A Case of Glycogen Storage Disease Type 1a Mimicking Familial Chylomicronemia Syndrome.

Glycogen storage disease type 1a (GSD1a) is an autosomal recessively inherited inborn error of metabolism caused by a mutation in the G6PC gene, which encodes the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α) enzyme. This enzyme plays a role in the final step of gluconeogenesis and glycogenolysis. Patients carrying GSD1a show growth retardation, hypoglycemia, hepatomegaly, hepatic steatosis, hyperlipidemia, hyperuricemia and lactic acidemia. Long-term symptoms include gouty arthritis and uric acid stones, osteoporosis, renal failure, intestinal impairment, cirrhosis and hepatic adenomas, and eventually, hepatocellular carcinoma. Hyperlipidemia is the indicator of poor metabolic control in GSD1a. Patients with variable levels of triglycerides (TGs) have been reported in the literature. We present a case of GSD1a that presented with severe hypertriglyceridemia (HTG) mimicking familial chylomicronemia syndrome.

A 7-year-old Boy with Hand Tremors and a Novel Mutation for L-2-hydroxyglutaric Aciduria.

L-2-hydroxyglutaric aciduria (L2HGA), which is a rare autosomal recessive metabolic disorder caused by mutations in the encoding L2HGDH gene. Neurological symptoms are the main predominant clinical signs. The distinctive feature is the specific multifocal lesion of the white matter detected on magnetic resonance imaging (MRI). A 7-year-old male patient of Turkish origin was admitted to the hospital because of hand tremors. Physical examination revealed macrocephaly, intention tremors, walking disability and ataxic gait. Urine organic acid analysis showed increased excretion of L-2-hydroxyglutaric acid (L2HG acid). Analysis of the L2HGDH gene revealed a novel homozygous c.368A>G, p. (Tyr123Cys) mutation. L-2-hydroxyglutaric aciduria is a cerebral organic aciduria that may lead to various neurological complications. Early recognition of symptoms of L2HGA is important for initiation of supportive therapy that may slow down the progression of the disease.

COBALAMIN C DEFICIENCY WITH INFANTILE SPASM AND CUTANEOUS FINDINGS: A UNIQUE CASE.

Cobalamin C (CbIC) deficiency is a rare disorder of vitamin B12 metabolism which results from impaired conversion of both its active forms methylcobalamin and adenosylcobalamin. Early onset cblC typically presents in the first year of life with hypotonia, lethargy, seizures, microcephaly, hydrocephalus, developmental delay and other multisystem involvement including hematologic, ocular, renal, hepatic and cardiac symptoms. We report a case of a female infant with cblC deficiency who presented with seizures, developmental delay and hypopigmented cutaneous lesions. To our knowledge, the patient is the first diagnosed with cblC deficiency who had skin hypopigmentation.

Continuous glucose monitoring in children with glycogen storage disease type I.

BACKGROUND/OBJECTIVES: Glycogen storage disease type I (GSD I) is an autosomal recessive metabolic disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-α catalytic unit characterizes GSD Ia and defects in the glucose-6-phosphate transporter protein characterize GSD Ib. Type Ia involves the liver, kidney and intestine (and Ib also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, severe fasting hypoglycemia within 3-4 h after a meal, hyperlactatemia, hyperuricemia and hyperlipidemia. The aim of the present study was to examine the safety and efficacy of a continuous subcutaneous glucose monitoring system to determine the magnitude and significance of hypoglycemia in GSD I and to evaluate the efficacy of the revised dietary treatment. SUBJECTS/METHODS: Sixteen children with GSD I were studied over a 72-h period. Continuous glucose monitoring (CGM) was repeated in all patients 3-6 months after the first monitoring to examine the effects of revised dietary instructions on glycemic control. RESULTS: All the patients completed the study without any major adverse events. Significant periods of asymptomatic hypoglycemia (below 4 mmol/l, 70 mg/dl) were noted. There was a close correlation between CGM sensor and capillary blood glucose values measured by a glucometer. CGM indicated a considerable reduction in duration of hypoglycemia, liver size and improvements in secondary metabolic derangements such as hyperlacticacidemia and hyperlipidemia. CONCLUSIONS: CGM could be applied in the clinical setting to help the physician to identify hypoglycemic events, and repeated CGM may serve as a safe and useful tool for the assessment of the long-term management of patients with GSD I.

An extremely rare case: osteosclerotic metaphyseal dysplasia.

OMD (osteosclerotic metaphyseal dysplasia) is a very rare sclerosing bone disorder, first described by G. Nishimura in two Japanese siblings in 1993 (6). We report the case of a 12-month-old male with hypotonia, developmental delay and sclerosis of the metaphyses and epiphyses of specific bones. This 36-week gestation boy was born to a 26 year old gravida 5 para 1 Turkish mother and a 27 year old nonconsanguineous father. Radiographic findings obtained during the hospital stay included bilateral symmetrical osteosclerosis of the metaphyseal portions of the long bones in the upper and lower extremities with osteopenic shafts. Narrow bands of metaphyseal osteosclerosis were detected in the short tubular bones of the hands and feet. Growing parts of bilateral scapula, iliac, pubic and ischial bones show sclerotic bands. In addition superior and inferior plates of vertebras, transverse processes of sacral vertebras, all visible epiphyses, carpal and tarsal bones also show sclerotic changes. The scalp was unaffected. Based on the clinical, radiographic, and laboratory findings, a diagnosis of OMD was made. We do not know any of the osteosclerotic bone disorder with changes including hypotonia, mental and motor developmental delay and metaphyseal sclerosis of the bones with a unique distribution except OMD. The syndrome is characterized by developmental delay of a progressive nature, hypotonia, elevated alkaline phosphatase, and late-onset spastic paraplegia 18 years ago. Our patient is the 4th case of OMD described in the literature share some clinical and radiological similarities with other three reported cases of osteosclerotic metaphyseal dysplasias.

SRD5A3-CDG: a patient with a novel mutation.

Congenital disorders of glycosylation (CDG) are genetic diseases with an extremely broad spectrum of clinical presentations due to defective glycosylation of glycoproteins and glycolipids. Some 45 CDG types have been reported since the first clinical description in 1980. Protein glycosylation disorders are defects in protein N- and/or O-glycosylation. Dolichol phosphate is the carrier of the N-glycan during their assembly first at the outside and subsequently at the inside of the endoplasmic reticulum (ER) membrane, and hence is a key molecule in protein glycosylation. Recently, defects have been identified in the last three steps of the dolichol phosphate biosynthesis: dolicholkinase deficiency (DK1-CDG), steroid 5alpha-reductase type 3 deficiency (SRD5A3-CDG), and dehydrodolichyl diphosphate synthase deficiency (DHDDS-CDG). We report on a patient with SRD5A3-CDG carrying a novel (homozygous) mutation. The diagnostic features of this novel inborn error of glycosylation are psychomotor retardation, nystagmus, visual impairment due to variable eye malformations, cerebellar abnormalities/ataxia, and often ichthyosiform skin lesions.

A novel mutation of the claudin 16 gene in familial hypomagnesemia with hypercalciuria and nephrocalcinosis mimicking rickets.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a mutation in the gene CLDN16, which encodes paracellin 1 (claudin-16), atight junction protein mediating paracellular transport which is expressed in the thick ascending loop of Henle and in the distal convoluted tubule, where reabsorption of magnesium occurs. We present a 4 years old Turkish female child with a chief complaint of hypocalcemic tetany. A diagnosis of FHHNC was confirmed by genetic testing for a mutation in claudin 16 gene. Claudin 16 gene revealed homozygosity for the p.K183E(AAA>GAA) C. 547A>G indicating the diagnosis of hypomagnesemia with hypercalciuria and nephrocalcinosis. To our knowledge, this is the first case of FHHNC reported in Turkish population diagnosed at molecular level.

An infantile case of Zellweger syndrome presented with Kabuki-like phenotype.

Zellweger syndrome is a peroxisomal disorder resulting from the mutations in PEX genes generally presenting in the neonatal period with profound hypotonia seizures, inability to feed, liver cysts with hepatic dysfunction, chondrodysplasia punctata. Kabuki make-up syndrome is a multiple congenital anomalies and mental retardation syndrome with characteristic facial appearance, skeletal abnormalities, dermatoglyphic abnormalities, mental retardation and short stature. Abnormal liver functions and some atypical findings were also reported in some patients with Kabuki syndrome. In this report a case with late onset Zellweger syndrome who had some phenotypical findings which are also seen in Kabuki Syndrome will be presented. The inclusion of Zellweger syndrome into the differential diagnosis of the patients with Kabuki-like phenotype in addition to abnormal liver functions is emphasized.

Multisystem involvement in a patient due to accumulation of amylopectin-like material with diminished branching enzyme activity.

We report a 13-year-old boy with multisystem involvement secondary to accumulation of amylopectin-like material. He was born to consanguineous parents at full term without any complications and his maternal perinatal history was uneventful. His parents were cousins. He had normal growth and development except for his weight. His sister died from an unexplained cardiomyopathy at the age of 8 years. Our patient's initial symptom was severe heart failure. Since he also had a complaint of muscle weakness, electromyography was performed which showed muscle involvement. The diagnosis was suggested by tissue biopsy of skeletal muscle showing intracellular, basophilic, diastase-resistant, periodic acid-Schiff-positive inclusion bodies and was confirmed by the presence of a completed branching enzyme deficiency. Similar intracytoplasmic inclusion-like bodies were also found in liver biopsy, but very few in number compared with the skeletal muscle. The patient died from an intercurrent infection. Postmortem endomyocardial biopsy revealed the same intracytoplasmic inclusions as described above affecting almost all myocardial cells. Ultrastructural examination of liver biopsy was nondiagnostic; however, myocardium showed prominent, large, intracytoplasmic deposits. Glycogen branching enzyme gene sequence was normal, and thus classical branching enzyme deficiency was excluded. Our patient represents the first molecular study performed on a patient in whom there was multiple system involvement secondary to accumulation of amylopectin-like material. We suggest that this is an as yet undefined and different phenotype of glycogen storage disease associated with multisystemic involvement.

Effect of enteral and parenteral nutrition on growth parameters of hospitalized Turkish children.

This study was conducted to investigate growth and the complications in the hospitalized pediatric patients receiving either enteral (n = 26) or parenteral (n = 15) nutrition. Anthropometric measures as well as the results of biochemical analyses and complete blood counts were recorded. Weight, height and weight for height were expressed in z scores. The improvement in z scores for the 26 children receiving enteral nutrition in weight for age (P = 0.001), height for age (P = 0.002) and weight for height (P = 0.008) were all statistically significant. There were also significant correlations between the changes in weight for age (r2 = 0.15, P = 0.0049) and height for age (r2 = 0.64 and P = 0.0001) z scores and the time for follow up. Corresponding z scores in the parenteral nutrition group were not statistically significant. This study indicated that enteral nutrition provides significant improvement not only in weight but also height of sick hospitalized pediatric patients.

Serum carnitine levels in newborns with perinatal asphyxia and relation to neurologic prognosis.

Neonatal hypoxic encephalopathy is one of the major causes of permanent neurological sequel. This study was conducted to investigate serum total, free and acylcarnitine levels in asphyxiated newborns with or without encephalopathy. Serum total, free and acylcarnitine levels were investigated in 21 newborns with and seven asphyxiated newborns without signs of encephalopathy. The newborns with encephalopathy were further divided into grade 1, 2 and 3 encephalopathy groups. Serum total and acylcarnitine concentrations of the whole encephalopathy group were significantly lower than the non-encephalopathy group (p = 0.042 for both). Serum total and acylcarnitine concentrations of grade 3 encephalopathy group were significantly lower than the non-encephalopathy group (p = 0.014 and p = 0.040, respectively). No significant differences were noticed for free carnitine levels. Total carnitine levels were positively correlated with birth weight and 10th minute apgar score, whereas acylcarnitine levels were found to correlate with cord blood pH and free carnitine levels with birth weight. Cord blood pH, and total carnitine levels were found to be the most significant determinants of the neurological outcome at one year of age. It was emphasized that carnitine deficiency could occur in severely affected asphyxiated newborns and it is related to the outcome at one year of age.

Plasma homocysteine and lipoprotein (a) levels as risk factors for atherosclerotic vascular disease in epileptic children taking anticonvulsants.

AIM: To assess the effect of anticonvulsant treatment on plasma homocysteine level and lipoprotein (a) in epileptic children. METHODS: Plasma total homocysteine, folate, vitamin B12 and lipoprotein (a) concentrations were measured in 111 epilectic children taking anticonvulsant drugs for longer than 12 mo. Forty-six healthy, sex- and age-matched children served as controls. RESULTS: Patients and controls differed significantly in concentrations of homocysteine (p < 0.05) and lipoprotein (a) (p < 0.001). The number of patients with homocysteine concentrations of >9 microM was significantly higher in the patient group than in the control group. A significant inverse relationship was found between vitamin B12 folate levels and plasma homocysteine levels in the patient group; 28.8% of the patient group had lipoprotein (a) concentrations above the cut-off value (30 mg/dl) for increased risk of early atherosclerosis, whereas none of the control patients had concentrations above this value. CONCLUSION: These data indicate that prolonged anticonvulsant treatment could increase plasma homocysteine and lipoprotein (a) concentrations and that it may be useful to measure the levels routinely in order to prevent atherosclerosis in epileptic children taking anticonvulsant drugs.

Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth.

This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I.

Endomysium antibodies in the diagnosis of celiac disease in short-statured children with no gastrointestinal symptoms.

BACKGROUND: Endomysium antibodies (EmAb) are strongly associated with untreated celiac disease and are suggested to be diagnostic. The aim of the present study was to assess the value of anti-EmAb for celiac disease screening in children with short stature. METHODS: In 84 children with height less than the third percentile for age, preliminary work-ups were made to find a cause for their short stature and then their serum was assayed for anti-EmAb by indirect immunofluorescence tests using monkey esophagus. RESULTS: Seven children were strongly positive for EmAb and all had positive histologic findings for celiac disease. CONCLUSIONS: Our results show that there is an association with occult celiac disease and idiopathic short stature and that the serum anti-EmAb test is useful in identifying such cases.

Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid.

Dual energy X-ray absorptiometry (DXA) was used to assess lumbar spine (L2-4) and femoral neck bone mineral density (BMD) in 36 children taking either carbamazepine or valproic acid for longer than one year, for generalized idiopathic epilepsy. Patients were matched with controls. Biochemical parameters of bone mineral metabolism were also measured. BMD values at both the femur neck and lumbar spine in both the carbamazepine and valproic acid groups were not significantly different from that of the control group. Serum levels of calcium were subnormal and alkaline phosphatase levels were high in the carbamazepine group. Urinary calcium levels were significantly lower in both groups than in the control group (p< or =0.05) and also significantly lower in the valproic acid group than in the carbamazepine group (p< or = 0.05). There were no other significant biochemical changes in either group. In conclusion, the results suggest that valproic acid and carbamazepine monotherapies have minimal effects on bone mineral metabolism, but routine monitoring of risk and consideration of prophylactic vitamin D supplementation is important.

Bone mineral density in childhood obesity.

There are several metabolic and hormonal disturbances in childhood obesity. The purpose of this study was to determine the relationship between childhood obesity and bone mineral density (BMD). We studied BMD in 37 obese children and in 37 non-obese children. BMD was measured at L2-L4 level by using dual energy X-ray absorptiometry. BMD was significantly related to age, height and weight. The mean BMD in the obese children and control group was 0.655 +/- 0.175 and 0.626 +/- 0.159 g/cm2, respectively, without any statistically significant difference (p>0.05). There was no correlation between BMD values and osteocalcin or calcitonin levels. According to Tanner's pubertal staging, the mean BMD of pubertal obese children was higher than that of prepubertal obese children. BMD of the pubertal obese children was significantly higher than that of the pubertal control group (p<0.05). Girls had higher mean BMD values than boys. In conclusion, our results show that BMD is not influenced by obesity in children but higher values in puberty were observed in obese children which may due to hormonal changes.

Pattern of human leukocyte antigens in Turkish children with celiac disease.

BACKGROUND: Regional variations in the human leukocyte antigen (HLA) distribution patterns of celiac disease (CD) have been reported. The aim of the present study was to assess the distribution of HLA class I and class II in Turkish children with CD and to compare the findings with a control group. METHODS: Human leukocyte antigen typing was performed in 33 children with CD and in 77 healthy individuals, who served as controls, by using standard National Institutes of Health lymphocytotoxicity techniques. RESULTS: A positive association was found between HLA A2 (42 vs 19% for sick subjects compared with healthy controls, respectively), B8 (39 vs. 9% for sick subjects compared with healthy controls, respectively), CW7 (45 vs. 25% for sick subjects compared with healthy controls, respectively), DR3 (70 vs. 17% for sick subjects compared with healthy controls, respectively), DR7 (30 vs. 13% for sick subjects compared with healthy controls, respectively) and DQ2 (52 vs. 34% for sick subjects compared with healthy controls, respectively). The combinations of DR3-DQ2 (30 vs. 12% for sick subjects compared with healthy controls, respectively), DR3-DR4 (21 vs. 1% for sick subjects compared with healthy controls, respectively) and DR7-DQ2 (21 vs. 6% for sick subjects compared with healthy controls, respectively) were also found to be significantly important in children with CD. The highest relative risk (RR) was for HLA B8 in class I (RR 6.50), for DR3 (RR 11.30) in class II and for combination of DR3-DR4 (RR 20.46). The highest etiologic fraction (EF) was for the DR3 antigen (EF 0.55). CONCLUSIONS: The present study emphasizes that HLA genotypes are an important background to CD development, but some additional susceptibility factors remain to be identified.

Bone mineral density and metabolism in children treated with L-thyroxine.

It has been suggested that long term treatment with L-thyroxine could reduced bone mineral density (BMD). The purpose of this study was to determine whether BMD is decreased by L-thyroxine treatment in children. Dual energy X-ray absorptiometry (DEXA) was used to assess lumbar spine (L2-4) and femur neck BMD in 40 children aged 9-15 years, taking L-thyroxine (100 micrograms/m2/day) for a mean period of 1.45 +/- 0.60 years for colloid diffuse goiter. Patients were matched with controls for age, sex, weight, height and pubertal stage. BMD at both the femur neck and lumbar spine was not significantly different from that of the control group. No correlation was found between BMD values and TSH levels which is the index of tissue hyperthyroidism. BMD was also not correlated with duration of the therapy. Osteocalcin, alkaline phosphatase, calcitonin and parathormone levels were measured to asses bone turnover; none of them were significantly different from those of controls and they did not change during follow up. In conclusion we suggest that long-term L-thyroxine therapy in children has no adverse effect on BMD.

Effects of 5-fluorouracil and zinc on healing of colonic anastomoses in rabbits.

OBJECTIVE: To find out if 5-fluorouracil (5-FU) given intraperitoneally to rabbits impaired the healing of colonic anastomoses, and whether giving zinc might reverse the effect. DESIGN: Laboratory study. SETTING: Teaching hospital, Turkey. ANIMALS: 32 New Zealand white rabbits. INTERVENTIONS: All animals had 1cm of large bowel resected 10cm proximal to the peritoneal reflection and continuity restored by end-to-end anastomosis. They were divided into four groups and given intraperitoneal injections of saline (control group), 5-FU 10mg/kg/day in a concentration of 5mg/ml saline (5-FU alone group), zinc 2mg/kg/day (zinc alone group), and the same doses of 5-FU and zinc (5-FU + zinc group). The injections were given immediately after operation and daily for 4 days. The rabbits were killed at 7 days. MAIN OUTCOME MEASURES: Bursting pressures, tissue hydroxyproline concentrations, tissue zinc concentrations, and light and electron microscopic appearances. RESULTS: Six rabbits died of the complications of anaesthesia and 4 of sepsis leaving 7, 6, 7, and 6 rats in the four groups respectively. Mean (SD) anastomotic bursting pressures were significantly reduced in the 5-FU group compared with controls (5 (2) compared with 7 (1) mm Hg, p: 0.05) and collagen synthesis (indicated by reduced tissue hydroxyproline concentrations) was also decreased (7.1 (0.9) compared with 9.1 (1.5), p < 0.05). Rabbits given 5-FU + zinc had significantly higher bursting pressures than those given 5-FU alone (9 (2) compared with 5 (2), p: 0.01). Bursting pressures were also significantly higher in those given zinc alone, but hydroxyproline concentrations were similar to those in the control group. Histological examination showed that 5-FU alone significantly impaired the healing process, and those in the 5-FU + zinc group healed better than those in the 5-FU alone group. CONCLUSIONS: 5-FU given intraperitoneally significantly impaired the healing of colonic anastomoses in rabbits, and zinc reversed this effect.