Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Opening up design science: The challenge of designing for reuse and joint development

The purpose of this paper is to advance design science by developing a framework for research on reuse and the relationship between external IT artifacts and their users. A design science approach to IS research needs to grapple with the fact that a number of relevant, economically attractive, external IT artifacts cannot be designed from scratch nor meaningfully evaluated based on the current state of development, and so design science research will struggle with incomplete cycles of design, relevance, and rigor. We suggest a strategic research agenda that integrates the design of the relationship between an external IT artifact and the user by considering the impact artifacts exert on users. Three dimensions derived from adaptive structuration theory inform our framework on three levels of design granularity (middle management, top management, and entrepreneur): agenda considers the dynamic properties of technological objects, adaptability refers to the functional affordance of external artifacts in development, and auspice captures the symbolic expression and scope for interpretation. We derive implications for research design

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Genetic studies of neurodevelopment

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Changes in PDE4D isoforms in the hippocampus of a patient with advanced Alzheimer disease [1]

10.1001/archneur.64.3.456Archives of Neurology643456-457ARNE

15 years of reuse experience in evolutionary prototyping for the defense industry

International audienceAt Thales Defense Mission Systems, software products first go through an industrial prototyping phase. We elaborate evolutionary prototypes which implement complete business behavior and fulfill functional requirements. We elaborate and evolve our solutions directly with end-users who act as stake-holders in the products' design. Prototypes also serve as models for the final products development. Because software products in the defense industry are developed over many years, this prototyping phase is crucial. Therefore, reusing software is a high-stakes issue in our activities. Component-oriented development helps us to foster reuse throughout the life cycle of our products. The work presented in this paper stems from 15 years of experience in developing prototypes for the defense industry. We directly reuse component implementations to build new prototypes from existing ones. We reuse component interfaces transparently in multiple prototypes, whatever the underlying implementation solutions. This kind of reuse spans prototypes and final products which are deployed on different execution platforms. We reuse non-component legacy software that we integrate in our component architectures. In this case, we seamlessly augment standard classes with component behavior, while preserving legacy code. In this paper, we present our component programming framework with a focus on component reuse in the context of evolutionary prototyping. We report three scenarios of reuse that we encounter regularly in our prototyping activity