Bendt Brock Jacobsen

In this study, a second case of hyperinsulinemic hypoglycemia due to activation of glucokinase is reported. The 14-year-old proband had a history of neonatal hypoglycemia, treated with diazoxide. He was admitted with coma and convulsions due to nonketotic hypoglycemia. His BMI was 34 kg/m(2), and his fasting blood glucose ranged from 2.1 to 2.7 mmol/l, associated with inappropriately high serum levels of insulin, C-peptide, and proinsulin. An oral glucose tolerance test (OGTT) showed exaggerated responses of these peptides followed by profound hypoglycemia. Treatment with diazoxide and chlorothiazide was effective. His mother never had clinical hypoglycemic symptoms, even though her fasting blood glucose ranged from 2.9 to 3.5 mmol/l. Increases in serum insulin, C-peptide, and proinsulin in response to an OGTT suggested a lower threshold for glucose-stimulated insulin release (GSIR). Screening for mutations in candidate genes revealed a heterozygous glucokinase mutation in exon 10, substituting valine for alanine at codon 456 (A456V) in the proband and his mother. The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S(0.5) (the concentration of glucose needed to achieve the half-maximal rate of phosphorylation) from 8.04 (wild-type) to 2.53 mmol/l. The mutant's Hill coefficient was decreased, and its maximal specific activity k(cat) was increased. Mathematical modeling predicted a markedly lowered GSIR threshold of 1.5 mmol/l. The theoretical and practical implications are manifold and significant.

Myelodysplastic syndrome (MDS) in childhood is considered to be very rare, but sound epidemiologic data are lacking. We report a population-based study of MDS in Denmark from 1980 to 1991. The medical charts were reviewed of 988 children identified from the Danish National Hospital Discharge Registry with a diagnosis of myeloid leukemia or blood cytopenia. Blood and bone marrow smears from all cases of possible MDS were re-evaluated. The cases were categorized according to the FAB classification, with the exception of chronic myelomonocytic leukemia (CMML) in which more than 5% myeloblasts in the blood was accepted. Juvenile chronic myeloid leukemia (JCML) was included as CMML. MDS was diagnosed in 46 children representing 9% of all hematologic malignancies in children less than 15 years of age. The annual incidence was 4.0/million and did not increase with time. Refractory anemia with excess of blasts and CMML each accounted for one third of the cases. Down syndrome was present in seven children. Other predisposing conditions included Fanconi anemia, neurofibromatosis, constitutional trisomy 8 mosaicism, and familial leukemia. Only one child had therapy-related MDS. The study indicates that the incidence of childhood MDS is higher than generally assumed and approximate to the incidence of acute myeloid leukemia.

Lavard L, Ranlov I, Perrild H, Andersen O, Jacobsen BB. Incidence of juvenile thyrotoxicosis in Denmark, 1982-1988. A nationwide study. Eur J Endocrinol 1994;130:565–8. ISSN 0804–4643 The objective of this study was to ascertain the annual incidence density of thyrotoxicosis in children under the age of 15 years in Denmark in 1982–1988. The design was based on computerized hospital registration of patient admittances in all departments of paediatrics and internal medicine of Denmark (Faroe Islands and Greenland excluded). Fifty-six children (48 girls and 8 boys) had a confirmed diagnosis of thyrotoxicosis, giving a national incidence density of 0.79/100 000 person-years. In children aged 0–4 years the incidence was very low (0.1/100 000), with no sex difference. In boys aged 5–9 years a similar low incidence was found, while in boys aged 10–14 years the incidence increased to 0.48/100 000. In girls aged 5–9 years the incidence increased to 0.96/100 000, reaching a maximum of 3.01 in the 10–14-year-old girls. In children of > 4 years of age a female preponderance of 6.7:1 was significant. It is concluded that thyrotoxicosis is a rare disorder in Danish children under the age of 15 years, and the incidence increases with age. Female preponderance is significant from early childhood. Lene Lavard, Department of Paediatrics, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark

SUBACUTE necrotizing encephalomyelopathy, or Leigh's syndrome, 1 is a degenerative disorder characterized by progressive deterioration of brain-stem functions, ataxia, convulsions, hypotonia, and failure to thrive. The histopathologic changes are found in the brain stem, basal ganglia, cerebellar cortex, and dentate nucleus, and they consist of bilateral symmetrical areas of rarefaction, loss of myelin, and cell proliferation in the capillaries and glia. This disorder occurs in infancy and early childhood and is inherited as an autosomal-recessive trait, but the basic biochemical defect is unknown.We report on a syndrome in a boy suffering from attacks mimicking acute morphine poisoning with prolonged apnea . . .

OBJECTIVE: Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known. METHODS: From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, n=141; Norway, n=26; UK, n=34), 108 children had no K(ATP)-channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised. RESULTS: In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type. CONCLUSION: In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.