A new case of Congenital Hyperinsulinemic Hypoglycemia due to M/SCHAD deficiency: the contribution of metabolic and molecular diagnosis for the management

Congenital Hyperinsulinemic Hypoglycemia (CHH) is a rare metabolic disease (prevalence <1/1.000.000) characterized by a persistent hypoglycemia and high secretion of insulin in the neonatal and infancy period. An early management of patients with CHH is mandatory to avoid brain damage. Recent advances in molecular analysis have linked CHH to mutations in nine genes: ABCC8, KCNJ11, GCK causing either diazoxide-responsive or diazoxide-unresponsive Hyperinsulinemic Hypoglycemia, and GLUD1, HADH, SLC16A1, UCP2, HNF4A and HNF1A, causing generally diazoxide-responsive CHH. However, HADH defect is the most common form in presence of consanguinity and diazoxide-responsiveness. The HADH gene codifies the M/SCHAD mitochondrial enzyme, which catalyses the penultimate reaction in the β-oxidation of medium and short-chain fatty acids, causing in some affected individuals an elevated plasmatic hydroxybutyrylcarnitine and urinary medium-chain dicarboxylic, and 3-hydroxydicarboxylic metabolites. To date about 40 cases of M/SCHAD defect have been reported in literature.We report here a new case of CHH due to M/SCHAD deficiency. The index case was a Pakistan infant, born from consanguineous parents, showing a diazoxide-responsive hyperinsulinism and organic aciduria. The M/SCHAD deficiency was confirmed by the molecular diagnosis performed by sequencing of HADH gene, which revealed the presence of the nonsense mutation c.706C>T (p.R236*) in HADH gene, at homozygous state, while both parents were heterozygous for the mutated allele. The patient started diazoxide treatment at the maximum dose of 10 mg/kg/day, which resulted in adverse drug reactions (hypertrichosis, peripheral edemas and persistent hypertension) gradually solved with antihypertensive regimen. Diazoxide was progressively titrated to 2 mg/kg/ day with good results in glycemic control and no hypertensive crisis. Low organic aciduria was followed.In conclusion, when the metabolic profile suggests a CHH disorder, the molecular analysis is necessary for the precise diagnosis and the appropriate counseling to the parents, also for the possibility of a prenatal diagnosis. In this setting, the definitive diagnosis of CHH, due to M/SCHAD deficiency, may suggest also the most appropriate therapeutic intervention to avoid both risk of worsening or adverse drug effect

Impact of molecular diagnostics in an asymptomatic amateur athlete found to be affected by hypertrophic cardiomyopathy

The prevention of sudden cardiac death in asymptomatic athletes, unknowingly suffering from cardiac disease, is an important objective that involves many areas of the medical profession and of the healthcare systems in general. Here we report the case of an asymptomatic amateur athlete, who, in the setting of pre-participation screening to obtain clearance to take part in competitive sporting event, underwent cardiac clinical and instrumental examinations to ensure the absence of cardiomyopathy. Electrocardiography revealed mild repolarization abnormalities and echocardiography showed borderline septal wall thickness. Anamnestic and instrumental data suggested an underlying genetic alteration. Molecular analysis revealed double heterozygosity for mutations in the TNNT2 (c.832C>T; p.R278C) and MYBPC3 (c.2689_2690ins19nt; p.G897AfsX159) genes. Molecular analysis led to an accurate characterization of the cardiac alteration present in this athlete. This case report highlights that molecular analysis can reveal DNA alterations in asymptomatic athletes, which in many cases could cause sudden cardiac death. This and previous cases show that Clinical Molecular Biology is now an essential addition to the clinical and instrumental approach to the evaluation of cardiac wellness, which could otherwise remain obscure