Andrea Bevot

Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk.

Aim:u2002 To investigate neurodevelopmental outcome and hearing in preterm children with breast milk transmitted human cytomegalovirus (HCMV) infection.

Long-term cognitive and neurological outcome of preterm infants with postnatally acquired CMV infection through breast milk

Introduction Long-term follow-up data on preterm infants with breast milk–acquired postnatal cytomegalovirus (CMV) infection are sparse. Aim To systematically evaluate the long-term cognitive outcome and prevalence of cerebral palsy (CP) in patients after postnatal CMV infection. Patients and methods All surviving infants <1500u2005g born in our centre between 1 June 1995 and 1 June 2000, and with postnatal CMV infection acquired at up to 3u2005months of corrected age, were eligible for our study; this included neurological and neurocognitive assessment, using the Kaufman Assessment Battery for Children (K-ABC) at the age of >4u2005years. A blinded and controlled matched-pairs design was used with gestational age, gender and date of birth as matching criteria. Results Of 50 eligible children, 42 (84%) could be tested. There was no difference in the prevalence of cerebral palsy. Following CMV infection during their hospital stay, infants had significantly lower results in the simultaneous processing scale of the K-ABC (p=0.029) after correction for additional risk factors like socioeconomic status (SES). Results for the sequential and achievement scales were only slightly reduced (p>0.05). Conclusions It seems possible that breast milk-acquired CMV infection has a detrimental influence on cognitive development of preterm infants.

Postnatal Human Cytomegalovirus Infection in Preterm Infants Has Long-Term Neuropsychological Sequelae

OBJECTIVEnTo evaluate whether an early postnatal infection poses a long-term risk for neuropsychological impairment to neonates born very prematurely.nnnSTUDY DESIGNnAdolescents born very preterm (n = 42, 11.6-16.2 years, mean = 13.9; 15 girls; 19 with and 23 without an early postnatal human cytomegalovirus [CMV] infection) and typically developing, term born controls (n = 24, 11.3-16.6 years, mean = 13.6; 12 girls) were neuropsychologically assessed with the German version of the Wechsler Intelligence Scale and the Developmental Test for Visual Perception.nnnRESULTSnAs expected, the full cohort of adolescents born preterm had significantly lower scores than term born controls on IQ (preterm: mean [SD] = 98.43 [14.83], control: 110.00 [8.10], P = .015) and on visuoperceptive abilities (95.64 [12.87] vs 106.24 [9.95], P = .016). Furthermore, adolescents born preterm with early postnatal CMV infection scored significantly lower than those without this infection regarding overall cognitive abilities (92.67 [14.71] vs 102.75 [13.67], P = .030), but not visuoperceptive abilities (91.22 [10.88] vs 98.96 [13.45], P > .05).nnnCONCLUSIONSnIn our small but well-characterized group, our results provide evidence for adverse effects of early postnatal CMV infection on overall cognitive functions in adolescents born preterm. If confirmed, these results support the implementation of preventive measures.

Surgical management of extremely low birth weight infants with neonatal bowel perforation: a single-center experience and a review of the literature.

Background: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are major causes of morbidity in infants with extremely low birth weight (ELBW). Objective: To evaluate the surgical procedures applied, and the survival and long-term outcome of ELBW infants with NEC and FIP in a single-center study. Methods: Inborn and outborn ELBW infants (<1000 g) with NEC and FIP were analyzed retrospectively from 2002 to 2007. Data collected include surgical procedures, survival as well as complications, length of partial parenteral nutrition and hospital stay. The short-term and long-term outcomes after 2–7 years were assessed and compared with a matched control group. Results: Out of 280 ELBW infants, 28 underwent surgery, 19 because of FIP and 9 for NEC. Fourteen infants in the FIP group were treated with primary laparotomy and 5 with peritoneal drainage (PD). In the NEC group, only 1 infant was treated with PD. PD was used for unstable patients and was always followed by secondary laparotomy after stabilization. Five of 28 (18%) surgically treated ELBW infants and 4 (14%) matched controls died. The following complications occurred in the surgical group: complete (n = 1) or minor wound dehiscence (n = 4), stoma prolapse (n = 5), parastomal hernia (n = 2), stoma fistula (n = 1), and wound infection (n = 2). Dependency on parenteral nutrition was significantly shorter in infants with FIP, while there were no differences in time to stoma closure and length of hospital stay between those with FIP and those with NEC. Eleven of 23 (47.8%) surviving patients with FIP or NEC showed developmental delay, compared with 9 of 24 (37.5%) in the controls. Conclusions: The management of EBLW infants with NEC and FIP remains challenging. Our treatment approach was associated with low mortality. Developmental delay seems to be caused by extreme prematurity rather than NEC- or FIP-related bowel perforation.

Schoolchildren born VLBW or VLGA show height-related changes in body composition and muscle function but no evidence of metabolic syndrome risk factors. Results from the NEOLONG study.

Abstract Background: Children born small for gestational age (SGA) are at risk for the metabolic syndrome (MetS) as adults. We examined whether indicators of MetS could be identified in pre-pubertal children born very preterm. Methods: Parameters associated with MetS were studied in 141 pre-pubertal schoolchildren with either very low birth weight (VLBW) or GA <32 weeks (SGA: n=43). Results: At 8.3±0.8 years, 36 children (SGA: n=15) were classified short. There were no differences between the SGA and appropriate for age (AGA) groups; nor were dissimilarities observed between short children and those with normal height for parameters such as body mass index (BMI), serum levels of hormones, HDL cholesterol, triglycerides, glucose, insulin, HOMA-IR, body composition, resting energy expenditure, grip strength and jump force. Conclusions: Neither SGA at birth nor short stature at follow-up (irrespective of size at birth), could be associated with parameters that indicate an increased risk for the MetS during childhood.

Long-term neurobiological consequences of early postnatal hCMV-infection in former preterms: a functional MRI study.

Early postnatal infection with human cytomegalovirus (hCMV) may contribute to an adverse cognitive outcome in early preterm‐born children (PT). We here set out to explore whether long‐term neurobiological consequences of such an infection are detectable using fMRI in children and adolescents who were born very preterm and who either did (PThCMV+) or did not (PThCMV−) suffer from an early postnatal hCMV‐infection, when compared with typically developing healthy control (HC) subjects. Overall, data from 71 children and adolescents could be included, 34 PT (of which 15 were PT hCMV+ and 19 were PT hCMV−) and 37 HC. Using a recently established “dual use” fMRI task, we investigated language and visuospatial functions. There were significant activation differences in the left hippocampus (PT > HC and PThCMV+ > HC), and in the right anterior cingulate cortex (PThCMV− > PThCMV+) when performing the language task. Surprisingly, only a small region in the occipital cortex showed a significant activation difference (HC > PT HCMV−) when performing the visuospatial task. Targeted analyses revealed differences in gray matter volume, but not density, in several brain regions. Our results suggest that long‐term neurobiological consequences of an early postnatal hCMV infection are detectable even in older children and adolescents formerly born very preterm, compatible with a higher effort when performing a cognitive task. This suggests that measures to prevent such an infection are warranted. Furthermore, an interrelation of brain structure and function was detected that may constitute a severe confound when using fMRI to compare structurally differing groups. Hum Brain Mapp 35:2594–2606, 2014.

ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.

IntroductionAlpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency.MethodsBased on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients.ResultsWe found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50xa0% of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4xa0years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40xa0year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype–phenotype correlation.DiscussionALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.

Interstitial 9q34.11-q34.13 deletion in a patient with severe intellectual disability, hydrocephalus, and cleft lip/palate.

Interstitial deletions of chromosome bands 9q34.11–q34.13 are rare. We report on a 16‐year‐old female patient with severe intellectual disability, congenital hydrocephalus, cleft lip and palate, talipes equinovarus, epilepsy, kyphoscoliosis, convergent strabismus, severe short stature, dystrophy, and facial dysmorphic signs. Array analysis revealed a 3.7u2009Mb interstitial deletion in 9q34.11–q34.13. The deletion harbors more than 60 genes, including SPTAN1, DYT1/TOR1A, ABL1, ASS1, LAMC3, POMT1, DOLK, and GLE1, mutations in which have previously been associated with monogenic disorders. This is the first patient with a deletion of this size and position in 9q34.11–q34.13. Reports of additional patients with aberrations in this region will be needed to establish karyotype–phenotype correlations and to gain information on the contribution of individual genes for the clinical manifestations.

Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?

AbstractBackgroundMost microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions.ResultsWe report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13xa0Mb, whereas the smallest deletion of 432xa0kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3.n Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.ConclusionsWe suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.