprotein B and lipoprotein A levels were higher in nPCOS compared to controls (P < 0.05). ADMA and ox-LDL levels did not differ in the three groups. Leptin was significantly higher in obPCOS compared with that in the other two groups (P < 0.001) and it was correlated with triglycerides (r = 0.62), VLDL cholesterol (r = 0.45), lipoprotein A (r = 0.38) and AI (r = 0.43) in the PCOS group (P < 0.05). CONCLUSION: Our data demonstrate that ADMA and ox-LDL levels in adolescent PCOS subjects were not different than those in controls. Abnormal lipid profile was shown in obese and nonobese girls with PCOS and leptin was related with these lipid abnormalities in the PCOS subjects.

Cholesteryl ester storage disease in a young child presenting as isolated hepatomegaly treated with simvastatin.

Cholesteryl ester storage disease (CESD) is an autosomal recessive disorder resulting from lysosomal acid lipase deficiency and is usually characterized by hepatomegaly and hyperlipidemia. This paper reports a two-year-old boy who had hepatosplenomegaly, hyperlipidemia and hypertransaminasemia determined incidentally. The liver biopsy sample was orange-yellow in appearance. Microscopically, microvesicular steatosis and birefringent crystals were seen in liver biopsy. The diagnosis of CESD was confirmed by the reduced human acid lipase activity in peripheral leukocytes. Simvastatin therapy was given and tolerated without side effects. Our patient is the youngest reported case in the literature treated with 3-hydroxy 3-methyl glutaryl (HMG) CoA reductase inhibitor.

Effects of oral glutamine supplementation on children with solid tumors receiving chemotherapy.

In recent years, there have been reports that glutamine support improves immune functions in adult patients with malignancy, but there is a lack of data in children. Oral glutamine support of 4 g/m2/day was given to 21 children with various solid tumors, aged 1-17 years (9.86 +/- 5.38) for all 5 days of a chemotherapy course. The same parameters in another course of the same protocol without glutamine supplementation were considered as controls. There were significant improvements of some nutritional and immunological parameters in the glutamine-supplemented course. Also glutamine seemed to reduce antibiotic necessity. Oral glutamine supplementation could be considered in children with solid tumors receiving chemotherapy.

Antioxidant effect of vitamin E in the treatment of nutritional iron deficiency anemia.

Oxidant status and antioxidants play important roles in anemias. The present study was conducted to investigate the oxidant-antioxidant status in iron deficiency anemia (IDA), and to evaluate the antioxidant effect of vitamin E in IDA treatment. Ten patients with IDA aged nine months were given only iron treatment, whereas another 10 patients were administered both iron and vitamin E. The complete blood count, plasma malonyldialdehyde (MDA) level, erythrocyte superoxide dismutase level, and the serum vitamin E level, both before and within the treatment phases were examined. The reticulocyte count at the first week of treatment was found lower in the vitamin E-treated group. The mean corpuscular volume (MCV) was found higher in the vitamin E-treated group at the end of therapy. The malonyldialdehyde levels of the group treated with vitamin E were found lower during treatment. These results suggest that iron administration in IDA treatment may stimulate lipid peroxidation, and that vitamin E supplied with iron may reduce the MDA production. The hematological indications of the findings of our study are that the reticulocyte response develops earlier and the microcytosis recovery occurs more rapidly in the vitamin E-administered group in comparison with the group treated with iron only.

Free oxygen radical-induced lipid peroxidation and antioxidant in infants receiving total parenteral nutrition.

OBJECTIVE: Increased oxygen-derived free radical activity has been reported during total parenteral nutrition (TPN) in infants particularly linked to the fat infusion. It is possible that partial enteral feeding can ameliorate some of the complications of TPN. By this study we aimed to investigate free radical formation and antioxidant activity in term and preterm infants during TPN and/or enteral feeding. STUDY DESIGN: We had 6 groups of term and preterm infants made up of 10 patients each. Group I had only enteral feeding, Group II enteral plus parenteral feeding, Group III only parenteral feeding. Plasma malondialdehyde (MDA), superoxide dismutase (SOD), vitamin E and vitamin C levels were measured in all infants. Blood samples of infants receiving only TPN and TPN plus enteral feeding were measured on the 1st and 5th days, and 3h after the end of lipid infusion. RESULTS: There was no difference between the term and preterm infants in terms of MDA, SOD, vitamin C and E levels taken baseline and after parenteral, and enteral plus parenteral feeding on the 1st and 5th days. When 3 groups of both term and preterm infants were compared with each other none of the parameters showed a statistically significant difference. In addition, we compared baseline and 1st and 5th days of TPN therapy in both term and preterm infants fed only parenterally and enteral plus parenteral feedings. In term infants fed both parenterally and parenteral plus enterally, the MDA levels before TPN were significantly higher than that of the levels of patients on parenteral nutrition on the 5th day. On the 1st and 5th days of TPN therapy, the levels of vitamin C was significantly decreased, in term and preterm infants fed only parenterally, levels of vitamin E was increased, in term and preterm infants fed both parenterally and parenteral plus enterally. Also, when compared to their base line the SOD levels of the term infants detected on the 1st and 5th days were significantly high. CONCLUSION: Free radical production is increased by the administration of TPN and may be linked to its adverse effects. It may be assumed that long-term complications of preterm infants receiving TPN may be reduced by further strengthening the antioxidant capacities of the TPN solutions.

The co-existence of Fabry and celiac diseases: a case report.

We present a patient with Fabry disease with remarkable diagnostic findings and gluten-sensitive enteropathy. An 11-year-old girl was admitted to hospital with weight loss, anorexia, nausea, vomiting, flank pain, acroparesthesia, and painful extremities. Her mother had end-stage renal failure secondary to Fabry disease. On physical examination, she had growth retardation. Ophthalmological examination showed characteristic whorl-like corneal opacities and Fabry disease was confirmed with low alpha-galactosidase A (alpha-gal A) activity. Her painful attacks were treated with carbamazepine, but vomiting and nausea continued. Laboratory studies revealed positive serum anti-endomysium and anti-gliadin antibodies. Small intestinal biopsy showed subtotal villous atrophy compatible with gluten-sensitive enteropathy. Following treatment with a gluten-free diet, her gastrointestinal symptoms completely disappeared within a few weeks and then she had catch-up growth. In her long-term follow-up, proteinuria appeared and renal involvement was confirmed by characteristic renal biopsy findings. Following these clinicopathological findings, enzyme replacement therapy was started. In conclusion, although heterozygous females can be asymptomatic or are expected to have a mild course of the disease, a severe clinical course in our patient in the 2nd decade is of particular interest. In addition, Fabry disease occurring with gluten-sensitive enteropathy, a very rare co-existence, is emphasized.