Objective: Mutations in the gene encoding phospholipase A 2 group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A 2 . Methods:We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations. Results:Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations. The neuroaxonal dystrophies are degenerative disorders that share the pathologic feature of axonal spheroids in brain. Spheroids are poorly understood axonal swellings that occur in infantile neuroaxonal dystrophy (INAD), pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome), idiopathic neurodegeneration with brain iron accumulation (NBIA), and Schindler disease. INAD is a severe psychomotor disorder with early onset and rapid progression of hypotonia, hyperreflexia, and tetraparesis. Conclusion:1 Spheroids are found in both the central and peripheral nervous systems in INAD, and iron accumulates in brain in a subset of these patients. 2,3 The term "neurodegeneration with brain iron accumulation" is used both as a descriptor

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.

Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in 5 probands with ADCL features and found 5 de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5) and c.2124del25 (CL-6). Four probands (CL-1, -2, -3, -6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGFβ) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications,

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An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.T he understanding of human obesity has benefited greatly from advances in molecular genetics. In addition to the identification of many mechanistically illuminating, highly penetrant monogenic disorders, genome-wide association studies (GWAS) have identified multiple common genetic variants strongly associated with body mass index (BMI) (1-5). Many of these loci are within, or close to, genes which, to date, have not been recognized to encode proteins with a role in the control of energy homeostasis. Of note, these genes show a strong preponderance to being highly expressed in the central nervous system, a finding which is congruent with the fact that monogenic disorders leading to obesity largely exert their effects through a disruption of the central control of appetite and energy balance (6). Murine models have proven to be highly useful in bridging the gap between the identification of a variant as being associated with an adiposity phenotype and the understanding of how that variant actually influences energy balance. For example, the robust correlation between BMI and polymorphisms in the first intron of the human fat mass and obesity-associated (FTO) gene has been followed by loss and gain of function studies in genetically modified mice, supporting the notion that a number of neighboring genes including IRX3 (which is the gene most likely mediating the effect of the human SNP), RPGRIP1L, and FTO itself can all play a role in the control of energy balance and body composition (7-13). A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18, has been repeatedly demonstrated in both adults and children (2, 14-18). Like the genes in the vicinity of FTO, TMEM18 had not been recognized as having a role in energy homeostasis before its identification by GWAS, and relatively little is known about its function, save that it is expressed in the brain and that it encodes a 140-aa protein reported to contain three transmembrane domain (19) which may act as a DNAbinding protein (20)...