Early and lethal neurodegeneration with myasthenic and myopathic features Academic Article uri icon

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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.

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

publication date

  • August 15, 2017