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Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.

ABSTRACT: PURPOSE:The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the ?-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). METHODS:Prospective natural history protocol. RESULTS:In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. CONCLUSION:Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.

SUBMITTER: Lam C

PROVIDER: S-EPMC7477955 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.

Lam Christina C Ferreira Carlos C Krasnewich Donna D Toro Camilo C Latham Lea L Zein Wadih M WM Lehky Tanya T Brewer Carmen C Baker Eva H EH Thurm Audrey A Farmer Cristan A CA Rosenzweig Sergio D SD Lyons Jonathan J JJ Schreiber John M JM Gropman Andrea A Lingala Shilpa S Ghany Marc G MG Solomon Beth B Macnamara Ellen E Davids Mariska M Stratakis Constantine A CA Kimonis Virginia V Gahl William A WA Wolfe Lynne L

Genetics in medicine : official journal of the American College of Medical Genetics 20160707 2

<h4>Purpose</h4>The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the β-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG).<h4>Methods</h4>Prospective natural history protocol.<h4>Results</h4>In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clin ...[more]

PMID: 27388694

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Project description:BackgroundNGLY1 deficiency is a rare autosomal recessive disorder caused by loss in enzymatic function of NGLY1, a peptide N-glycanase that has been shown to play a role in endoplasmic reticulum associated degradation (ERAD). ERAD dysfunction has been implicated in other well-described proteinopathies, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The classical clinical tetrad includes developmental delay, hypolacrima, transiently elevated transaminases, and hyperkinetic movement disorders. The musculoskeletal system is also commonly affected, but the orthopaedic phenotype has been incompletely characterized. Best practices for orthopaedic clinical care have not been elucidated and considerable variability has resulted from this lack of evidence base. Our study surveyed patients enrolled in an international registry for NGLY1 deficiency in order to characterize the orthopaedic manifestations, sequelae, and management.ResultsOur findings, encompassing the largest cohort for NGLY1 deficiency to date, detail levels of motor milestone achievement; physical exam findings; fracture rates/distribution; frequency of motor skill regression; non-pharmacologic and non-procedural interventions; pharmacologic therapies; and procedural interventions experienced by 29 participants. Regarding the orthopaedic phenotype, at time of survey response, we found that over 40% of patients experienced motor skill regression from their peak. Over 80% of patients had at least one orthopaedic diagnosis, and nearly two-thirds of the total had two or more. More than half of patients older than 6 years had sustained a fracture. Related to orthopaedic non-medical management, we found that 93 and 79% of patients had utilized physical therapy and non-operative orthoses, respectively. In turn, the vast majority took at least one medication (including for bone health and antispasmodic therapy). Finally, nearly half of patients had undergone an invasive procedure. Of those older than 6 years, two-thirds had one or more procedures. Stratification of these analyses by sex revealed distinctive differences in disease natural history and clinical management course.ConclusionsThese findings describing the orthopaedic natural history and standard of care in patients with NGLY1 deficiency can facilitate diagnosis, inform prognosis, and guide treatment recommendations in an evidence-based manner. Furthermore, the methodology is notable for its partnership with a disease-specific advocacy organization and may be generalizable to other rare disease populations. This study fills a void in the existing literature for this population and this methodology offers a precedent upon which future studies for rare diseases can build.

Project description:BackgroundCongenital anomalies are a major cause of co-morbidity in children. Diagnostic code lists are increasingly used to identify congenital anomalies in administrative health records. Evidence is lacking on comparability of these code lists.ObjectivesTo compare prevalence of congenital anomalies and prognostic outcomes for children with congenital anomalies identified in administrative health records using three different code lists.MethodsWe developed national cohorts of singleton livebirths in England (n = 7 354 363, 2003-2014) and Scotland (n = 493 556, 2003-2011). Children with congenital anomalies were identified if congenital anomaly diagnosis was recorded at birth, during subsequent hospital admission or as cause of death before 2 years old. We used three code lists: the EUROCAT list for congenital anomaly surveillance in Europe; the Hardelid list developed to identify children with chronic conditions (including congenital anomalies) admitted to hospital in England; and the Feudtner list developed to indicate children with complex chronic conditions (including congenital anomalies) admitted to hospitals in the United States. We compared prevalence, and risks of postnatal hospital readmission and death according to each code list in England and Scotland.ResultsPrevalence of congenital anomalies was highest using the EUROCAT list (4.1% of livebirths in England, 3.7% in Scotland), followed by Hardelid (3.1% and 3.0% of livebirths, respectively) and Feudtner (1.8% and 1.5% of livebirths, respectively). 67.2%-73.3% of children with congenital anomalies in England and 65.2%-77.0% in Scotland had at least one postnatal hospital admission across the three code lists; mortality ranged between 42.6-75.4 and 41.5-88.7 deaths per 1000 births in England Scotland, respectively. The risk of these adverse outcomes was highest using Feudtner and lowest using EUROCAT code lists.ConclusionsThe prevalence of congenital anomalies varied by congenital anomaly code list, over time and between countries, reflecting in part differences in hospital coding practices and admission thresholds. As a minimum, researchers using administrative health data to study congenital anomalies should report sensitivity analyses using different code lists.

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Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.

Publications

Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.

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