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

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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)657-664
Number of pages8
JournalNeurology
Volume89
Issue number7
DOIs
Publication statusPublished - 15 Aug 2017

Cite this

Schorling, D. C., Rost, S., Lefeber, DI. J., Brady, L., Müller, C. R., Korinthenberg, R., ... Kirschner, J. (2017). Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. Neurology, 89(7), 657-664. https://doi.org/10.1212/WNL.0000000000004234
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. / Early and lethal neurodegeneration with myasthenic and myopathic features : A new ALG14-CDG. In: Neurology. 2017 ; Vol. 89, No. 7. pp. 657-664.
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title = "Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG",
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.",
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Schorling, DC, Rost, S, Lefeber, DIJ, Brady, L, Müller, CR, Korinthenberg, R, Tarnopolsky, M, Bönnemann, CG, Rodenburg, RJ, Bugiani, M, Beytia, M, Krüger, M, Van Der Knaap, M & Kirschner, J 2017, 'Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG' Neurology, vol. 89, no. 7, pp. 657-664. https://doi.org/10.1212/WNL.0000000000004234

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

In: Neurology, Vol. 89, No. 7, 15.08.2017, p. 657-664.

Research output: Contribution to journalArticleAcademicpeer-review

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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

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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.

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Schorling DC, Rost S, Lefeber DIJ, Brady L, Müller CR, Korinthenberg R et al. Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. Neurology. 2017 Aug 15;89(7):657-664. https://doi.org/10.1212/WNL.0000000000004234