Sustained Immune Tolerance Induction in Enzyme Replacement Therapy-Treated CRIM-Negative Patients with Infantile Pompe Disease

BACKGROUND: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of /=51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values o

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways

NSD1 mutations in Sotos syndrome alter the DNA methylation landscape of genes involved in somatic growth and neuronal transmission

Sotos syndrome (OMIM 117550) is a rare genetic overgrowth disorder associated with malformations and neurodevelopmental problems including intellectual and behavioural issues. Individuals with Sotos syndrome are haploinsufficient for NSD1 (nuclear receptor-binding SET domain protein 1), a histone lysine methyltransferase important for multiple aspects of normal development. Recently, NSD1 was shown to bind near various promoter elements, regulating multiple genes via interactions with H3K36me and RNA polymerase II. These data suggest a potential role for NSD1 in regulating trans…link_to_OA_fulltex

Beals syndrome (congenital contractural arachnodactyly): prenatal ultrasound findings and molecular analysis

We report the prenatal findings in two cases of Beals syndrome. Both pregnancies presented with clinical features of arthrogryposis multiplex congenita/fetal akinesia syndrome (AMC/FAS), including clenched fists and multiple joint contractures on repeat prenatal ultrasound examinations. The first case was diagnosed as having Beals syndrome on physical examination shortly after birth and the diagnosis was confirmed by DNA analysis, shown as a point mutation in the fibrillin 2 (FBN2) gene. The second case was diagnosed with Beals syndrome following microarray analysis on amniocytes, which showed a deletion of the FBN2 gene. Although most cases with AMC/FAS carry a poor prognosis, Beals syndrome is consistent with normal cognitive development and a better prognosis. Thus, making the correct diagnosis is crucial, both pre- and postnatally, for accurate counseling and management. Copyright (C) 2014 ISUOG. Published by John Wiley & Sons Ltd

Social skills impairments in girls with Turner syndrome

INTRODUCTION: Turner syndrome (TS) is one of the most common sex chromosome abnormalities caused by complete or partial monosomy of the X chromosome, with a prevalence of 1/2000 female live births. Individuals with TS present with short stature, gonadal dysfunction and other systemic malformations. A specific neuro-cognitive profile has been reported, sometimes including impaired social cognition. Autism and autism spectrum disorders (ASD) are reported in 5% and 25% of TS patients respectively. Skuse et al, 1997 reported that females who inherit their single X-chromosome from their father have better social skills than females who inherit it from their mother. The authors hypothesized that an imprinted locus on the X-chromosome is relevant to social functioning. Hypothesis: Females with TS demonstrate parent of origin- specific differences in social cognition. Methods and Results: We recruited 28 individuals with TS (age 3-18 years) and their parents at the Pediatric Endocrinology Clinic. We collected buccal samples from the proband and both parents. In addition, parents completed two social skills questionnaires for their daughters, one used originally by Skuse et al and the Social Responsiveness Scale (SRS) that assesses social awareness, social cognition, social communication, social motivation, and autistic mannerisms. SRS total scores fall into three categories: normal (T score ≤59); mild to moderate, consistent with mild ASD (T score=60-75); and severe, consistent with autism (≥76). We compared the scores for groups of girls with TS carrying a single maternal vs paternal X chromosome, as well as a group with karyotypes other then XO. In 14/28 patients (50%) scores were> 60. In 7/28 (25%), scores were in the mild/moderate ASD range and in 7/28 (25%), scores were in the severe autism range. Score differences for the sub-scales of SRS showed higher scores for autistic mannerisms. A good correlation between Skuze et al and the currently SRS was found (R� = 0.80). We did not find any correlation in social skill measures with parent of origin of the X chromosome in our small TS cohort. Conclusions: We found the rate of autistic features in TS to be significantly higher than previously reported. These data have significant implications for genetic counseling. We suggest that individuals with TS be routinely screened for ASD for early identification and initiation of behavioral interventions.link_to_OA_fulltex

Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2

Flavin adenine dinucleotide (FAD) synthase (EC 2.7.7.2), encoded by human flavin adenine dinucleotide synthetase 1 (FLAD1), catalyzes the last step of the pathway converting riboflavin (Rf) into FAD. FLAD1 variations were identified as a cause of LSMFLAD (lipid storage myopathy due to FAD synthase deficiency, OMIM #255100), resembling Multiple Acyl-CoA Dehydrogenase Deficiency, sometimes treatable with high doses of Rf; no alternative therapeutic strategies are available. We describe here cell morphological and mitochondrial alterations in dermal fibroblasts derived from a LSMFLAD patient carrying a homozygous truncating FLAD1 variant (c.745C > T) in exon 2. Despite a severe decrease in FAD synthesis rate, the patient had decreased cellular levels of Rf and flavin mononucleotide and responded to Rf treatment.We hypothesized that disturbed flavin homeostasis and Rf-responsiveness could be due to a secondary impairment in the expression of the Rf transporter 2 (RFVT2), encoded by SLC52A2, in the frame of an adaptive retrograde signaling to mitochondrial dysfunction. Interestingly, an antioxidant response element (ARE) is found in the region upstream of the transcriptional start site of SLC52A2. Accordingly, we found that abnormal mitochondrial morphology and impairments in bioenergetics were accompanied by increased cellular reactive oxygen species content and mtDNA oxidative damage. Concomitantly, an active response to mitochondrial stress is suggested by increased levels of PPAR gamma-co-activator-1 alpha and Peroxiredoxin III. In this scenario, the treatment with high doses of Rf might compensate for the secondary RFVT2 molecular defect, providing a molecular rationale for the Rf responsiveness in patients with loss of function variants in FLAD1 exon 2