TY - JOUR
T1 - Early and lethal neurodegeneration with myasthenic and myopathic features
T2 - A new ALG14-CDG
AU - Schorling, David C.
AU - Rost, Simone
AU - Lefeber, DIrk J.
AU - Brady, Lauren
AU - Müller, Clemens R.
AU - Korinthenberg, Rudolf
AU - Tarnopolsky, Mark
AU - Bönnemann, Carsten G.
AU - Rodenburg, Richard J.
AU - Bugiani, Marianna
AU - Beytia, Maria
AU - Krüger, Marcus
AU - Van Der Knaap, Marjo
AU - Kirschner, Jan
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85027506334&partnerID=8YFLogxK
U2 - https://doi.org/10.1212/WNL.0000000000004234
DO - https://doi.org/10.1212/WNL.0000000000004234
M3 - Article
C2 - 28733338
SN - 0028-3878
VL - 89
SP - 657
EP - 664
JO - Neurology
JF - Neurology
IS - 7
ER -