Neuropediatrics 2016; 47 - PS01-06
DOI: 10.1055/s-0036-1583602

Early Lethal Neurodegeneration with Myasthenic and Myopathic Features: A New Genetic Syndrome Due to Previously Undescribed ALG14 Mutations

D. Schorling 1, S. Rost 2, R. Korinthenberg 1, M. Krüger 3, M. Beytia 2, 4, C. R. Müller 2, C. Bönnemann 5, J. Kirschner 1
  • 1Division of Neuropaediatrics and Muscle Disorders, University Medical Center, Freiburg, Germany
  • 2Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany
  • 3Center of Pediatric and Adolescent Medicine, University Medical Center, Freiburg, Germany
  • 4Department of Neuropaediatrics, University Medical Center Würzburg, Würzburg, Germany
  • 5National Institute of Neurological Diseases and Stroke, NIH, Bethesda, Maryland, United States

Background/Purpose: Two sisters, born as second and third child of parents without known consanguinity exhibited marked muscular hypotonia with pronounced contractures and respiratory failure right after birth. CK was found to be normal. Biopsy of quadriceps muscle showed an unspecific myopathic pattern. Electrophysiologic testing showed pathologic decrement, but treatment with pyridostigmine led only to temporary improvement. Both sisters developed progressive therapy-refractory seizures with hypsarrhythmia in EEG and severe cerebral atrophy. The first sister died of respiratory failure at age of 6.5 months, the second sister of bradycardia at age of 3 months.

Methods: Analysis of SMN1, ACTA1, RAPSN, CHRND, CHRNA1, CHRNB1 and DOK7 was conducted via Sanger-Sequencing in the first sibling. Whole-Exome-Sequencing was performed after hybridization-based enrichment in both siblings using an Illumina HiSEq. 2000. Sanger sequencing of exons 2 and 4 of ALG14 was done in all family members to confirm findings.

Results: Compound heterozygous missense mutations in exon 2 and exon 4 of ALG14 were found in both affected sisters (exon 2: c.220.G > A p.Asp74Asn; exon 4: c.422T > G p.Val141Gly). Both parents were carriers of either one of these variants. No mutation was found in the healthy sister. None of the identified variants has been described previously.

Conclusion: We report the case of two siblings showing the same symptoms of an early lethal progressive peripheral and central neurodegenerative disease with severe myasthenia, therapy-refractory epilepsy and cerebral atrophy. We believe this phenotype to be caused by changes in ALG14 as other mutations in this gene were identified only recently to be causative for congenital myasthenic syndromes.