Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis.
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by mutations in ORNT1 gene that encodes a mitochondrial ornithine transporter. It has variable clinical presentations with episodic hyperammonemia, liver dysfunction, and chronic neurological manifestations. In this work, we report the findings of HHH syndrome in 3 Saudi siblings. The 4-year-old proband presented with recurrent Reye-like episodes, hypotonia, and multiple stroke-like lesions on brain MRI. Biochemical and molecular analysis confirmed that she had HHH syndrome. She significantly improved on protein restriction and sodium benzoate. Her two older siblings have milder phenotypes with protein intolerance and learning problems. In comparison to their sister, their homocitrulline and orotic acid were only mildly elevated even before treatment. The three patients were homozygous for a novel mutation in ORNT1 with a Gly220Arg change. In view of the CNS lesions, which initially were felt to be suggestive of MELAS, we sequenced the entire mtDNA genome and no potential pathogenic mutations were detected. Analysis of ORNT2 did not provide explanation of the clinical and biochemical variability. This work presents a yet unreported CNS involvement pattern, notably multiple supratentorial stroke-like lesions in association with HHH syndrome. Moreover, it illustrates considerable clinical/biochemical correlation, and describes a novel mutation. We suggest including HHH syndrome in the differential diagnosis of patients found to have stroke-like lesions on brain MRI.
Al-Hassnan
Zuhair N
ZN
Department of Medical Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
Rashed
Mohamed S
MS
Al-Dirbashi
Osama Y
OY
Patay
Zoltan
Z
Rahbeeni
Zuhair
Z
Abu-Amero
Khaled K
KK
D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D002956:Citrulline / Q000031:analogs & derivatives / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005526:Food, Formulated; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins; D009154:Mutation / Q000235:genetics; D009952:Ornithine / Q000378:metabolism; D010375:Pedigree; D012529:Saudi Arabia; D020160:Sodium Benzoate / Q000627:therapeutic use; D020521:Stroke / Q000235:genetics / Q000473:pathology / Q000503:physiopathology