Spectrum of bone marrow pathology and hematological abnormalities in methylmalonic acidemia

Patients with isolated methylmalonic acidemia (MMA) may present with a wide range of hematological complications including anemia, leukopenia, thrombocytopenia, and pancytopenia. However, there are very limited data on the development of hemophagocytosis or myelodysplasia in these patients. We report three patients with isolated MUT related MMA who presented with severe refractory pancytopenia during acute illness. Their bone marrow examination revealed a wide spectrum of pathology varying from bone marrow hypoplasia, hemophagocytosis to myelodysplasia with ring sideroblasts. We discuss their management and outcome. This report emphasizes the need for bone marrow examination in these patients with refractory or unexplained severe cytopenia, to confirm bone marrow pathology, and to rule out other diseases with similar clinical presentation for a better clinical outcome.

     

甲基丙二酸血症脑损伤机制研究进展

甲基丙二酸血症是由于甲基丙二酰辅酶A变位酶或其辅酶腺苷钴胺素缺陷所致的一种遗传性代谢疾病。患者体内甲基丙二酸及其他代谢产物蓄积，造成脑组织损伤，可表现为各种不同程度的智力发育迟缓及严重的神经功能障碍。甲基丙二酸血症的脑损伤机制至今尚不完全明确，目前研究主要集中在：线粒体功能障碍、神经元细胞凋亡、细胞骨架磷酸化改变及髓鞘形成障碍等脑神经结构损伤；神经节苷脂和突触可塑性异常等脑神经发育损伤；以及认知和行为改变等脑功能损伤。     

Proximal Renal Tubular Acidosis in Methylmalonic Acidemia

A patient with methylmalonic acidemia was found to have a persistent hyperchloremic acidosis. Investigation documented the presence of a proximal renal tubular acidosis. Between 14 and 18 months of age the urinary pH was as high as 8.0 when the serum bicarbonate was 17 mEq/liter and the threshold for bicarbonate was at 16-17 mEq/liter. When restudied at 33 months of age, the threshold had risen to 20 mEq/liter, but this was still abnormal and supplemental treatment was required to keep the serum concentration of bicarbonate above 20 mEq/liter. It is postulated that organic acid metabolites which accumulate in this and related disorders may interfere with renal tubular function as has been shown for maleic acid in experimental animals.     

Elevated methylmalonic acidemia (MMA) screening markers in Hispanic and preterm newborns

Analysis of California newborn screening (NBS) data revealed a high prevalence of Hispanic infants testing positive for methylmalonic acidemia (MMA), a trend seen for both true- and false-positive cases. Here we show that Hispanic infants have significantly higher levels of MMA screening markers than non-Hispanics. Preterm birth and increased birth weight were found to be associated with elevated MMA marker levels but could not entirely explain these differences. While the preterm birth rate was higher in Blacks than Hispanics, Black infants had on average the lowest MMA marker levels. Preterm birth was associated with lower birth weight and increased MMA marker levels suggesting that gestational age is the stronger predictive covariate compared to birth weight. These findings could help explain why MMA false-positive results are more likely in Hispanic than in Black infants, which could inform screening and diagnostic procedures for MMA and potentially other disorders in newborns.     

Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene

Methylmalonyl-CoA mutase (MCM) apoenzyme deficiency is a rare metabolic disease that may result in distinct biochemical phenotypes of methylmalonic acidemia (MMA), namely mut(o) and mut-. We analyzed a cohort of 40 MCM-deficient patients with MMA affected by either the mut(o) or the mut- form of the disease. By direct sequencing of cDNA and gDNA of the MUT gene, we detected 42 mutations, 29 of which were novel mutations. These included five frameshift mutations (insertion, deletion, or duplication of a single nucleotide), five sequence modifications in consensus splice sites, six nonsense and 12 missense mutations, and a large genomic deletion including exon 12. We explored how the 12 novel missense mutations might cause the observed phenotype by mapping them onto a three-dimensional model of the human MCM generated by homology with the P. shermanii enzyme. In this work we update the spectrum of MCM mutations (n=84), and then discuss their prevalence and distribution throughout the coding sequence in relation to the enzyme structure.     

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Background/aim Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT , MMAA , MMAB , MMADHC , MCEE genes. Mutation screening identified 30 different types of mutations. Results While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.     

Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy

A patient diagnosed at 9 months with a milder form of propionic acidemia was functioning at a near normal intellectual level and a normal neurological level at age 8. After 2-week history of feeling "poorly" but functioning normally, she became acutely ill and succumbed to heart failure and ventricular fibrillation in 12 h. At post-mortem the heart was hypertrophied and had low carnitine levels, despite carnitine supplementation and repeatedly normal plasma carnitine levels. The findings in this patient provide a possible mechanism for the cardiac complications that are becoming more apparent in propionic acidemia.     

Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.     

Mutations in mut methylmalonic acidemia: Clinical and enzymatic correlations

Mut methylmalonic acidemia is caused by mutations in the MUT locus encoding the enzyme methylmalonyl CoA mutase. Genotypic and phenotypic variability in this disease has been studied extensively by biochemical and somatic cell genetic techniques, by molecular cloning, and by gene transfer. Mutations have been identified that cause classic mut^o phenotypes in which there is no detectable enzymatic activity, mut⁻ phenotypes in which there is residual cobalamin-dependent activity, as well as a subset within both mut^o and mut⁻ phenotypes that exhibit interallelic complementation. These mutations illustrate the position, structure, and function of critical domains within this cobalamin-binding enzyme and provide new insights into the biochemical and clinical consequences of enzyme deficiency. © 1997 Wiley-Liss, Inc.     

Case reports of successful pregnancy in women with maple syrup urine disease and propionic acidemia

We report on 2 women with organic acidemias, one with classical maple syrup urine disease and another with mild propionic acidemia in which protein restricted diets and carnitine supplementation were successfully employed to manage pregnancies. Healthy infants were delivered without maternal metabolic decompensation. © 1992 Wiley-Liss, Inc.     

Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): Review and report of thirty novel mutations

Glutaric acidemia type I (GA1) is caused by mutations in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCD). Sixty-three pathogenic mutations identified by several laboratories are presented, 30 of them for the first time, together with data on expression in Escherichia coli and relationship to the clinical and biochemical phenotype. In brief, many GCD mutations cause GA1, but none is common. There is little if any relationship between genotype and clinical phenotype, but some mutations, even when heterozygous, seem especially common in patients with normal or only minimally elevated urine glutaric acid. Hum Mutat 12:141–144, 1998. © 1998 Wiley-Liss, Inc.     

FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome

Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in 10 new subjects with a total of 7 novel deleterious variants; 5 null and 2 missense substitutions. All patients exhibited congenital lactic acidemia, most of them with severe encephalopathic presentation, and global developmental delay. Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis.     

Complement activation in diabetic ketoacidosis and its treatment

Recent studies support the presence of an inflammatory response during the treatment of diabetic ketoacidosis (DKA). The objectives of this study were to monitor the complement activation products C3a, C4a, Bb, and C5b-9 prior to, during, and after correction of DKA. All patients had increased levels of C3a at 6-8 h and 24 h (P<0.05). C4a was increased in only one patient. Bb showed an upward trend at 6-8 h, and was significantly elevated at 24 h (P<0.05); sC5b-9 was elevated in all patients prior to treatment or in the first 6-8 h of treatment. Results indicate that the alternative pathway may be the primary pathway of activation. These results extend the observation that both DKA and its treatment produce varying degrees of immunologic stress during the time when acute complications are most likely to occur.     

Aldosterone and PCO2 enhance K-dependent chloride absorption in rat distal colon

We have previously demonstrated that, in the absence of Na⁺ in vitro, the rate of colonic K⁺ absorption is increased by increasing PCO₂. Chronic secondary hyperaldosteronism induced by dietary Na-depletion further stimulated K⁺ absorption under these conditions. Because the observed increments in CO₂-dependent K⁺ absorption were not accompanied by corresponding changes in short-circuit current, macroscopic electroneutrality must have been maintained either by anion absorption or by cation secretion. Colonic Cl^– absorption is known to respond to increased PCO₂ both in vivo and in vitro, but its response under Na-free conditions and the relationship to K⁺ absorption have not been examined. To determine the relationship of Cl^– absorption to K⁺, we measured unidirectional fluxes of ³⁶Cl and the response to PCO₂ in voltage-clamped segments of rat distal colon. Our findings indicate that the rate of Cl^– absorption is increased by increasing CO₂, both in the presence and absence of Na⁺. Under Na-free conditions, Cl^– absorption is inhibited by acetazolamide and by the absence of K⁺; K⁺ absorption (⁸⁶Rb or ⁴²K flux) is inhibited in a reciprocal fashion by the absence of Cl^–. The rates of K⁺ and Cl^– absorption are similar in controls and after secondary hyperaldosteronism due to a Na-deficient diet. These findings suggest that K⁺ and Cl^– absorption are closely coupled under Na-free conditions, most likely due to the operation of parallel, aldosterone-responsive H⁺-K⁺ and Cl^–-HCO ₃ ^– exchange pathways.     

Molecular Genetic Characterization of 151 Mut‐Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT

Isolated methylmalonic aciduria (MMA) is an autosomal‐recessive disorder of propionate metabolism that is most commonly caused by mutations in the methylmalonyl‐CoA mutase (MUT) gene (mut‐type MMA). We investigated a cohort of 151 patients, classifying 114 patients as mut⁰ and 32 as mut^? (five not defined). As per the definition, mut^? patients showed a higher propionate incorporation ratio in vitro, which was correlated to a considerably later age of onset compared with mut⁰ patients. In all patients, we found a total of 110 different mutations, of which 41 were novel. While the missense alleles p.Asn219Tyr, p.Arg369His, and p.Arg694Trp recurred in >10 alleles, 47 mutations were identified only once, suggesting many patients carry private mutations. Deficient alleles in the mut^? subclass were almost exclusively caused by missense mutations, found disproportionately in the C‐terminal cofactor binding domain. On the contrary, only half of the mut⁰ mutations were of the missense type. Western blot analysis revealed reduced MUT protein for all 34 cell lines (27 mut⁰, seven mut^?) tested, suggesting protein instability as a major mechanism of deficiency in mut‐type MMA. This large‐scale evaluation helps to characterize the landscape of MUT mutations and their relationship to dysfunction and disease.     

一氧化氮与感染性休克关系的实验和临床研究进展

一氧化氮(ｎｉｔｒｉｃｏｘｉｄｅ,ＮＯ)是由多种细胞产生的广泛存在的生物分子 ,在多种疾病的病程中均有作用 ,在细胞水平上产生有利的或不利的影响。它在感染性休克的发病机制中发挥重要的作用。有关ＮＯ在感染性休克中的地位和作用的文献非常丰富 ,由于篇幅的限制 ,不可能对所有的文章均加以论述。本文拟对ＮＯ在败血症和感染中毒性休克中的作用 ,以及阻断或增强其作用对实验结果及临床的影响加以综述。1　ＮＯ在败血症时合成增加败血症患者血液中的亚硝酸盐和硝酸盐水平明显上升 ,这些物质是ＮＯ合成时稳定的副产物。应用内毒素或炎细胞…