title: Clinical and molecular analysis of isovaleric acidemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene.
abstract: Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD). Accumulation of isovaleryl-CoA derivatives to toxic levels results in clinical symptoms of the disease. Here, we investigate the clinical and molecular features of Arab patients with IVA. Patients from five unrelated families were evaluated clinically and for defects in the IVD gene. Four novel mutations (p.F382fs, p.R392H, p.R395Q and p.E408K) have been identified with p.R395Q occurring in two families. In addition, molecular modeling of the identified missense mutations predicted their damaging effects on the protein and computational analysis of the p.F382fs mutation predicted the disruption of a 3' splicing site resulting in inactive or unstable gene product. Furthermore, we found an unusual case of a 17 years old female homozygous for the p.R392H mutation with no clinical symptoms. Our results illustrate a heterogeneous mutation spectrum and clinical presentation in the relatively small UAE population.
authors.affiliation: Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates. jhertecant@tawamhospital.ae
authors.forename: Jozef L
authors.initials: JL
authors.lastname: Hertecant
authors.forename: Imen
authors.initials: I
authors.lastname: Ben-Rebeh
authors.forename: Muhaned A
authors.initials: MA
authors.lastname: Marah
authors.forename: Thikra
authors.initials: T
authors.lastname: Abbas
authors.forename: Leila
authors.initials: L
authors.lastname: Ayadi
authors.forename: Salma
authors.initials: S
authors.lastname: Ben Salem
authors.forename: Fatma A
authors.initials: FA
authors.lastname: Al-Jasmi
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Said A
authors.initials: SA
authors.lastname: Al-Yahyaee
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
mesh_terms: D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005091:Exons; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D050769:Isovaleryl-CoA Dehydrogenase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D022821:RNA Splice Sites; D014479:United Arab Emirates
chemical_list: D022821:RNA Splice Sites; D050769:Isovaleryl-CoA Dehydrogenase