Methylmalonic acidemia/propionic acidemia - the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups

Abstract

Background: Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016.

Results: During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH₃ values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07).

Conclusion: MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.

Keywords: Liver transplantation; Methylmalonic acidemia; Newborn screening; Propionic acidemia.

Fig. 1

Metabolic pathway of propionyl-CoA and methylmalonyl-CoA. Methylmalonic acidemia (MMA, MIM#251000) is caused either by a defect in methylmalonyl coenzyme A mutase (MUT, encoded by the mut gene, on chromosome 6p12.3) or by a defect in the uptake, transport or synthesis of 5’-deoxyadenosylcobalamin (AdoCbl). A disruption of the synthesis of AdoCbl is attributable either to a defect in cblA (251100), which is caused by a mutation in the MMAA gene located on chromosome 4q31, or to a defect in cblB (251110), which is caused by a mutation in the MMAB gene located on chromosome 12q24. Combined methylmalonic acidemia and homocystinuria occurs in individuals with mutations in cblC (277,400, MMACHC gene, located on chromosome 1p34), cblD (277,410, MMADHC gene, located on chromosome 2q23), and cblF (277380). Propionic acidemia (PA MIM#606054, is caused by deficiency in propionyl-CoA carboxylase (PCC), a biotin-dependent carboxylase that is present in the mitochondrial matrix. This enzyme is composed by two subunits, which are encoded by pccA, located on chromosome 3q22. 3 and pccB, located on chromosome 13q32.3

Fig. 2

Admission length times of MMA and PA patients before and after LT

Fig. 3

Tube feeding time of MMA mut patients, displayed in percentage, before and in the 2nd year after LT

Fig. 4

Functional assessment (DQ/IQ) of isolated MMA and PA patients, categorized in LT(+) and LT(−) group