Presentation Information
[OE3-1]A patient with argininosuccinic aciduria and Silver-Russell syndrome due to maternal uniparental disomy chromosome 7
○Atsushi Hattori1, Torayuki Okuyama2,3, Tetsumin So2, Motomichi Kosuga2, Keiko Ichimoto4, Kei Murayama4, Masayo Kagami1, Maki Fukami1, Yasuyuki Fukuhara2 (1.Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2.Division of Medical Genetics, National Center for Child Health and Development, 3.Department of Pediatrics and Clinical Genomics, Saitama Medical University, 4.Center for Medical Genetics, Department of Metabolism, Chiba Children's Hospital)
Introduction: Argininosuccinic aciduria (ASA) is an autosomal recessive disorder caused by variants in ASL gene on chromosome 7. Maternal UPD chromosome 7 (UPD(7)mat) causes Silver-Russell syndrome (SRS). Here, we report a patient who had ASA and SRS due to UPD(7)mat.
Case: The patient was a boy who had hyperammonemia at the age of ten days. High plasma citrulline and argininosuccinate led to a clinical diagnosis of ASA. In addition to neuropsychomotor developmental delay, he also had severe feeding difficulty and growth retardation, which cannot be explained solely by ASA. He met all six criteria to diagnose SRS as per the Netchine-Harbison scoring system. Sequencing analysis revealed that the patient was homozygous for the c.1149-9G＞A variant of ASL. The mother was heterozygous for this variant whereas the father was homozygous for the wild-type allele. Sequencing analysis using cDNA derived from the patient’s lymphoblastoid cell line showed an ASL mRNA splicing alteration affecting active sites of the enzyme. Microsatellite analysis and microarray-based SNP genotyping revealed UPD(7)mat and loss of heterozygosity in a region containing ASL in the patient.
Discussion: ASA of the present case was caused by the ASL variant unmasked by isodisomy of a region containing ASL. His severe feeding difficulty and growth retardation probably resulted from SRS associated with UPD(7)mat. It is possible that feeding difficulty due to SRS causes catabolism and thereby exacerbates the neurotoxicity of ASA. The possible coexistence of SRS should be considered during the management of ASA.
Case: The patient was a boy who had hyperammonemia at the age of ten days. High plasma citrulline and argininosuccinate led to a clinical diagnosis of ASA. In addition to neuropsychomotor developmental delay, he also had severe feeding difficulty and growth retardation, which cannot be explained solely by ASA. He met all six criteria to diagnose SRS as per the Netchine-Harbison scoring system. Sequencing analysis revealed that the patient was homozygous for the c.1149-9G＞A variant of ASL. The mother was heterozygous for this variant whereas the father was homozygous for the wild-type allele. Sequencing analysis using cDNA derived from the patient’s lymphoblastoid cell line showed an ASL mRNA splicing alteration affecting active sites of the enzyme. Microsatellite analysis and microarray-based SNP genotyping revealed UPD(7)mat and loss of heterozygosity in a region containing ASL in the patient.
Discussion: ASA of the present case was caused by the ASL variant unmasked by isodisomy of a region containing ASL. His severe feeding difficulty and growth retardation probably resulted from SRS associated with UPD(7)mat. It is possible that feeding difficulty due to SRS causes catabolism and thereby exacerbates the neurotoxicity of ASA. The possible coexistence of SRS should be considered during the management of ASA.