@article {648, title = {Clinical, genetic, and pathologic characterization of Mexican founder mutation c.1387A>G.}, journal = {Neurol Genet}, volume = {5}, year = {2019}, month = {2019 Apr}, pages = {e315}, abstract = {

Objective: To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the c.1387A>G mutation.

Methods: Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in . Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.

Results: We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in . Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including . All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous c.826C>A limb-girdle muscular dystrophy.

Conclusions: The clinical features and muscle pathology in these newly reported patients homozygous for c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that c.1387A>G is a founder mutation with an estimated age of 60 generations (\~{}1,200-1,500 years).

}, issn = {2376-7839}, doi = {10.1212/NXG.0000000000000315}, author = {Lee, Angela J and Jones, Karra A and Butterfield, Russell J and Cox, Mary O and Konersman, Chamindra G and Grosmann, Carla and Abdenur, Jose E and Boyer, Monica and Beson, Brent and Wang, Ching and Dowling, James J and Gibbons, Melissa A and Ballard, Alison and Janas, Joanne S and Leshner, Robert T and Donkervoort, Sandra and B{\"o}nnemann, Carsten G and Malicki, Denise M and Weiss, Robert B and Moore, Steven A and Mathews, Katherine D} } @article {371, title = {Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.}, journal = {Mitochondrion}, volume = {34}, year = {2017}, month = {2017 05}, pages = {84-90}, abstract = {

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

}, keywords = {Child, Child, Preschool, Congenital Abnormalities, Gene Expression, Humans, Infant, Infant, Newborn, Male, Mitochondrial Proteins, Oxidative Phosphorylation, Peptide Elongation Factor G, RNA Splice Sites}, issn = {1872-8278}, doi = {10.1016/j.mito.2017.02.004}, author = {Simon, Mariella T and Ng, Bobby G and Friederich, Marisa W and Wang, Raymond Y and Boyer, Monica and Kircher, Martin and Collard, Renata and Buckingham, Kati J and Chang, Richard and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Van Hove, Johan L K and Freeze, Hudson H and Abdenur, Jose E} } @article {77, title = {ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 07}, pages = {653-60}, abstract = {

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

}, keywords = {Biomarkers, Congenital Disorders of Glycosylation, Female, Genes, Lethal, Glycosylation, Humans, Male, Mannosyltransferases, Mutation, Polysaccharides, Sequence Analysis, DNA, Survival Analysis}, issn = {1098-1004}, doi = {10.1002/humu.22983}, author = {Ng, Bobby G and Shiryaev, Sergey A and Rymen, Daisy and Eklund, Erik A and Raymond, Kimiyo and Kircher, Martin and Abdenur, Jose E and Alehan, Fusun and Midro, Alina T and Bamshad, Michael J and Barone, Rita and Berry, Gerard T and Brumbaugh, Jane E and Buckingham, Kati J and Clarkson, Katie and Cole, F Sessions and O{\textquoteright}Connor, Shawn and Cooper, Gregory M and Van Coster, Rudy and Demmer, Laurie A and Diogo, Luisa and Fay, Alexander J and Ficicioglu, Can and Fiumara, Agata and Gahl, William A and Ganetzky, Rebecca and Goel, Himanshu and Harshman, Lyndsay A and He, Miao and Jaeken, Jaak and James, Philip M and Katz, Daniel and Keldermans, Liesbeth and Kibaek, Maria and Kornberg, Andrew J and Lachlan, Katherine and Lam, Christina and Yaplito-Lee, Joy and Nickerson, Deborah A and Peters, Heidi L and Race, Valerie and R{\'e}gal, Luc and Rush, Jeffrey S and Rutledge, S Lane and Shendure, Jay and Souche, Erika and Sparks, Susan E and Trapane, Pamela and Sanchez-Valle, Amarilis and Vilain, Eric and V{\o}llo, Arve and Waechter, Charles J and Wang, Raymond Y and Wolfe, Lynne A and Wong, Derek A and Wood, Tim and Yang, Amy C and Matthijs, Gert and Freeze, Hudson H} } @article {158, title = {Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh{\textquoteright}s disease.}, journal = {Mol Genet Metab}, volume = {115}, year = {2015}, month = {2015 Aug}, pages = {161-7}, abstract = {

PURPOSE: 3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).

METHODS: Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.

RESULTS: Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients{\textquoteright} fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals.

CONCLUSION: We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient{\textquoteright}s NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.

}, keywords = {Abnormalities, Multiple, Adolescent, Amino Acid Metabolism, Inborn Errors, Carnitine, Child, Child, Preschool, Cohort Studies, Exome, Female, Fibroblasts, Humans, Infant, Infant, Newborn, Leigh Disease, Male, Mass Spectrometry, Neonatal Screening, Prognosis, Retrospective Studies, Sequence Analysis, DNA, Siblings, Thiolester Hydrolases}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2015.05.008}, author = {Stiles, Ashlee R and Ferdinandusse, Sacha and Besse, Arnaud and Appadurai, Vivek and Leydiker, Karen B and Cambray-Forker, E J and Bonnen, Penelope E and Abdenur, Jose E} }