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

Neurology. 2017 Aug 15;89(7):657-664. doi: 10.1212/WNL.0000000000004234. Epub 2017 Jul 21.

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.

Publication types

  • Case Reports

MeSH terms

  • Atrophy / pathology
  • Cerebrum / pathology*
  • Congenital Disorders of Glycosylation* / genetics
  • Congenital Disorders of Glycosylation* / pathology
  • Congenital Disorders of Glycosylation* / physiopathology
  • Epilepsy* / genetics
  • Epilepsy* / pathology
  • Epilepsy* / physiopathology
  • Fatal Outcome
  • Female
  • Humans
  • Infant
  • Male
  • Muscle Weakness* / genetics
  • Muscle Weakness* / pathology
  • Muscle Weakness* / physiopathology
  • N-Acetylglucosaminyltransferases / genetics*
  • Neurodegenerative Diseases
  • Pedigree
  • Phenotype
  • Syndrome

Substances

  • N-Acetylglucosaminyltransferases