Biomaterial Database

Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. 2017

David C Schorling, and Simone Rost, and Dirk J Lefeber, and Lauren Brady, and Clemens R Müller, and Rudolf Korinthenberg, and Mark Tarnopolsky, and Carsten G Bönnemann, and Richard J Rodenburg, and Marianna Bugiani, and Maria Beytia, and Marcus Krüger, and Marjo van der Knaap, and Jan Kirschner

From the Division of Neuropaediatrics and Muscle Disorders (D.C.S., R.K., M. Beytia, J.K.) and Center of Pediatric and Adolescent Medicine (M.K.), Faculty of Medicine, Medical Center, University of Freiburg; Department of Human Genetics (S.R., C.R.M., M. Beytia), Biozentrum, University of Würzburg, Germany; Department of Neurology, Translational Metabolic Laboratory, Donders Institute for Brain, Cognition and Behavior (D.J.L.), and Radboud Center for Mitochondrial Medicine, Department of Pediatrics (R.J.R.), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pediatrics (Neuromuscular and Neurometabolic Disorders) (L.B., M.T.), McMaster Children's Hospital, Hamilton, Canada; Neuromuscular and Neurogenetic Disorders of Childhood Section (C.G.B.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; Departments of Child Neurology (M. Bugiani, M.v.d.K.) and Pathology (M. Bugiani), VU University Medical Center; and Department of Functional Genomics (M.v.d.K.), VU University, Amsterdam Neuroscience, Amsterdam, the Netherlands.

OBJECTIVE To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features. METHODS This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation. RESULTS All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy. Three patients had congenital contractures. All patients died during their first year of life. In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement. Causative mutations in ALG14 were identified in all patients. The mutation c.220 G>A (p.Asp74Asn) was homozygous in 2 patients and heterozygous in the other 3 patients. Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln). In all cases, parents were found to be heterozygous carriers. None of the identified variants has been described previously. CONCLUSIONS We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in ALG14. These cases broaden the phenotypic spectrum associated with ALG14 congenital disorders of glycosylation as previously only isolated myasthenia has been described.

UI	MeSH Term	Description	Entries
D007223	Infant	A child between 1 and 23 months of age.	Infants
D008297	Male		Males
D010375	Pedigree	The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.	Family Tree,Genealogical Tree,Genealogic Tree,Genetic Identity,Identity, Genetic,Family Trees,Genealogic Trees,Genealogical Trees,Genetic Identities,Identities, Genetic,Tree, Family,Tree, Genealogic,Tree, Genealogical,Trees, Family,Trees, Genealogic,Trees, Genealogical
D010641	Phenotype	The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.	Phenotypes
D004827	Epilepsy	A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313)	Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001284	Atrophy	Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes.	Atrophies
D013577	Syndrome	A characteristic symptom complex.	Symptom Cluster,Cluster, Symptom,Clusters, Symptom,Symptom Clusters,Syndromes
D017351	N-Acetylglucosaminyltransferases	Enzymes that catalyze the transfer of N-acetylglucosamine from a nucleoside diphosphate N-acetylglucosamine to an acceptor molecule which is frequently another carbohydrate. EC 2.4.1.-.	N-Acetylglucosamine Transferases,N Acetylglucosamine Transferases,N Acetylglucosaminyltransferases,Transferases, N-Acetylglucosamine