109 research outputs found
Uncommon genetic syndromes and narrative production - Case Studies with Williams, Smith-Magenis and Prader- Willi Syndromes
This study compares narrative production among three syndromes with
genetic microdeletions: Williams syndrome (WS), Smith-Magenis syndrome
(SMS), and Prader-Willi syndrome (PWS), characterized by intellectual
disabilities and relatively spared language abilities. Our objective is to study
the quality of narrative production in the context of a common intellectual
disability. To elicit a narrative production, the task Frog! Where Are You was
used. Then, structure, process, and content of the narrative process were
analysed in the three genetic disorders:WS (n52), SMS (n52), and PWS (n52).
Data show evidence of an overall low narrative quality in these syndromes,
despite a high variability within different measures of narrative production.
Results support the hypothesis that narrative is a highly complex cognitive
process and that, in a context of intellectual disability, there is no evidence of
particular ‘hypernarrativity’ in these syndromes.This research was supported by the grants FEDER –
A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk insT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits
Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men
Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials
Current concepts of polymicrogyria
Polymicrogyria is one of the most common malformations of cortical development. It has been known for many years and its clinical and MRI manifestations are well described. Recent advances in imaging, however, have revealed that polymicrogyria has many different appearances on MR imaging, suggesting that is may be a more heterogeneous malformation than previously suspected. The clinical and imaging heterogeneity of polymicrogyria is explored in this review
Approach to epigenetic analysis in language disorders
Language and learning disorders such as reading disability and language impairment are recognized to be subject to substantial genetic influences, but few causal mutations have been identified in the coding regions of candidate genes. Association analyses of single nucleotide polymorphisms have suggested the involvement of regulatory regions of these genes, and a few mutations affecting gene expression levels have been identified, indicating that the quantity rather than the quality of the gene product may be most relevant for these disorders. In addition, several of the candidate genes appear to be involved in neuronal migration, confirming the importance of early developmental processes. Accordingly, alterations in epigenetic processes such as DNA methylation and histone modification are likely to be important in the causes of language and learning disorders based on their functions in gene regulation. Epigenetic processes direct the differentiation of cells in early development when neurological pathways are set down, and mutations in genes involved in epigenetic regulation are known to cause cognitive disorders in humans. Epigenetic processes also regulate the changes in gene expression in response to learning, and alterations in histone modification are associated with learning and memory deficits in animals. Genetic defects in histone modification have been reversed in animals through therapeutic interventions resulting in rescue of these deficits, making it particularly important to investigate their potential contribution to learning disorders in humans
Achieving the "triple aim" for inborn errors of metabolism: a review of challenges to outcomes research and presentation of a new practice-based evidence framework
Across all areas of health care, decision makers are in pursuit of what
Berwick and colleagues have called the “triple aim”: improving patient
experiences with care, improving health outcomes, and managing
health system impacts. This is challenging in a rare disease context, as
exemplified by inborn errors of metabolism. There is a need for evaluative
outcomes research to support effective and appropriate care for
inborn errors of metabolism. We suggest that such research should
consider interventions at both the level of the health system (e.g., early
detection through newborn screening, programs to provide access to
treatments) and the level of individual patient care (e.g., orphan drugs,
medical foods). We have developed a practice-
based evidence framework
to guide outcomes research for inborn errors of metabolism.
Focusing on outcomes across the triple aim, this framework integrates
three priority themes: tailoring care in the context of clinical heterogeneity;
a shift from “urgent care” to “opportunity for improvement”;
and the need to evaluate the comparative effectiveness of emerging
and established therapies. Guided by the framework, a new Canadian
research network has been established to generate knowledge that will
inform the design and delivery of health services for patients with
inborn errors of metabolism and other rare diseases.This work was supported by a CIHR Emerging Team Grant (“Emerging
team in rare diseases: acheiving the ‘triple aim’ for inborn errors
of metabolism,” B.K. Potter, P. Chakraborty, and colleagues, 2012–
2017, grant no. TR3–119195). Current investigators and collaborators
in the Canadian Inherited Metabolic Diseases Research Network
are: B.K. Potter, P. Chakraborty, J. Kronick, D. Coyle, K. Wilson, M.
Brownell, R. Casey, A. Chan, S. Dyack, L. Dodds, A. Feigenbaum, D.
Fell, M. Geraghty, C. Greenberg, S. Grosse, A. Guttmann, A. Khan,
J. Little, B. Maranda, J. MacKenzie, A. Mhanni, F. Miller, G. Mitchell,
J. Mitchell, M. Nakhla, M. Potter, C. Prasad, K. Siriwardena, K.N.
Speechley, S. Stocker, L. Turner, H. Vallance, and B.J. Wilson. Members
of our external advisory board are D. Bidulka, T. Caulfield, J.T.R.
Clarke, C. Doiron, K. El Emam, J. Evans, A. Kemper, W. McCormack,
and A. Stephenson Julian. J. Little is supported by a Canada Research
Chair in Human Genome Epidemiology. K. Wilson is supported by a
Canada Research Chair in Public Health Policy
Expanding the clinical phenotype of the mitochondrial m.13513G\u3eA mutation with the first report of a fatal neonatal presentation: importance of DNA collection for post-mortem diagnosis.
Epigenetics, copy number variation, and other molecular mechanisms underlying neurodevelopmental disabilities: New insights and diagnostic approaches
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