title: Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment--A retrospective chart review.
abstract: BACKGROUND
  Long chain fatty acid oxidation disorders (LC-FAODs) are caused by defects in the metabolic pathway that converts stored long-chain fatty acids into energy, leading to a deficiency in mitochondrial energy production during times of physiologic stress and fasting. Severe and potentially life threatening clinical manifestations include rhabdomyolysis, hypoglycemia, hypotonia/weakness, cardiomyopathy and sudden death. We present the largest cohort of patients to date treated with triheptanoin, a specialized medium odd chain (C7) triglyceride, as a novel energy source for the treatment of LC-FAOD.
  
  
  METHODS
  This was a retrospective, comprehensive medical record review study of data from 20 of a total 24 patients with LC-FAOD who were treated for up to 12.5 years with triheptanoin, as part of a compassionate use protocol. Clinical outcomes including hospitalization event rates, number of hospitalization days/year, and abnormal laboratory values were determined for the total period of the study before and after triheptanoin treatment, as well as for specified periods before and after initiation of triheptanoin treatment. Other events of interest were documented including rhabdomyolysis, hypoglycemia, and cardiomyopathy.
  
  
  RESULTS
  LC-FAOD in these 20 subjects was associated with 320 hospitalizations from birth to the end date of study. The mean hospitalization days/year decreased significantly by 67% during the period after triheptanoin initiation (n=15; 5.76 vs 17.55 vs; P=0.0242) and a trend toward a 35% lower hospitalization event rate was observed in the period after triheptanoin initiation compared with the before-treatment period (n=16 subjects >6 months of age; 1.26 vs 1.94; P=0.1126). The hypoglycemia event rate per year in 9 subjects with hypoglycemia problems declined significantly by 96% (0.04 vs 0.92; P=0.0091) and related hospitalization days/year were also significantly reduced (n=9; 0.18 vs 8.42; P=0.0257). The rhabdomyolysis hospital event rate in 11 affected subjects was similar before and after treatment but the number of hospitalization days/year trended lower in the period after triheptanoin initiation (n=9; 2.36 vs 5.94; P=0.1224) and peak CK levels trended toward a 68% decrease from 85,855 to 27,597 units in 7 subjects with reported peak CK values before and after treatment (P=0.1279). Triheptanoin was generally well tolerated. Gastrointestinal symptoms were the most commonly reported side effects.
  
  
  CONCLUSIONS
  This retrospective study represents the largest analysis reported to date of treatment of LC-FAOD with triheptanoin. The data suggest that triheptanoin improves the course of disease by decreasing the incidence and duration of major clinical manifestations and should be the focus of prospective investigations. Significant heterogeneity in the routine clinical care provided to subjects during the periods studied and the natural variation of clinical course of LC-FAODs with time emphasize the need of additional study of the use of triheptanoin.
authors.affiliation: University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, USA. Electronic address: gerard.vockley@chp.edu.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Marsden
authors.affiliation: University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCracken
authors.affiliation: University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: DeWard
authors.affiliation: University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Barone
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Hsu
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Kakkis
mesh_terms: D000293:Adolescent; D000328:Adult; D009202:Cardiomyopathies / Q000188:drug therapy / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000066891:Critical Care Outcomes; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy / Q000473:pathology; D007223:Infant; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D012189:Retrospective Studies; D012206:Rhabdomyolysis / Q000188:drug therapy / Q000473:pathology; D017741:Survivors; D014280:Triglycerides / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; C531010:triheptanoin
keywords: Long chain fatty acid oxidation disorder; Retrospective medical chart review; Safety and effectiveness; Triheptanoin