Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants

Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and 5 GSD Ia patients. In 5 patients, GSD III, VI, IX, cholesteryl-ester storage disease and Shwachman-Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172746 and 1:60461 live-births, respectively. Two variants were identified in G6PC gene: c.247C gt T (p.Arg83Cys) and c.518T gt C (p.Leu173Pro). In SLC37A4 gene, 6 variants were detected. Three previously reported variants c.81T gt A (p.Asn27Lys), c.162C gt A (p.Ser54Arg) and c.1042_1043delCT (p.Leu348Valfs*53) accounted for 87% of all analyzed alleles. Computational, transcription studies and/or clinical presentation in patients confirmed pathogenic effect of 3 novel variants: c.248G gt A (p.Gly83Glu), c.404G gt A (p.Gly135Asp) and c.785G gt A (p.Ser263Glyfs*33 or p.Gly262Asp). In the cohort, hepatomegaly, hypoglycemia and failure to thrive were the most frequent presenting signs of GSD Ia, while hepatomegaly and recurrent bacterial infections were clinical hallmarks of GSD Ib. All GSD Ib patients developed neutropenia while 20.6% developed inflammatory bowel disease. Our study revealed the highest worldwide incidence of GSD Ib. Furthermore, description of 3 novel variants will facilitate medical genetic practice.This is the peer reviewed version of the paper: Skakic, A., Djordjevic, M., Sarajlija, A., Klaassen, K., Tosic, N., Kecman, B., Ugrin, M., Spasovski, V., Pavlovic, S., & Stojiljkovic, M. (2018). Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants. Clinical Genetics, 93(2), 350–355. [https://doi.org/10.1111/cge.13093

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders?A successful strategy for clinical research of rare diseases

BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (</= 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies

Caretaker Quality of Life in Rett Syndrome: Disorder Features and Psychological Predictors

ObjectiveRett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact both patients' and caretakers' quality of life in Rett syndrome. We hypothesized that more severe clinical features would negatively impact caretaker physical quality of life but would positively impact caretaker mental quality of life.MethodsParticipants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic Rett syndrome. Demographic data, clinical disease features, caretaker quality of life, and measures of family function were assessed during clinic visits. The Optum SF-36v2 Health Survey was used to assess caretaker physical and mental quality of life (higher scores indicate better quality of life). Descriptive, univariate, and multivariate analyses were used to characterize relationships between child and caretaker characteristics and caretaker quality of life.ResultsCaretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) vs 44.5 (12.1). No differences were demonstrated between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (P = 0.006) and improved MCS (P = 0.003). Feeding problems were associated with poorer PCS (P = 0.007) and poorer MCS (P = 0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS.ConclusionsCaretaker quality of life in Rett syndrome is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact quality of life, and feeding difficulties may represent an important clinical target for improving both child and caretaker quality of life. The stability of quality-of-life scores between baseline and five years adds important value

Spontaneous Septum Pellucidum Fenestration Complicating Posthemorrhagic Hydrocephalus in an Extremely Low Birth Weight Infant

A 25 weeks' gestation infant developed posthemorrhagic hydrocephalus. On postnatal Day 29 an ultrasound of the brain showed a fenestration between the septum pellucidum and the left lateral ventricle which continued to enlarge as the clinical course deteriorated. Color Doppler showed low flow between the septum pellucidum leaflets suggesting a persistence of erythrocytes. However, color Doppler artifacts could have resulted in this interpretation. The infant died on day 34 from multiple organ failure. Despite spontaneous fenestration of the septum pellucidum being previously described, it has not been associated with hemorrhagic hydrocephalus. Serial scanning of intracranial structures by high frequency probes can allow better understanding of the pathophysiology of neurologic complications in preterm infants. © 2013

Sensorineural Hearing Loss in a Child with Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency

Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial.

To evaluate the efficacy and tolerability of levetiracetam or oxcarbazepine as monotherapy in children with newly diagnosed benign epilepsy with centrotemporal spikes (BECTS). Twenty-one children (11 males, 10 females), aged between 5 and 13 years (mean 10.5 years), and 18 (10 M, 8 F), aged between 3.3 and 14 years (mean 8.4 years), were randomised to receive monotherapy with levetiracetam or oxcarbazepine, respectively. LEV was titrated up to 20-30 mg/kg/once or twice a day, and OXC up to 20-35 mg/kg once or twice a day. Thirty-nine consecutive children (21 males, 18 females), aged between 3.3 and 14 years (mean 10.7 years), were recruited into the study. Twenty-one were randomised on LEV (11 male, 10 female; mean age 10.5 years), and 18 on OXC (10 male, 8 female; mean age 8.4 years). After a mean follow-up period of 18.5 months (range 12-24 months), 19 out of 21 patients (90.5%) on levetiracetam, and 13 out of 18 (72,22%) on oxcarbazepine did not have further seizures. Mean serum level of LEV was 4.1 microg/ml (range 1.3-9.0), and of OXC was 15.2 microg/ml (range 4.2-27.5). Adverse side effects on LEV were reported in 3 children (14.3%), represented by mild and transient decreased appetite (2) and cephalalgia (1). They were reported on OXC in 2/18 (11.1%), including headache (1), and sedation (1). These preliminary data from an open, parallel group study suggest that levetiracetam and oxcarbazepine may be potentially effective and well tolerated drugs for children with BECTS who require treatment

Topiramate: effects on serum lipids and lipoproteins levels in children.

The present controlled study aims to evaluate topiramate (TPM) effect on total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein, very low-density lipoprotein, apolipoproteins A1, B and lipoprotein (a). Seventy patients in evolving age suffering from various types of epilepsy, treated with TPM, (age range: 6 months-22 years) were evaluated before and after 12 months of treatment and compared with 110 sex- and age-matched subjects. At baseline, no significant difference was present between controls and children treated with TPM. After a year, the BMI did not show significant change in adults and remained into respective growth curve. No significant difference in lipids and lipoproteins neither between first and second evaluation nor between patients and controls was found. Some intra-group variation has been noticed: whilst controls maintained similar levels, the 70 patients on TPM monotherapy showed a slight decrease in TC, triglycerides and HDL. These fluctuations, however, occurred in the normal range so neither dietary nor pharmacological treatment of hyperlipidaemia after a year of TPM was necessary