title: Long-term follow-up of four patients affected by HHH syndrome.
abstract: BACKGROUND
  In hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, impaired ornithine transport across the mitochondrial membrane causes ornithine accumulation in cytoplasm. The resulting mitochondrial ornithine deficiency leads to reduced clearance of ammonia through the urea cycle. First described in 1969, no long-term follow-up has been reported.
  
  
  METHODS
  Four patients were followed up for 11 to 38y. Diagnosis was made by plasma amino acid analysis using ion exchange chromatography, HPLC orotic acid measurement, and (14)C-ornithine incorporation study using cultured fibroblasts. DNA from fibroblasts was amplified and sequenced. Blood ammonia was controlled by restriction of protein intake.
  
  
  RESULTS
  All patients had reduced (14)C-ornithine incorporation. Mutation analysis revealed two novel mutations in the ORNT1 gene. Neurologic outcome included memory loss, low IQ, tremor, spasticity of extremities, bladder incontinence, and abnormal gait. Neuroimaging revealed subcortical, cerebral and cerebellar atrophy, sparing the basal ganglia. Individual examination showed pyramidal signs, cerebellar signs, paraplegia, movement disorder, dystonia, and epilepsy. One patient had 3 pregnancies, one of which resulted in intrauterine growth retardation.
  
  
  CONCLUSIONS
  Our patients expand the clinical phenotype of adults with HHH. Long-term follow-up showed serious neurologic outcomes in all patients; three patients clearly exhibited progression of neurologic dysfunction despite control of hyperammonemia. Intracellular ornithine deficiency may adversely affect brain functions.
authors.affiliation: Korea Genetic Research Center, Cheong Ju, Heung Deok Gu, Republic of Korea. kimgene@unitel.co.kr
authors.forename: Sook Z
authors.initials: SZ
authors.lastname: Kim
authors.forename: Wung J
authors.initials: WJ
authors.lastname: Song
authors.forename: William L
authors.initials: WL
authors.lastname: Nyhan
authors.forename: Can
authors.initials: C
authors.lastname: Ficicioglu
authors.forename: Roseann
authors.initials: R
authors.lastname: Mandell
authors.forename: Vivian E
authors.initials: VE
authors.lastname: Shih
mesh_terms: D000328:Adult; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000596:Amino Acids / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins; D009952:Ornithine / Q000097:blood / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D013997:Time Factors; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000235:genetics / Q000503:physiopathology*
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D033681:Mitochondrial Membrane Transport Proteins; C442901:SLC25A15 protein, human; D009952:Ornithine