Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome.

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

Ophthalmological finding in a patient with lowe syndrome.

The authors present the ophthamological finding in a patient who at the age of 4.5 months was admitted due to a finding of total bilateral congenital cataract. The patient was observed by a neurologist for central hypotonia and mental retardation. Upon a complex examination of the patient, suspicion of Lowe syndrome was stated, which was confirmed by a metabolic examination and also by genetic tests. Upon an examination of the family, a genetic defect (mutation of OCRL1 gene) was confirmed also in the mother of the patient. A mild subcapsular opacification was present in the mother, beneath the posterior capsule. The patient was operated on for bilateral congenital cataract. Upon an examination under general anaesthesia, trabeculodysgenesis was diagnosed. Intraocular pressure remains within the norm. The patient is now aged 8 years, regularly monitored with regard to metabolic compensation, and by a neurologist and ophthalmologist, with satisfactory visual functions. Early diagnosis of the Lowe syndrome was determined on the basis of a complex examination of the patient within the framework of etiological diagnosis of bilateral congenital cataract. Key words: Lowe syndrome, oculo - cerebro - renal syndrome, congenital cataract, glaucoma, nystagmus.

GAI - distinct genotype and phenotype characteristics in reported Slovak patients.

OBJECTIVES: The clinical, biochemical and genetic findings in two Slovak patients with glutaric aciduria type I (GAI) are presented. BACKGROUND: GAI is a rare autosomal recessive neuro-metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan. This enzymatic defect gives rise to elevated levels of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC) in body fluids. METHODS: Biochemical and molecular-genetic tests were performed. Urinary organic acids were analysed by Gas Chromatography/Mass Spectrometry (GC/MS) and the entire coding region of the GCDH gene, including flanking parts, was sequenced. RESULTS: We found the presence of typical metabolic profile and novel causal pathogenic variants in both GAI patients. CONCLUSION: We present the first report of two Slovak patients with GAI, which differed in the clinical and biochemical phenotype significantly. They were diagnosed by two distinct approaches - selective and newborn screening. Their diagnosis was complexly confirmed by biochemical and later on molecular-genetic examinations. Though we agreed with a thesis that early diagnostics might positively influenced patient's health outcome, contradictory facts should be considered. Supposed extremely low prevalence of GAI patients in the general population and/or the existence of asymptomatic individuals with a questionable benefit of the applied therapeutic intervention for them lead to doubts whether the inclusion of disease into the newborn screening programme is justified well enough (Tab. 1, Fig. 3, Ref. 41).

Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data.

BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.