|Principal Investigator: Nicola Longo|
|Keywords: Organic Acidemias , MMA , PPA||Department: Pediatric Genetics|
|IRB Number: 00112253|
|Specialty: Pediatric Genetics|
|Sub Specialties: Medical Genetics|
|Recruitment Status: Not yet recruiting|
MMA and PA are rare, serious, life-threatening condition for which there is no approved treatment. Some patients respond to vitamin B12 supplementation; however, diet alone is inadequate to control a patient’s decline. Additionally, patients respond to liver and/or kidney transplant; however, transplant as a therapeutic option has serious limitations. Therefore, other therapeutic options are needed.
The purpose of this study is to collect comprehensive and reliable clinical information to characterize and describe the signs and symptoms of patients with MMA (mut0 or mut-) or PA (PCCA or PCCB deficiency). The data collected will inform the development of future treatments and may serve as a historical group for comparison with data obtained in future interventional studies.
The objectives of this natural history study include characterization of disease-related clinical events and disease markers for future interventional clinical studies, specifically:
Characterization of historical and prospective disease-related clinical events and events that require utilization of healthcare resources (e.g., metabolic crisis leading to emergency room [ER] visits, hospitalizations, intensive care unit (ICU) stays) and/or loss of school or work time or implementation of a sick day diet (preventive care to avoid a crisis, ‘sick day diet’ or ‘emergency treatment regimen’ defined as dietary alternations during times of increased metabolic demand especially when associated with an illness [Chapman 2012]) and/or treatments as well as socio-economic aspects of living with MMA or PA (e.g., access to education, job stability).
Collection of historical lab data and prospective laboratory results for MMA and PA disease markers (as applicable) will be valuable in understanding the variability in these biomarker levels over time within and between individual patients, and their potential relationship with clinical outcomes. Additionally, the magnitude of disease marker reduction and durability of effect post liver (MMA, PA) and/or kidney (MMA) transplantation will be investigated. These data will also provide context to potential changes in biomarker levels in patients participating in future interventional trials.
Disease specific biomarkers include:
Both MMA and PA: Plasma 2-methylcitrate (2-MC,), C0, C2, C3, C3/C2, total
carnitine, amino acids; Serum creatinine, and cystatin C
MMA Only: Plasma methylmalonic acid
PA Only: Plasma 3-HP and propionylglycine
The primary objective of this study is to:
• Evaluate and describe the natural history of MMA (mut0 and mut-) and PA (PCCA and PCCB deficient) patients and identify endpoints that may be utilized in future
The secondary objectives of this study are to:
• Assess healthcare utilization and treatment burden among patients with MMA or PA.
• Assess the health-related quality of life (QoL) of patients with MMA or PA
• Describe the relationship between biomarkers and selected clinical events and outcomes.
Patients of any age
Patient has a confirmed diagnosis of isolated MMA due to MUT deficiency (mut0 or mut-) based on the following criteria:
o Elevated plasma/serum/DBS or urine methylmalonic acid levels
o Presence of normal serum/plasma vitamin B12 and plasma homocysteine levels
o Confirmed by molecular genetic testing. Genetic testing can be performed after the administration of informed consent if not available, however, molecular genetic results must be confirmed before the second study visit.
– OR –
PA Only: Patient has a confirmed diagnosis of isolated PA based on the following criteria:
o Elevated plasma/DBS/urine 2-MC and/or 3-HP
o Elevated plasma/serum/DBS propionylcarnitine (C3)
o Confirmed by genetic testing for mutations of the PCCA or PCCB genes. Genetic testing can be performed after administration of informed consent if not available, however, molecular genetic results must be confirmed before the second study visit.
Patient (and/or legally authorized representative as applicable to local regulations) is willing and able to comply with study-related assessments and activities
Patient or legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulation
MMA Only: Patients diagnosed with isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria
PA Only: Patient has a confirmed diagnosis of multiple carboxylase deficiency