Journals
2014 EN
Jedraszak Guillaume · Girard Muriel · Mellos Antonio
+9 more
Simpson–Golabi–Behmel syndrome type 1 (SGBS1) ‐OMIM 312870‐ is a rare X‐linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre‐ and post‐natal macrosomia, distinctive facial dysmophism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient's liver disease is also proposed. © 2013 Wiley Periodicals, Inc.
Journals
2014 EN
Kline Antonie D. · Calof Anne L. · Schaaf Cheri A.
+18 more
Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20–21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally‐focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Migliavacca Michele P. · Sobreira Nara L. M. · Antonialli Graziela P.M.
+7 more
Van den Ende–Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553–559] identified homozygous mutations in SCARF2 , located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge‐velo‐cardio‐facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23‐year‐old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2 . The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2 . © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Meloni Vera Ayres · Guilherme Roberta Santos · Oliveira Mariana Moyses
+6 more
The chromosomal segment 6q24‐q25 comprises a contiguous gene microdeletion syndrome characterized by intrauterine growth retardation, growth delay, intellectual disability, cardiac anomalies, and a dysmorphic facial phenotype. We describe here a 10‐year follow‐up with detailed clinical, neuropsychological, and cytomolecular data of two siblings, male and female, who presented with developmental delay, microcephaly, short stature, characteristic facial dysmorphisms, multiple organ anomalies, and intellectual disability. Microarray analysis showed an 8.5 Mb 6q24.2‐q25.2 interstitial deletion. Fluorescence in situ hybridization analyses confirmed the deletions and identified an insertion of 6q into 8q13 in their father, resulting in a high recurrence risk. This is the first report in sibs with distinct neuropsychological involvement, one of them with stenosis of the descending branch of the aorta. © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Lonardo Fortunato · Di Natale Paola · Lualdi Susanna
+8 more
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare X‐linked disorder caused by deficient activity of the lysosomal enzyme, iduronate‐2‐sulfatase (IDS). Phenotypic expression of MPS II in female patients rarely occurs and may be the result of (i) structural abnormalities of the X chromosome, (ii) homozygosity for disease‐causing mutations, or (iii) skewed X‐chromosome inactivation, in which the normal IDS allele is preferentially inactivated and the abnormal IDS allele is active. We report here on a female patient with clinical MPS II manifestations, deficiency of IDS enzyme activity and a de novo balanced reciprocal X;9 translocation. As our patient has a skewed XCI pattern, but neither genomic IDS mutations nor abnormal IDS transcripts were detected, we speculate about the possible role of the chromosomal rearrangement in reducing the IDS translation efficiency. © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Castori Marco · Dordoni Chiara · Valiante Michele
+10 more
Joint hypermobility syndrome (JHS) and Ehlers‐Danlos syndrome, hypermobility type (EDS‐HT) are two markedly overlapping heritable connective tissue disorders. The cumulative frequency of JHS and EDS‐HT seems high, but their recognition remains an exclusion diagnosis based on different sets of diagnostic criteria. Although proposed by a panel of experts, clinical identity between JHS and EDS‐HT is still a matter of debate due to unknown molecular basis. We present 23 families with three or more individuals with a diagnosis of JHS and/or EDS‐HT. Rough data from the 82 individuals were used to assess the frequency of major and minor criteria, as well as selected additional features. A series of statistical tools were applied to assess intrafamilial and interfamilial variability, emphasizing intergenerational, and intersex differences. This study demonstrates marked heterogeneity within and between families in terms of agreement of available diagnostic criteria. In 21 pedigrees affected individuals belong to two or three phenotypic sub‐categories among JHS, EDS‐HT, and JHS + EDS‐HT overlap. Intergenerational analysis depicts a progressive shifting, also within the same pedigree, from EDS‐HT in childhood, to JHS + EDS‐HT in early adulthood and JHS later in life. Female‐male ratio is 2.1:1, which results lower than previously observed in unselected patients' cohorts. In these pedigrees, JHS, EDS‐HT, and JHS + EDS‐HT segregate as a single dominant trait with complete penetrance, variable expressivity, and a markedly evolving phenotype. This study represents a formal demonstration that EDS‐HT and JHS contitute the same clinical entity, and likely share the same genetic background, at least, in familial cases. © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Byrne Enda M. · Heath Andrew C. · Madden Pamela A.F.
+5 more
Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene‐based and SNP P ‐values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of P < 0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells. Our results suggest that genes encoding components of the molecular clock are not good candidates for harboring common variants that increase risk to bipolar disorder, schizophrenia, or major depressive disorder. © 2014 Wiley Periodicals, Inc.
Journals
2014 EN
Bleuze Michele M. · Wheeler Sandra M. · Dupras Tosha L.
+2 more
Several studies have shown that the human body generally conforms to the ecogeographical expectations of Bergmann's and Allen's rules; however, recent evidence suggests that these expectations may not hold completely for some populations. Egypt is located at the crossroads of Sub‐Saharan Africa, Southern Europe, and the Near East, and gene flow among groups in these regions may confound ecogeographical patterning. In this study, we test the fit of the adult physique of a large sample ( N = 163) of females and males from the Kellis 2 cemetery (Dakhleh Oasis, Egypt) against ecogeographical predictions. Body shape (i.e., body mass relative to stature) was assessed by the femur head diameter to bicondylar femur length index (FHD/BFL), and brachial and crural indices were calculated to examine intralimb proportions. Body shape in the Kellis 2 sample is not significantly different from high‐latitude groups and a Lower Nubian sample, and intralimb proportions are not significantly different from mid‐latitude and other low‐latitude groups. This study demonstrates the potential uniqueness of body shape and intralimb proportions in an ancient Egyptian sample, and further highlights the complex relationship between ecogeographic patterning and adaptation. Am J Phys Anthropol 153:496–505, 2014. © 2013 Wiley Periodicals, Inc.
Journals
2014 EN
Pupillo Elisabetta · Messina Paolo · Giussani Giorgia
+20 more
Objective To assess whether physical activity is a risk factor for amyotrophic lateral sclerosis (ALS). Methods From February 2008 to April 2012, 652 patients with ALS from European population‐based registries (France, Ireland, Italy, United Kingdom, Serbia) and 1,166 population controls (matched for age, sex, and residency) were assessed. Upon direct interview, data were collected on occupation and history of sport and leisure activities, physical activity, and accidental injuries. Physical exercise was defined as having spent time doing activities that caused an individual to breath hard at least once per month and was coded as none, job‐related, and/or sport‐related. Sport‐related and work‐related physical exercise were quantified using metabolic equivalents (METs). Risks were calculated using conditional logistic regression models (adjusting for age, country, trauma, and job‐related physical activity) and expressed as odds ratios (ORs) and adjusted ORs (Adj ORs) with 95% confidence intervals (CIs). Results Overall physical activity was associated with reduced odds of having ALS (Adj OR = 0.65, 95% CI = 0.48–0.89) as were work‐related physical activity (Adj OR = 0.56, 95% CI = 0.36–0.87) and organized sports (Adj OR = 0.49, 95% CI = 0.32–0.75). An inverse correlation was observed between ALS, the duration of physical activity ( p = 0.0041), and the cumulative MET scores, which became significant for the highest exposure (Adj OR = 0.34, 95% CI = 0.21–0.54). An inverse correlation between ALS and sport was found in women but not in men, and in subjects with repeated traumatic events. Interpretation Physical activity is not a risk factor for ALS and may eventually be protective against the disease. ANN NEUROL 2014;75:708–716
Journals
2014 EN
Cheung Tyler · Noecker Angela M. · Alterman Ron L.
+2 more
Objective To create a data‐driven computational model that identifies brain regions most frequently influenced by successful deep brain stimulation (DBS) of the globus pallidus (GP) for advanced, medication‐resistant, generalized dystonia. Methods We studied a retrospective cohort of 21 DYT1 primary dystonia patients treated for at least 1 year with bilateral pallidal DBS. We first created individual volume of tissue activation (VTA) models utilizing neuroimaging and postoperative stimulation and clinical data. These models were then combined into a standardized probabilistic dystonia stimulation atlas (DSA). Finally, we constructed a candidate target volume from electrodes demonstrating at least 75% improvement in contralateral symptoms, utilizing voxels stimulated by least 75% of these electrodes. Results Pallidal DBS resulted in a median contralateral hemibody improvement of 90% (mean = 83%, standard deviation [SD] = 20) after 1 year of treatment. Individual VTA models of the 42 active electrodes included in the study demonstrated a mean stimulation volume of 501mm[3][Vidailhet M, 2005] ([SD] = 284). The resulting DSA showed that areas most frequently stimulated were located squarely in the middle of the posterior GP, with a common target volume measuring 153mm 3 . Interpretation Our results provide a map of the region of influence of therapeutic DBS for dystonia and represent a potential target to refine current methods of surgical planning and stimulation parameters selection. Based on their role in alleviating symptoms, these regions may also provide anatomical and physiological information relevant to disease models of dystonia. Further experimental and clinical studies will be needed to validate their importance. Ann Neurol 2014;76:22–30