The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.

Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.

Maternal vitamin B12 deficiency detected in expanded newborn screening.

OBJECTIVES: Besides the inherited form, vitamin B(12) deficiency may be due to diet restrictions or abnormal absorption. The spread of newborn screening programs worldwide has pointed out that non-inherited conditions are mainly secondary to a maternal deficiency. The aim of our work was to study seven cases of acquired vitamin B12 deficiency detected during our newborn screening project. Moreover, we aimed to evaluate vitamin B(12) and related biochemical parameters status on delivering female to verify the consequences on newborns of eventually altered parameters. DESIGN AND METHODS: 35,000 newborns were screened; those showing altered propionyl carnitine (C3) underwent second-tier test for methylmalonic acid (MMA) on dried blood spot (DBS). Subsequently, newborns positive to the presence of MMA on DBS and their respective mothers underwent further tests: serum vitamin B(12), holo-transcobalamin (Holo-TC), folate and homocysteine; newborns were also tested for urinary MMA content. A control study was conducted on 203 females that were tested for the same parameters when admitted to hospital for delivery. RESULTS: Approximately 10% of the examined newborns showed altered C3. Among these, seven cases of acquired vitamin B(12) deficiency were identified (70% of the MMA-positive cases). Moreover, our data show a high frequency of vitamin B(12) deficiency in delivering female (approximately 48% of examined pregnants). CONCLUSIONS: We suggest to monitor vitamin B(12) and Holo-TC until delivery and to reconsider the reference interval of vitamin B(12) for a better identification of cases at risk. Finally, newborns from mothers with low or borderline levels of vitamin B(12) should undergo second-tier test for MMA; in the presence of MMA they should be supplemented with vitamin B(12) to prevent adverse effects related to vitamin B(12) deficiency.