Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut.

INTRODUCTION: Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult. METHOD: Cross-sectional analysis of data from the European Registry and Network for Intoxication type Metabolic Diseases (Chafea no. December 1, 2010). RESULTS: Data from 28 cblA and 95 mut patients in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval, six patients from the mut group died, while all cblA patients survived. CONCLUSION: Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients.

Cost-effectiveness of liver transplantation in methylmalonic and propionic acidemias.

Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.

Clinical outcome and long-term management of 17 patients with propionic acidaemia.

UNLABELLED: A retrospective study was performed on the clinical outcome and long-term treatment of 17 patients with propionic acidaemia diagnosed during the last 20 years in our hospital. The study group consisted of 12 patients with early onset type of disease and 5 patients with late onset. Seven (41%) patients died, five with early onset and two with late onset. The deceased early onset patients had a median survival of 0.4 years while the deceased late onset patients died at the age of 2.8 and 4 years respectively. Median age of the living early onset patients was 5.2 (1-9.25) years, the late onset patients were 4, 7 and 23 years old. Patients were all treated with natural protein restriction and in most cases carnitine and metronidazole were added. The early onset patients were almost all treated with daily home tube feeding. The mean natural protein intake of early onset patients (6.3 +/- 1.5 g/day) was significantly lower than the natural protein intake of late onset patients (17.6 +/- 5.3 g/day). Supplemental protein intake was higher in early onset patients. The general neurological outcome of our study group was satisfactory with a better outcome for early onset patients. As to growth, many patients showed a failure to thrive, this was particularly for height. The strong protein restriction during the first years of life probably contributed to this. CONCLUSION: The prognosis for patients with propionic acidaemia appeared to be satisfactory in terms of survival and outcome characteristics such as neurological and mental development. Despite these results the authors feel that the prognosis and quality of life of these patients might be improved with liver transplantation or possibly somatic gene therapy in the future.

Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia.

We performed a retrospective study of all patients with methylmalonic acidemia diagnosed during the past 20 years. Only those patients who were nonresponsive to vitamin B12 in vivo and in vitro were included. The final study group consisted of 26 patients, of whom 16 had a neonatal (early) onset; in 10 patients the diagnosis was made after 2 months to 2.2 years (late onset). Of the early-onset patients, 14 (87%) died, with a mean survival time of 1.5 years (range, 10 days to 2.5 years), whereas four of the late-onset patients (40%) died (range, 1.2 to 15 years). At present, eight patients are alive; their mean age is 4.6 years (range, 1 to 10 years). In the early 1970s, treatment was based on the principles of treating patients with phenylketonuria: restricting natural protein intake and supplementing essential amino acids, vitamins, and trace elements. After about 1980, nasogastric tube feeding became a mainstay of the therapy, natural protein restriction became stricter, and the use of essential amino acid mixtures diminished. Carnitine was added to the therapy and, in later years, metronidazole. Since these changes were implemented, the number of episodes of metabolic decompensation and hospitalizations has decreased. Mean survival time of the patients, in particular those with early onset, has only slightly improved, partly because of psychosocial problems in many of these families. Almost all the patients, especially those with early onset, had some degree of neurologic impairment and mental retardation, and many patients were at less than 2 SD for weight or height or both. In contrast, the neurologic and mental status of the late-onset patients was frequently normal, and their weight and height were more often within normal limits. Our results show that the treatment of methylmalonic acidemia still poses considerable problems; despite intense medical efforts and familial stress, the prognosis for the early-onset patients is disappointing. The patients with late-onset disease, however, appear to have a fairly good prognosis with the present therapeutic approach. Liver transplantation or possibly genetic therapy might improve our results in the future.