Error Of Vitamin B12 Metabolism Research Articles

Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria

The cblC type of combined methylmalonic aciduria (MMA) and homocystinuria (HC) is the most common inborn error of vitamin B(12) metabolism and is caused by mutations in the MMACHC gene. To elucidate the spectrum of mutations that causes combined MMA and HC in Chinese patients, the MMACHC gene was sequenced in 79 unrelated Chinese patients. Sequence analysis identified 98.1% of disease alleles and found that all patients had at least one MMACHC mutation. A total of 24 mutations were identified. Out of the 24 mutations identified, 9 were novel ones, including missense mutations (c.365A>T and c.452A>G), nonsense mutations (c.315C>G and c.615C>A), deletions (c.99delA and c.277-3_c.303del30), duplications (c.248dupT and c.626dupT) and an insertion (c.445_446insA). The c.609G>A, c.658_660delAAG, c.482G>A, c.394C>T and c.80A>G mutations were the most common mutations and accounted for 80% of disease alleles. Haplotype analysis suggests that the spread of the c.80A>G, c.609G>A and c.658_660delAAG mutations in Chinese patients were caused by a founder effect. The results indicate that defects occurring in the MMACHC gene are the major cause of this disease in Chinese patients with combined MMA and HC, and direct mutation analysis can therefore be used as a rapid confirmatory diagnosis among these Chinese patients.

LMBRD1: the gene for the cblF defect of vitamin B12 metabolism

To date, only very few genetic disorders due to defects in lysosomal membrane transport are known. This paper reviews the identification of the underlying molecular defect causing an intriguing inborn error of vitamin B₁₂ metabolism, namely, defective lysosomal release of vitamin B₁₂ (cblF defect). Using microcell-mediated chromosome transfer of wild-type human chromosomes into immortalized fibroblasts from a cblF patient and genome-wide homozygosity mapping in 12 unrelated cblF patients, we identified LMBRD1 as a positional candidate gene on chromosome 6q13. Five different frameshift mutations leading to loss of function of both LMBRD1 alleles were detected in the affected patients. Transfection of the LMBRD1 wild-type construct into fibroblasts derived from cblF patients restored cobalamin coenzyme synthesis and function. LMBRD1 encodes a novel lysosomal membrane protein with significant homology to lipocalin membrane receptors. These studies give further insight into the intracellular transport of vitamins, challenge the views on lipocalin receptors, and add to our understanding of lysosomal diseases.

COBALAMIN C DISEASE AND EXPANDED NEWBORN SCREENING: THE CALIFORNIA EXPERIENCE.

Cobalamin C (cblC) disease is the most common inborn error of vitamin B12 metabolism. Patients have elevated methylmalonic acid (MMA) and homocysteine and typically have a poor prognosis. Common features include mental retardation, nystagmus, pigmentary retinopathy, and neurodegeneration. Treatment includes protein restriction and hydroxocobalamin, betaine, carnitine, and folic acid supplementation. California initiated expanded newborn screening (NBS) in July 2005. Since that time, there have been 10 cases of cblC disease confirmed by fibroblast complementation analysis and/or biochemical studies, resulting in a surprisingly high estimated prevalence of 1 in 60,000. An additional three newborns have been identified in Northern California in whom confirmatory studies are pending. Because 8 of 10 cases are Hispanic, we estimate the prevalence in the Hispanic population to be 1 in 37,000. In the confirmed cases, initial NBS results showed an elevated C3 level ranging from 6.5 to 13.1 μmol/L and an elevated C3/C2 ratio ranging from 0.29 to 0.45 (reference range

E Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

e Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

Potential for clinical misdiagnosis of combined methylmalonic aciduria/homocysteinemia (MMA/HCYS) due to absence of acute metabolic derangement

The cobalamin C (cbl C) complementation group of combined MMA/HCYS is the most common o f the inborn errors of vitamin B12 metabolism, affecting both methylmalonyl-CoA and homocysteine (Hcys) degradation. We have recently diagnosed 2 patients with this disorder. AH. a 3 week old male, presented with lethargy, decreased oral intake, dehydration and pancytopenia. There had been a preceding upper respiratory infection. Parents were first-cousin Saudi Arabians. VM, a Hispanic female, presented at 19 days of life with lethargy. hyptonicity, dehydration, cough, decreased oral intake, significant thrombocytopenia, and mild pancytopenia. For both, worsening neurologic status was accompanied by seizures, and sepsis was suspected followed by appropriate intervention. Subsequent metabolic work-up revealed MMAIHCYS; fibroblast analysis for AH verified the cbl C complementation subgroup (Dr. D. Rosenblatt, Montreal, Canada; studies in VM are pending, although she likely falls within the same subgroup). Plasma total Hcys remains persistently elevated in AH (26-39 uM, n=8; nl < 10) and was 216 uM for VM (n=l). CSF total Hcys was 35 uM for VM (nl < 0.08). We conclude that I) diagnosis of patients with MMA/HCYS of the cbl C complementation subgroup may be hampered by absence of acute metabolic derangement (acidosis, hyperammonemia, hypoglycemia, ketosis) combined with features (lethargy, obtundation) suggesting sepsis; and 2) significantly increased CSF Hcys may be the underlying cause of altered neurologic status in these patients.

4: Newly described error of vitamin B12 metabolism

Nutrition BulletinVolume 10, Issue 3 p. 133-133 4: Newly described error of vitamin B12 metabolism First published: September 1985 https://doi.org/10.1111/j.1467-3010.1985.tb01201.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume10, Issue3September 1985Pages 133-133 RelatedInformation

853 METHYLMALONIC ACIDURIA ASSOCIATED WITH FAILURE OF LYSOSOMAL RELEASE OF VITAMIN B12

Inborn errors of vitamin B12 metabolism affect the synthesis of only Ado-B12 (Cbl A and Cbl B), total vitamin B12 accumulation and the synthesis of both Ado-Bl2 and CH3-B12 (Cbl C and Cbl D) or the synthesis of only CH3-B12 (Cbl E). It is known that after transcobalamin II (TCII)-B12 binds to specific receptors on the plasma membrane, the complex is internalized by means of adsorptive endocytosis, following which the endocytic vesicle fuses with a lysosome, and the TCII is degraded by lysosomal proteases releasing free B12 which exits the lysosome. Fibroblasts from a patient with minimal methylmalonic aciduria accumulated normal total vitamin B12 but only unbound CN-B12 when incubated in TCII-[57Co]-CN-B12. In contrast to control fibroblasts virtually all of the B12 was found in the lysosomal fraction of the cells. Treatment of the cells with chloroquine resulted in the accumulation of TCII-bound B12, in the lysosomal fraction in both control and mutant fibroblasts. These data suggest that fibroblasts from this patient are able to endocytose TCII-B12 and to release the B12 from TCII in the lysosome. Because the mutant cells do not allow the B12 to efflux across the lysosomal membrane, they accumulate neither Ado-B12 nor CH3-B12. The defect thus appears to involve vitamin B12 transport across the lysosomal membrane.

Retinal Degeneration in Vitamin B12 Disorder Associated with Methylmalonic Aciduria and Sulfur Amino Acid Abnormalities

A 33-month-old boy with an inborn error of vitamin B12 metabolism characterized by methylmalonic aciduria, homocystinuria, cystathioninuria , and hypomethioninemia had poor vision and a progressive retinal pigmentary degeneration. The child had early growth retardation with microcephaly, developmental delay, and a megaloblastic anemia. The retinal lesions were first noted when he was 1 year of age and, by ophthalmoscopy and by electroretinographic testing, have progressed. Treatment with hydroxocobalamin and L-methionine improved the anemia and the biochemical abnormalities but apparently did not halt the retinal degeneration. We believe the retinopathy is a feature of this disease, particularly in patients with infantile involvement. The retinal lesion may be caused by an unidentified abnormality of sulfur amino acid metabolism.

Studies of Methylmalonyl Coenzyme A Carbonylmutase Activity in Methylmalonic Acidemia. I. Correlation of Clinical, Hepatic, and Fibroblast Data

Methylmalonyl-CoA carbonylmutase (mutase) activity was measured in fibroblast extracts from 15 patients with methylmalonic acidemia and in extracts of postmortem tissues from 6 of these children. Propionate oxidation and synthesis of 5-deoxyadenosylcobalamin (AdoCbl, the vitamin B12 coenzyme that is part of the mutase holoenzyme) were measured in intact fibroblasts. Mutase activity was low in the absence of added AdoCbl in fibroblast extracts from both control subjects and patients. When the assay included supplemental AdoCbl, mutase activity increased in the control subjects (to 24.0 pmol succinate/mg protein/min) and in extracts from eight of the patients (20.8 pmol/mg protein/min), but showed almost no change in extracts from the other seven patients (0.16 pmol/mg protein/min). We have defined the eight fibroblast lines that showed normal mutase activity in the presence of AdoCbl as "responsive lines" and the other seven lines as "nonresponsive." In the liver or kidney extracts of postmortem tissues, mutase activity responded to AdoCbl supplementation if fibroblast mutase activity from that patient had responded, and failed to respond if fibroblast activity failed to respond. Mean propionate oxidation in intact fibroblasts was much higher in control lines than in either responsive or nonresponsive lines (0.728 vs 0.097 vs 0.080 nmol CO2/10(6) cells/hr, respectively). AdoCbl synthesis was normal (0.27 pg AdoCbl/mg cells wet weight) in nonresponsive fibroblasts but was undetectable (less than 0.005 pg/mg cells) in the responsive lines. Thus, the deficiency of mutase activity in responsive fibroblast lines is due to the failure to synthesize significant amounts of AdoCbl, whereas the deficiency in nonresponsive lines is due to some other abnormality, presumably a defect in the mutase apoenzyme.