Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 pathogenicity, 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 MDS-associated 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.
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PMID:Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure. 2110 80

Deoxyguanosine kinase (dGK) deficiency, a rare severe cause of mitochondrial DNA (mtDNA) depletion, has two forms of presentation: hepatocerebral syndrome and isolated hepatic disease. The authors report three cases with neonatal liver failure due to dGK deficiency. Consanguinity was present in all patients. One patient had a brother who died with a probable diagnosis of neonatal haemochromatosis. All patients had progressive cholestatic liver failure, hypoglycaemia, hyperlactacidaemia, elevated ferritin levels and nystagmus, since first day of life. Liver tissue study revealed: cholestasis, iron deposits, microvesicular steatosis and fibrosis/cirrhosis. Only one patient was submitted to liver transplantation. The other two died, at 2 and 5 months of age. mtDNA quantification and DGUOK gene study should be considered in infants/neonates with acute liver failure and systematically performed in patients with hepatocerebral presentation. Differential diagnosis with neonatal haemochromatosis is needed. Liver transplantation might be a therapeutic option. Early diagnosis is important for genetic counselling.
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PMID:Neonatal liver failure due to deoxyguanosine kinase deficiency. 2260 37