Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia

Abstract

Objectives: To present the very long-term follow up of patients with cobalamin A (cblA) deficiency.

Methods: A retrospective case series of adult (>16 years) patients with molecular or enzymatic diagnosis of cblA deficiency.

Results: We included 23 patients (mean age: 27 ± 7.6 years; mean follow-up: 24.9 ± 7.6 years). Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%). Eight patients presented with chronic symptoms, and one had an adult-onset mild cblA deficiency. Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13). Initial management consisted of protein restriction (57%), B12 (17%), or both (26%). The main long-term problems were intellectual disability (39%) and renal failure (30%). However, 56.5% of the patients were living independently. Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12.

Conclusions: We provide a detailed picture of the long-term outcome of a series of adult cblA patients, mostly diagnosed before the enzymatic and molecular era. We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay. In addition, we describe a patient with a milder adult-onset form. Early B12 supplementation seems to protect from severe renal insufficiency.

Keywords: Adult; Methylmalonic aciduria; cobalamin A deficiency; kidney disease; late-onset; mental retardation; vitamin B12.

FIGURE 1

Correlation between the initial chronic treatment and the long‐term clinical outcome. The patients who received B12 (± protein restricted diet) are compared with the patients who received only a protein restricted diet or no treatment at all (patient with early onset and late diagnosis). Total n = 22/23: Patient #4 Lond 05 was not included because of adult‐onset disease). The patients without treatment had the worst outcome; intellectual disability was found in about 30%–40% of the patients, independently of the initial treatment modality (B12, protein restriction); instead, only one case (14%) of moderate and late‐onset renal failure was found in patients treated early with B12 as compared to 33% with chronic kidney disease in the group who did not initially receive B12 supplementation