Skip to main content

Conference Program

Subpage Hero

Loading

Clinical Characterization of Classical Homocystinuria due to Cystathionine-beta Synthase Deficiency: Results from the ACAPPELLA Study 

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Classical homocystinuria (HCU) caused by cystathionine β-synthase deficiency is a rare genetic metabolic disorder that results in excessive accumulation of homocysteine (Hcy). HCU is associated with serious vascular, neurologic, skeletal, and ocular complications, with thromboembolism being a major cause of morbidity and mortality. Current standard-of-care treatment includes a protein-restricted diet and supplementation with methionine (Met)-free formula, pyridoxine (vitamin B6), and betaine. However, it is unclear to what extent the current standard of care prevents HCU-related complications.

Methods:
ACAPPELLA is an ongoing, prospective, longitudinal, multicenter, multinational natural history study which has planned to enroll up to 150 patients with HCU aged 1–65 years, conducted at 10 sites across the US, UK, Canada, and Ireland. In addition to recording participants’ diets and medications, this study is investigating many biochemical and clinical assessments including eye (visual acuity and slit lamp examination), bone (dual-energy X-ray absorptiometry [DXA]), and cognitive assessments (National Institutes of Health Toolbox-Cognition Battery [NIHTB-CB]) to gain a better understanding of HCU disease progression. Patient-reported outcomes such as the Quality-of-Life Short Form 36-item survey, EQ-5D, and Quality of Life in Neurological Disorders (Neuro-QoL) will also evaluate the impact of HCU disease progression on quality of life.

 

Results:
As of 8 March 2023, 71 patients were enrolled with a mean participation duration of 2.1 (SD 1.1) years: mean age 22 (range 5–53); 48% children <18 years, 51% female. The median tHcy over the first 7 visits was 125 µM for adults; 98 µMfor children (mean 112 µM [SD 82]). 43% of patients, 17 (49%) adult and 12 (38%) pediatric, had median tHcy >100 µM (the current clinical target). Despite prescribed treatment of betaine (n=51), pyridoxine (n=40), Met-free formula (n=31) or any combination of two (n=32) or three (n=17) of these, the mean tHcy for each group remained >100 µM. Results indicative of reductions in bone mineralization (DXA mean hip z-score: -0.78) and cognitive function (overall NIHTB-CB mean inhibitory control score: 86.2 [where 100 is the 50th percentile]) were observed in adults and children. Updates from a more recent data cut of this study will be presented at ACMG 2025. 

Conclusion:
ACAPPELLA is the largest and most comprehensive prospective natural history study of HCU. The results from this study demonstrate that with currently available treatments, patients continue to have elevated tHcy levels and HCU-related complications. Thus, there is an urgent need for new treatments for HCU.

Agenda

Sponsors