Spectrum of neuro-developmental disorders in children with congenital hyperinsulinism due to activating mutations in GLUD1.

Background: Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation. Objective: The aim of this study was to determine the clinical profile and long-term neurological outcomes in children with HI/HA syndrome. Method: This study is a retrospective review of patients with GLUD1 mutation, treated at two centers in the UK and Russia, over a 15-year period. Different risk factors for neuro-developmental disorders were analysed by Mann-Whitney U test and Fisher's exact P test. Results: We identified 25 cases with GLUD1 mutations (12 males). Median age of presentation was 7 months (12 h-18 months). Hypoglycaemic seizures were the presenting feature in 24 (96%) cases. Twenty four cases responded to diazoxide and protein restriction whilst one patient underwent partial pancreatectomy. In total, 13 cases (52%) developed neurodevelopmental manifestations. Epilepsy (n = 9/25, 36%), learning difficulties (n = 8/25, 32%) and speech delay (n = 8/25, 32%) were the most common neurological manifestation. Median age of presentation for epilepsy was 12 months with generalised tonic-clonic seizures being the most common (n = 4/9, 44.4%) followed by absence seizures (n = 3/9, 33.3%). Early age of presentation (P = 0.02), diazoxide dose (P = 0.04) and a mutation in exon 11 or 12 (P = 0.01) were associated with neurological disorder. Conclusion: HI/HA syndrome is associated with wide spectrum of neurological disorders. These neurological manifestations were more frequent in cases with mutations affecting the GTP-binding site of GLUD1 in our cohort.

Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1.

SUMMARY: Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5-12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1. LEARNING POINTS: Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia. If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected. Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects. The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Characterization of a de novo balanced 1;Y translocation in a phenotypically normal twin male infant.

OBJECTIVE: To report a translocation between an autosome and the Y chromosome. DESIGN: Amniocentesis of a fetus because of mother's advanced age followed by karyotype and PCR analysis. SETTING: Tertiary health center. PATIENT(S): A phenotypically normal twin male infant. INTERVENTION(S): Karyotype with G and Q banding and amplification of testis-specific protein 1-Y and of azoospermia factor (AZF) a, AZFb, AZFc, and distal AZFc regions of Y chromosome. MAIN OUTCOME MEASURE(S): Karyotype, PCR. RESULT(S): We report a phenotypically normal twin male infant with de novo 46,ChiY,t(1;Y)(p22;p11) that was found in amniocentesis. In genetic counseling, it was recommended that the fetus be monitored through a detailed prenatal ultrasonographic examination, which did not indicate any pathological findings. A phenotypically normal male baby was born who is now a 12-month-old healthy infant. The karyotype was confirmed in the peripheral blood with G and Q banding. Amplification of testis-specific protein 1-Y, AZFa, AZFb, AZFc, and distal AZFc regions of the Y chromosome did not reveal any deletions. CONCLUSION(S): We cannot predict whether this male infant will have oligospermia or azoospermia as an adult and, furthermore, whether in case of fertility there is a risk for unbalanced autosome;Y translocations in the offspring, with congenital malformations and dysmorphic features. This case illustrates the complexities in counseling for prenatally diagnosed de novo autosome;Y translocations and the need for additional cases to be reported.