OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort.

OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X-linked OTC gene. Phenotype-genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and OTC gene sequencing to genetic counseling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11%), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60%, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra-hepatic variability of OTC activity and X inactivation profile (range of variability: 30% and 20%, respectively) without correlation between both parameters for 3 of the 4 livers. Ninety disease-causing variants were found, 27 of which were novel. Mutations were classified as "mild" or "severe," based on male phenotypes and/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio = 1.365; P = 1.6e-06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.

Dodecyl creatine ester-loaded nanoemulsion as a promising therapy for creatine transporter deficiency.

Creatine transporter (CrT) deficiency is an X-linked intellectual disability caused by mutations of CrT. Aim: This work focus on the preclinical development of a new therapeutic approach based on a microemulsion (ME) as drug delivery system for dodecyl creatine ester (DCE). Materials & methods: DCE-ME was prepared by titration method. Novel object recognition (NOR) tests were performed before and after DCE-ME treatment on Slc6a8-/y mice. Results: Intranasal administration with DCE-ME improved NOR performance in Slc6a8-/y mice. Slc6a8-/y mice treated with DCE-ME had increased striatal ATP levels mainly in the striatum compared with vehicle-treated Slc6a8-/y mice which was associated with increased expression of synaptic markers. Conclusion: These results highlight the potential value of DCE-ME as promising therapy for creatine transporter deficiency.

Topography of brain damage in metabolic hypoglycaemia is determined by age at which hypoglycaemia occurred.

AIM: Having previously shown that comorbidity is a major determinant of neurological sequelae in hypoglycaemia, our aim was to describe the neuroimaging patterns of brain damage in different hypoglycaemic situations and to elucidate the factors that determine lesion topography. METHOD: We reviewed 50 patients (31 females, 19 males) with symptomatic hypoglycaemia (<2.8 mmol/L) occurring between 1 day and 5 years of age (median 4 d) who had undergone magnetic resonance imaging (MRI; at least axial T2-weighted, sagittal T1-weighted, and coronal fluid-attenuated inversion recovery [FLAIR]-weighted imaging). MRI was performed during the follow-up examination at least 1 month after the occurrence of symptomatic hypoglycaemia, i.e. between 1 month and 5 years of age (median 3 mo). Hypoglycaemia resulted from three inborn errors of metabolism: congenital hyperinsulinism (33 patients), fatty acid ß-oxidation disorders (13 patients), or glycogen storage disease type I (four patients). We selected the patients with clear MRI abnormalities and analysed their topography according to aetiology and age at occurrence of the lesion. RESULTS: The topography of the brain lesions depended on age: from the neonatal period to 6 months of age, lesions predominantly involved the posterior white matter; between 6 and 22 months the basal ganglia, and after 22 months the parietotemporal cortex (p=0.04). INTERPRETATION: The relationship between brain lesions and age could reflect the maturation sequence of the brain.

Functional imaging of the pancreas: the role of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy.

Congenital hyperinsulinism (HI) of infancy, the most frequent cause of hypoglycaemia in young children, is a neuro-endocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormal pancreatic insulin secretion. This inappropriate secretion of insulin induces severe hypoglycaemias that require aggressive treatment to prevent the high risk of irreversible brain damage. Focal and diffuse forms of HI share a similar clinical presentation, but their treatment is dramatically different. Selective surgical resection can cure focal HI whilst diffuse forms require near-total pancreatectomy if resistant to medical treatment. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive method, technically difficult to perform, which requires general anaesthesia. The pancreas is one of the most heavily innervated peripheral organs in the body, and its functional imaging with positron emission tomography (PET) is difficult to perform, in part because of the vast number of physiological roles and cell types that characterize this organ. However, HI, as all neuro-endocrine diseases, is notable for the ability to take up amine precursors and to convert them into biogenic amines. Therefore, we have evaluated the use of PET with [18F]fluoro-L-DOPA, a precursor of catecholamines, to image the pancreas and distinguish focal from diffuse HI.