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Pronicka E.,Childrens Memorial Health Institute CMHI | Weglewska-Jurkiewicz A.,Childrens Memorial Health Institute CMHI | Taybert J.,Childrens Memorial Health Institute CMHI | Pronicki M.,Childrens Memorial Health Institute CMHI | And 10 more authors.
Journal of Applied Genetics | Year: 2011

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogeneity, c.813_814insTTT (p. Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDSassociated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates. © The Author(s) 2010.

Pronicka E.,Childrens Memorial Health Institute CMHI | Weglewska-Jurkiewicz A.,Childrens Memorial Health Institute CMHI | Weglewska-Jurkiewicz A.,University of Gdansk | Pronicki M.,Childrens Memorial Health Institute CMHI | And 8 more authors.
Medical Science Monitor | Year: 2011

Background: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion. Material/Methods: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. Results: The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion). Conclusions: Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy. © Med Sci Monit.

Bossowski A.,Medical University of Bialystok | Sawicka B.,Medical University of Bialystok | Szalecki M.,Childrens Memorial Health Institute CMHI | Koput A.,Medical University of Bialystok | And 2 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2010

Leptin, adiponectin and resistin, mainly produced by adipocytes, play a major role in body weight regulation. Disturbances in the maintenance of normal body weight are found to occur also in thyroid diseases. There is a close relationship of the changes in thyroid hormones with the contents of adipose tissue and adipocyte-secreted proteins regulating energetic metabolism in the body. The study objective was to analyze the levels of leptin, adiponectin and resistin in children with untreated Graves' disease, subclinical hypothyroidism in Hashimoto's thyroiditis and in children with simple goiter. The study involved 78 patients with Graves' disease (29 girls and 2 boys, aged 6-21 years, mean 15.2) and with Hashimoto's thyroiditis (30 girls and 2 boys, aged 9-18 years, mean 14.5). The control group consisted of adolescents with simple goiter (13 girls and 2 boys, aged 9-18 years, mean 14.8). The levels of leptin, adiponectin and resistin were determined using the ELISA method (R&D System, USA). Patients with untreated Graves' disease showed higher adiponectin level than the patients with hypothyroidism in Hashimoto's thyroiditis and in simple goiter (14.24±0.89 vs. 9.18±2.65, 10.15±2.5, p<0.007, p<0.01), but lower resistin level as compared to simple goiter and Hashimoto's thyroiditis (10.24±5.2 vs. 13.29±3.8, 12.2±2.8, p<0.01, NS). The analysis of leptin levels revealed no significant differences between children with subclinical hypothyroidism and untreated Graves' disease (4.42±0.87 vs. 3.1±0.45 NS). In conclusion, we suggest that disturbances in thyroid hormones in thyroid diseases have an essential effect on the levels of adiponectin and resistin released by adipose tissue. © Freund Publishing House Ltd.

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