Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Methylmalonic acidaemia (MMA) is a genetic disorder caused by defects in methylmalonyl-CoA mutase or in any of the different proteins involved in the synthesis of adenosylcobalamin. The aim of this work was to examine the biochemical and clinical phenotype of 32 MMA patients according to their genotype, and to study the mutant mRNA stability by real-time PCR analysis. Using cellular and biochemical methods, we classified our patient cohort as having the MMA forms mut (n = 19), cblA (n = 9) and cblB (n = 4). All the mut (0) and some of the cblB patients had the most severe clinical and biochemical manifestations, displaying non-inducible propionate incorporation in the presence of hydroxocobalamin (OHCbl) in vitro and high plasma odd-numbered long-chain fatty acid (OLCFA) concentrations under dietary therapy. In contrast, mut (-) and cblA patients exhibited a milder phenotype with propionate incorporation enhanced by OHCbl and normal OLCFA levels under dietary therapy. No missense mutations identified in the MUT gene, including mut (0) and mut (-) changes, affected mRNA stability. A new sequence variation (c.562G>C) in the MMAA gene was identified. Most of the cblA patients carried premature termination codons (PTC) in both alleles. Interestingly, the transcripts containing the PTC mutations were insensitive to nonsense-mediated decay (NMD).

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A prospective longitudinal study was conducted to analyze the evolution of the nutritional status of 34 children (12 girls and 22 boys), aged 1.5-15.8 years (median age 9.06), undergoing autologous peripheral blood stem cell transplantation (PBSCT). The nutritional status was evaluated at baseline, days +1 and +7, discharge, and day +30 by dietary or parenteral intake, anthropometric and laboratory measurements, and nitrogen balance. At baseline, changes in anthropometric (53%) and biochemical measurements (83%) are frequent but mild. The mean caloric intake was normal. Children with normal values for the anthropometric parameters all had an intake > 80% (p < .01). No correlation was found between the anthropometric and biochemical parameters. During transplantation, significant changes (p < .001) were found for energy intake, albumin, transferrin, and nitrogen balance. Fibronectin, prealbumin, and retinol-binding protein showed only a few changes. All but prealbumin recovered on day +30. No correlation was found between the nutritional status and toxicity or infection in children undergoing autologus PBSCT. The changes in the nutritional status observed at the start of transplantation correlated with the nutrional intake. Anthropometric and biochemical changes are complementary. The results may be ascribable to the fact that the patients in this series had mild malnutrition.

BackgroundCellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.ResultsThis paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.ConclusionsThe present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0862-y) contains supplementary material, which is available to authorized users.

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