Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type

Nogueira, Célia; Aiello, Chiara; Cerone, R.; Martins, Esmeralda; Caruso, U.; Moroni, Isabella; Rizzo, Cristiano; Diogo, Luísa; Leão, Eliseth Ribeiro; Kok, Fernando

doi:10.1016/j.ymgme.2007.11.005

Cited by 82 publications

(85 citation statements)

References 12 publications

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“…The results also imply that the c.394C4T and c.482G4A mutations identified in these Chinese patients may come from several different origins. As the c.394C4T and c.482G4A mutations occur at a CpG site and have also been observed in other populations, 5,7,[11][12]14 the recurrence of the c.394C4T and c.482G4A mutations in Chinese cblC patients is probably due to a CpG mutation hotspot 28 within the MMACHC gene rather than inherence of an ancestral allele. The CpG dinucleotide mutational hotspots within the MMACHC gene may also explain the recurrence of the c.217C4T, c.457C4T, c.481C4T and c.616C4T mutations in Chinese patients and other populations.…”

Section: Resultsmentioning

confidence: 54%

“…7,[9][10][11][12][13] Mutation analysis of cblC patients has shown that the c.271dupA mutation accounts for 40-55% of all disease alleles in European populations. 7,11 Several ethnic-specific mutations have also been observed, including the c.331C4T mutation in Cajun, FrenchCanadian, Italian and Portuguese and the c.394C4T mutation in Asiatic-Indian, Pakistani, Middle Eastern, Italian and Portuguese. 7,11,14 In Hong Kong, one cblC patient has been also identified as having a compound heterozygous genotype composed of the c.394C4T and c.536_537insAT mutations.…”

Section: Introductionmentioning

confidence: 99%

“…7,11 Several ethnic-specific mutations have also been observed, including the c.331C4T mutation in Cajun, FrenchCanadian, Italian and Portuguese and the c.394C4T mutation in Asiatic-Indian, Pakistani, Middle Eastern, Italian and Portuguese. 7,11,14 In Hong Kong, one cblC patient has been also identified as having a compound heterozygous genotype composed of the c.394C4T and c.536_537insAT mutations. 10 In addition, among East Asians, the c.609G4A mutation has also been observed.…”

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Yang

Chang³

et al. 2010

J Hum Genet

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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.365A4T and c.452A4G), nonsense mutations (c.315C4G and c.615C4A), deletions (c.99delA and c.277-3_c.303del30), duplications (c.248dupT and c.626dupT) and an insertion (c.445_446insA). The c.609G4A, c.658_660delAAG, c.482G4A, c.394C4T and c.80A4G mutations were the most common mutations and accounted for 80% of disease alleles. Haplotype analysis suggests that the spread of the c.80A4G, c.609G4A 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.

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Section: Resultsmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Yang

Chang³

et al. 2010

J Hum Genet

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“…The condition is inherited as an autosomal recessive disorder. Over 40 mutations have been reported, but one mutation, 271dupA, accounts for 40% of all cases which mainly occur in Europe [99] .…”

Section: Pathophysiologymentioning

confidence: 99%

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

114

111

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Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

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“…12 However, compound heterozygosity of this mutation with a missense mutation, such as c.482G.A on exon 4 (predicted protein p.Arg161Gln), tends to result in late-onset disease, which may be due to higher expression of the late-onset allele compared with the early-onset allele. 12,13,[19][20][21][22] Two other case reports have described patients who were also compound heterozygotes for c.271dupA and c.482G.A (Table 2). 20,23 Both patients presented with neuropsychiatric, hematologic, genitourinary, and musculoskeletal complaints, similar to our patient.…”

Section: Discussionmentioning

confidence: 99%

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

Rahmandar¹,

Bawcom²,

Romano

et al. 2014

Pediatrics

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Although cobalamin (cbl) C deficiency is the most common inherited disorder of vitamin B12 metabolism, the late-onset form of the disease can be difficult to recognize because it has a broad phenotypic spectrum. In this report, we describe an adolescent female exposed to unknown illicit substances and sexual abuse who presented with psychosis, anorexia, seizures, and ataxia. The patient’s diagnosis was delayed until a metabolic workup was initiated, revealing hyperhomocysteinemia, low normal plasma methionine, and methylmalonic aciduria. Ultimately, cblC deficiency was confirmed when molecular testing showed compound heterozygosity for mutations (c.271dupA and c.482G>A) in the MMACHC gene. This diagnosis led to appropriate treatment with hydroxocobalamin, betaine, and folate, which resulted in improvement of her clinical symptoms and laboratory values. This patient demonstrates a previously unrecognized presentation of late-onset cblC deficiency. Although neuropsychiatric symptoms are common in late-onset disease, seizures and cerebellar involvement are not. Furthermore, anorexia has not been previously described in these patients. This case emphasizes that inborn errors of metabolism should be part of the differential diagnosis for a teenager presenting with altered mental status, especially when the diagnosis is challenging or neurologic symptoms are unexplained. Correct diagnosis of this condition is important because treatment is available and can result in clinical improvement.1

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Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type

Cited by 82 publications

References 12 publications

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

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

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

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