Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome.
Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2. Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia.
Dorota M
DM
Monies
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Saudi Arabia.
Hindi N
HN
Al-Hindi
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia; Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Saudi Arabia.
Mohamed A
MA
Al-Muhaizea
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia.
Dyala J
DJ
Jaroudi
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia.
Banan
B
Al-Younes
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia.
Ewa A
EA
Naim
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia.
Salma M
SM
Wakil
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia. Electronic address: meyerb@kfshrc.edu.sa.
Brian F
BF
Meyer
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Saudi Arabia; Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Saudi Arabia.
Saeed
S
Bohlega
D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005190:Family; D005260:Female; D006031:Glycosylation; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009135:Muscular Diseases / Q000175:diagnosis; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000175:diagnosis; D009210:Myofibrils / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C097753:PDCD6 protein, human
Congenital disorder of glycosylation; Myasthenia; Myopathy