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Sayson B.,BC Childrens Hospital | Sayson B.,University of British Columbia | Popurs M.A.M.,BC Childrens Hospital | Lafek M.,BC Childrens Hospital | And 8 more authors.
Molecular Genetics and Metabolism | Year: 2015

Background: Intellectual developmental disorders (IDD. 11Abbreviations:Intellectual developmental disorders (IDD)Inborn Errors of Metabolism (IEM)Treatable Intellectual Disability Endeavour (TIDE)Whole Exome Sequencing (WES).), characterized by a significant impairment in cognitive function and behavior, affect 2.5% of the population and are associated with considerable morbidity and healthcare costs. Inborn errors of metabolism (IEM) currently constitute the largest group of genetic defects presenting with IDD, which are amenable to causal therapy. Recently, we created an evidence-based 2-tiered diagnostic protocol (TIDE protocol); the first tier is a 'screening step' applied in all patients, comprising routinely performed, wide available metabolic tests in blood and urine, while second-tier tests are more specific and based on the patient's phenotype. The protocol is supported by an app (. www.treatable-ID.org). Objective: To retrospectively examine the cost- and time-effectiveness of the TIDE protocol in patients identified with a treatable IEM at the British Columbia Children's Hospital. Methods: We searched the database for all IDD patients diagnosed with a treatable IEM, during the period 2000-2009 in our academic institution. Data regarding the patient's clinical phenotype, IEM, diagnostic tests and interval were collected. Total costs and time intervals associated with all testing and physician consultations actually performed were calculated and compared to the model of the TIDE protocol. Results: Thirty-one patients (16 males) were diagnosed with treatable IDD during the period 2000-2009. For those identifiable via the 1st tier (. n=. 20), the average cost savings would have been $311.17 CAD, and for those diagnosed via a second-tier test (. n=. 11) $340.14 CAD. Significant diagnostic delay (mean 9. months; range 1-29 months) could have been avoided in 9 patients with first-tier diagnoses, had the TIDE protocol been used. For those with second-tier treatable IDD, diagnoses could have been more rapidly achieved with the use of the Treatable IDD app allowing for specific searches based on signs and symptoms. Conclusion: The TIDE protocol for treatable forms of IDD appears effective reducing diagnostic delay and unnecessary costs. Larger prospective studies, currently underway, are needed to prove that standard screening for treatable conditions in patients with IDD is time- and cost-effective, and most importantly will preserve brain function by timely diagnosis enabling initiation of causal therapy. © 2015 Elsevier Inc..

Armstrong L.,Treatable Intellectual Disability Endeavour in British Columbia | Armstrong L.,University of British Columbia | Biancheri R.,Child Neurology and Psychiatry Unit | Shyr C.,Treatable Intellectual Disability Endeavour in British Columbia | And 16 more authors.
Neurogenetics | Year: 2014

We report the second family with AIMP1 deficiency, due to a homozygous truncating AIMP1 (g.107248613 C>T) mutation. This female showed early-onset developmental arrest, intractable epileptic spasms, microcephaly, and a rapid clinical course leading to premature death, associated with cerebral atrophy and myelin deficiency on brain MRI. Clinical and neuroimaging findings are consistent with a primary neuronal degenerative disorder, rather than with the previously reported Perlizaeus-Merzbacher-like phenotype. Given its critical role in neurofilament assembly 16, impaired myelin formation is due to neuronal/axonal dysfunction. We propose that AIMP1 deficiency be added to the differential diagnosis of infantile onset, progressive neurodegenerative disease. © 2014 Springer-Verlag.

Tarailo-Graovac M.,Molecular Therapeutics | Tarailo-Graovac M.,University of British Columbia | Sinclair G.,Treatable Intellectual Disability Endeavour in British Columbia | Sinclair G.,Biochemical Genetics Laboratory | And 24 more authors.
Orphanet Journal of Rare Diseases | Year: 2015

Background: Phosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in lethality. However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations. Methods and results: Here, we report on a new missense PIGA germline mutation [g.15342986C>T (p.S330N)] identified via WES followed by Sanger sequencing, in a Chinese male infant presenting with developmental arrest, infantile spasms, a pattern of lesion distribution on brain MRI resembling that typical of maple syrup urine disease, contractures, dysmorphism, elevated alkaline phosphatase, mixed hearing loss (a combination of conductive and sensorineural), liver dysfunction, mitochondrial complex I and V deficiency, and therapy-responsive dyslipidemia with confirmed lipoprotein lipase deficiency. X-inactivation studies showed skewing in the clinically unaffected carrier mother, and CD109 surface expression in patient fibroblasts was 57% of that measured in controls; together these data support pathogenicity of this mutation. Furthermore, we review all reported germline PIGA mutations (1 nonsense, 1 frameshift, 1 in-frame deletion, five missense) in 8 unrelated families. Conclusions: Our case further delineates the heterogeneous phenotype of this condition for which we propose the term 'PIGA deficiency'. While the phenotypic spectrum is wide, it could be classified into two types (severe and less severe) with shared hallmarks of infantile spasms with hypsarrhythmia on EEG and profound XLIDD. In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination, as well as hypotonia and elevated alkaline phosphatase along with liver, renal, and cardiac involvement; its course is often fatal. The less severe form of PIGA deficiency does not involve facial dysmorphism and multiple CNS abnormalities; instead, patients present with milder IDD, treatable seizures and generally a longer lifespan. © 2015 Tarailo-Graovac et al.; licensee BioMed Central.

Stockler S.,BC Childrens Hospital | Stockler S.,University of British Columbia | Corvera S.,University of Massachusetts Medical School | Lambright D.,University of Massachusetts Medical School | And 29 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in receptor-mediated endocytosis. The clinical presentation includes intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis. Biochemical findings include transient cobalamin deficiency, severe hypertriglyceridemia upon ketogenic diet, microalbuminuria and partial cathepsin D deficiency.Methods and results. Whole exome sequencing followed by Sanger sequencing confirmed a rare (frequency:0.003987) homozygous missense mutation, g.15,116,371 G > A (c.1273G > A), in ZFYVE20 resulting in an amino acid change from Glycine to Arginine at position 425 of the Rbsn protein (p.Gly425Arg), as the only mutation segregating with disease in the family. Studies in fibroblasts revealed expression and localization of Rbsn-5G425R in wild-type manner, but a 50% decrease in transferrin accumulation, which is corrected by wild-type allele transfection. Furthermore, the patient's fibroblasts displayed an impaired proliferation rate, cytoskeletal and lysosomal abnormalities.Conclusion: These results are consistent with a functional defect in the early endocytic pathway resulting from mutation in Rbsn-5, which secondarily disrupts multiple cellular functions dependent on endocytosis, leading to a severe multi-organ disorder. © 2014 Stockler et al.; licensee BioMed Central Ltd.

Salvarinova R.,Rm K3 201 | Salvarinova R.,University of British Columbia | Ye C.X.,Treatable Intellectual Disability Endeavour in British Columbia | Ye C.X.,Molecular Therapeutics | And 22 more authors.
Neurogenetics | Year: 2015

We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis. © 2014, Springer-Verlag Berlin Heidelberg.

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