The disorders of propionyl-CoA and vitamin B12 (cobalamin) metabolism comprise a group of collectively common inherited enzymopathies in the organic acidemia category. Affected patients can display a wide range of symptoms and rate of disease progression, making delineating the natural history and designing clinical trials very challenging. In aggregate, the frequency of complications, their precipitants, long-term sequelae, optimal treatment regimens and effects of early intervention remain ill-defined for this large group of patients, who still face substantial disease associated morbidity and a poor prognosis for long-term survival. Because newborn screening for this group of disorders has become routine in the US, Australia, and many developed nations, there are growing cohorts of affected infants and children, who face a grim prognosis in the absence of disease-specific therapies. Liver, kidney, or combined organ transplantation, the only currently available treatment option for the more severely affected patients, ameliorates metabolic instability but does not provide a cure for MMA or PA patients, who remain at risk for extrahepatic disease manifestations including neurological progression, vision and hearing loss, and sequelae of transplantation such as chronic immunosuppression, organ rejection and other transplant complications. The characterization of patients with methylmalonic acidemia (MMA) and related disorders is accomplished via a dedicated NHGRI natural history study, Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders (ClinicalTrials.gov Identifier: NCT00078078). Through this clinical protocol, we have continued to enroll patients with MMA and cobalamin metabolic disorders and have evaluated > 200 affected individuals. The NIH MMA protocol has accrued the largest single center cohort of MMA patients in the world. A more recent endeavor to study propionic acidemia was initiated in late 2016 though NHGRI protocol Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia (ClinicalTrials.gov Identifier:NCT02890342). Like the methylmalonic acidemia (MMA) protocol, this clinical effort is unique in that it is the only dedicated natural history study being conducted on PA that utilizes an intensive dedicated hospital visit to perform detailed clinical phenotyping. At present, >40 patients have been evaluated and another 10-15 are expected to enroll before the end of 2020. This cohort, like that of MMA, is the largest diverse PA patient cohort assembled to date, and continues to expand in size. We have continued to focus on the clinical characterization of patients to inform our understanding of these common organic acidemias. We remain as opinion leaders in the debate regarding medical food use in MMA and PA (reference 1). In the last year, our studies of the NIH PA cohort has allowed new insights into the natural history of kidney disease in propionic acidemia. Through our recently established propionic acidemia natural history protocol, we discovered that CKD is common in adults with PA (reference 2), and is associated with cardiac dysfunction. In addition to providing the first detailed description of the renal phenotype in patients with PA, this manuscript provides important clinical guidelines for the monitoring and diagnosis of kidney disease in a growing, and aging, patient population. Active efforts include defining the metabolic phenotype of MMA and PA patients with stable isotopes; the construction of an integrated clinical outcomes database for MMA and PA; the analysis of cardiac phenotypes in cblC (in collaboration with NHLBI colleagues); the delineation of the natural history of PA; and the identification and validation of protein biomarkers that correlate with disease severity in MMA and PA. Translational investigations have continued to focus on preclinical experiments that will enable new treatments for MMA to reach the clinic. This past year we reported on a new, viable mouse model to study acute and chronic hepatic disease using transgenesis (reference 3). We created a transgene that insulated the murine muscle creatine kinase (MCK) promoter to drive Mut expression in the skeletal muscle of the Mmut-/-mice. The resulting Mmut-/-;TgINS-MCK-Mmut animals were rescued from the neonatal lethality, but manifested the clinical and biochemical features of severe MMA, including growth retardation, decreased survival, massively elevated serum methylmalonic acid concentrations, and hepatorenal mitochondrial pathology. Restoration of hepatic Mmut activity, by transgenesis or liver-directed gene therapy in mice, or liver transplantation in MMA patients, drastically reduced plasma FGF21 and was associated with improved clinical outcomes. Our studies identify mitocellular hormesis as one possible mechanism for adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker for the hepatic mitochondriopathy of MMA. Beyond the mechanistic insights obtained with this new mouse model are the practical applications to study liver directed genomic therapies for MMA, such as AAV gene addition therapy, systemic mRNA therapy, and genome editing. Our MMA mouse models have also been useful to study common disorders, such as kidney disease. In collaboration with Dr Michael MacMahon PhD, a physical chemist, and his colleagues at Johns Hopkins University, we assessed an alternative, and non-invasive, approach for monitoring renal function based on administration of a pH sensitive MRI contrast agent, iodopamol (reference 4). Our results demonstrate that MRI is superior to other biomarkers for the early detection and functional monitoring of CKD, particularly in disorders that alter renal pH and perfusion such as MMA. We believe this method will one day have special applicability to measuring the GFR in children due to the noninvasive nature of the imaging protocol, and ability to simultaneously obtain anatomic and functional data. We continue to characterize knock-out and transgenic mouse models of disorders that present in our patient population, including MMAA deficiency, combined malonic-methylmalonic acidemia due to acyl-coA synthase family member 3 (ACSF3) deficiency, cobalamin C deficiency (MMACHC), and propionic acidemia (PCCA, PCCB). We also assist collaborators (reference 5). In the next year, we will continue to characterize the mutant mice using genomic, proteomic and metabolomic analyses, then test new therapeutics, such as mRNA therapy, AAV gene therapy, genome editing and microbiome manipulations. We have also initiated a parallel effort to model lethal metabolic disorders such as MUT MMA, cobalamin C deficiency, and propionic acidemia in zebrafish with the anticipation that the zebrafish models will be amendable to the facile testing of small molecules, possibly in a high throughput fashion. We have continued to focus on gene therapy as treatment for methylmalonyl-CoA mutase (MUT) deficiency (reference 6), the most common and severe form of isolated MMA, propionic acidemia, and cobalamin C deficiency. We have developed new AAV vectors for PCCA and MMUT deficiency, garnered intellectual property (references 7 and 8), and partnered with a company that is dedicated to bring genome editing to the clinic for MMUT MMA.
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