Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. (15th August 2017)

• Record Type: Journal Article
• Authors: Schorling, David C.; Rost, Simone; Lefeber, Dirk J.; Brady, Lauren; Müller, Clemens R.; Korinthenberg, Rudolf; Tarnopolsky, Mark; Bönnemann, Carsten G.; Rodenburg, Richard J.; Bugiani, Marianna; Beytia, Maria; Krüger, Marcus; van der Knaap, Marjo; Kirschner, Jan
• Is Part Of: Neurology. Volume 89:Number 7(2017)
• Publication Date: 2017-08-15
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000004234
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : 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.