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

Abstract

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.

Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

“…Mut À and cblB patients had intermediate phenotypes, while B 12 -responsive cblA subjects had the best long-term prognosis. 31 Large patient registries have confirmed the earlier observations on the importance of the underlying genetic and enzymatic defect on disease mortality, morbidity, and multisystem complications 40,44,46 and have helped evaluate older and newer biomarkers against molecular, biochemical, and clinical severity scores. 5,8,39,47,51,80 Multiomics profiling of over 200 patient fibroblast lines allowed a powerful integrated analysis of whole genome and transcriptome sequencing, data-independent acquisition mass spectrometry proteotyping, and metabolomics that enabled novel associations of various biomarkers with cell phenotypes and clinical severity scores.…”

“…Mut − and cblB patients had intermediate phenotypes, while B 12 ‐responsive cblA subjects had the best long‐term prognosis 31 . Large patient registries have confirmed the earlier observations on the importance of the underlying genetic and enzymatic defect on disease mortality, morbidity, and multisystem complications 40,44,46 and have helped evaluate older and newer biomarkers against molecular, biochemical, and clinical severity scores 5,8,39,47,51,80 …”

“…The design of early phase clinical trials is particularly challenging for rare disorders like MMA, where the molecular, biochemical, and clinical phenotype is heterogenous, the approach to dietary and pharmaceutical management variable, and morbidity and disease progression highly individualized. Over the past five decades, case reports and small patient series [27][28][29][30] have been fortified by focused natural history studies (clinicaltrials.gov identifier: NCT00078078) [31][32][33][34][35] and large international collaborative efforts (E-IMD) 25,[36][37][38][39][40][41][42][43][44] that together have been instrumental in documenting different aspects of the natural history of the disease, improving understanding of phenotypegenotype correlations, 8,45 identifying biomarkers reflecting disease severity and progression, 3,5,[46][47][48] and developing informed consensus treatment guidelines in order to standardize the widely different management approaches implemented across various metabolic centers. 25,36,[49][50][51] These are critical prerequisites for assessing the efficacy of various therapies in current and future interventional trials.…”

How guideline development has informed clinical research for organic acidurias (et vice versa)

“…For MMA it has been shown that the genetic cause of the condition directly affects the long‐term clinical outcome, where the severe MMUT‐deficient cases (termed mut 0 ) show the highest excretion of urinary methylmalonic acid which is directly correlated to the likelihood of developing chronic kidney disease in the long term 70 . Patients can be further segregated by classifying them into categories of increasing severity, ranging from mut 0 (loss of enzymatic function of MMUT) to cblB , to mut − (MMUT defect with some residual activity) and cblA , where the latter two show more attenuated disease courses including a lower rate of kidney and neurocognitive complications 70–72 …”

Rare Disease Registries Are Key to Evidence-Based Personalized Medicine: Highlighting the European Experience

“…This knowledge is of relevance for the optimization of the diagnostic process, patient clinical paths, healthcare planning, and counselling of parents having a child with a rare disease. For example, comparative phenotyping helped to identify the need to carefully monitor renal function not only in individuals with isolated methylmalonic acidurias but also in individuals with other organic acidurias such as propionic aciduria and glutaric aciduria type 1 ( 24 , 38 ) since chronic kidney dysfunction was already well known in methylmalonic aciduria ( 39 , 40 ), but was underestimated in propionic aciduria and unknown in glutaric aciduria type 1 before. Patient registries also allow comparison between different diagnostic journeys and related health outcomes on an international level, especially if there are known rigid differences in diagnostic approaches between countries, that may be evaluated against each other, as is the case with differing national newborn screening panels.…”