Methylmalonic Acidemia- Updated Information in Recognition and Response to Treatment by Patients attending a multidisciplinary clinic

TITLE: Methylmalonic Acidemia- Updated Information in Recognition and Response to Treatment by Patients attending a multidisciplinary clinic

AUTHORS: Ashley Apruzzese, MD1, Jody Weiss-Burns, MS1, Devina Prakash, MD1,  Berrin Ozturk and Patricia Galvin-Parton, MD1.

INSTITUTIONS (ALL): 1Pediatrics, SUNY Stony Brook, Stony Brook, NY, 11794-8111, United States.

BACKGROUND: There are 10 different inherited defects in the cobalamine pathway which frequently go unrecognized.  These disorders can be fatal if treatment is not started early or lead to continued neurological deterioration if the appropriate combination of therapy is not started. When recognized, these disorders can have a positive outcome. These disorders were added to NY State newborn screening in 2005.  We present 12 patients who were detected because of a critical presentation prior to newborn screening and 12 patients who were referred through the expanded newborn screening program.

OBJECTIVE: We wished to compare treatment modalities and outcome with patients we identified because of a critical presentation in the hospital with patients who were referred to us because of screens which were positive on the expanded newborn screen.

DESIGN/METHODS: All patients had full hematologic and metabolic work-ups as a result of abnormal symptoms or abnormal screening.  A short summary of each patient’s hospital admission, diagnostic work-up and outcome from the before and after group is included.

RESULTS: One patient showed near absence of transcobalamin II in plasma. After the first year of treatment, bone marrow profile normalized and MMA levels were within treatment range. After 10 years of treatment and further DNA confirmation, this patient is showing subtle tremors. This was an unexpected late finding for this disorder and may contribute to the natural history of the disorder. Another patient identified before 2005, had abnormal prenatal ultrasounds and at birth displayed dysmorphic features and microcephaly. At 4 months of age, he presented with elevated levels of MMA and homocysteine. He was started on daily injections of hydroxycobalamin and folate. Biochemical Levels normalized but imaging studies showed continued loss of white matter and continued ventriculomegaly possibly due to late treatment. He died at 6 months in respiratory failure.  Since then, we have detected other Cbl C and A defects through the newborn screening program.  In addition, we have detected offspring of vegan mothers with high levels of MMA. All patients who were diagnosed before the newborn screening program were evaluated as critically ill infants and all have had long lasting intellectual delays and some with poor outcome. The group detected through newborn screening has either been asymptomatic at the time of diagnostic confirmation or with mild manifestations of their disorder.

CONCLUSIONS: Patients diagnosed with either methylmalonic acidemia or propionic acidemia have better outcomes since their earlier identification through the Newborn Screening Program. We now have patients with Cbl A or C defects detected both before and after initiation of NBS for these disorders and have been able to document improved outcome in the latter cases. Infants nursing from vegan mothers were identified in the current NBS program with elevated MMA levels and have displayed hypotonia until either the mothers received treatment, altered their dietary habits or the infants were switched to commercial formulas. These mothers not only had cobalamin deficiency but also were also found to be folate deficient which placed them at higher risk for neural tube defects. This was an unexpected finding that was detected because of newborn screening and we believe this detection will lead to healthier pregnancies and avoid potential neural tube or other neural crest defects when these women can be identified and placed on folic acid supplementation. We make a comparison with other historic childhood disorders such as the recommendation for immunizations for childhood infectious diseases which has eliminated the appearance of these disorders in current medical practice. Recent medical school graduates rarely have seen full blown clinical cases of measles, mumps, rubella, H flu meningitis or chicken pox and read about the natural history of these disorders in textbooks. Due to implementation of the expanded newborn screening program, the fatal appearance of methylmalonic acidemia or propionic acidemia may be similarly eliminated.