Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5years of ACADM sequencing

Smith, Emily H.; Thomas, Cheryl; McHugh, David; Gavrilov, Dimitar; Raymond, Kimiyo; Rinaldo, Piero; Tortorelli, Silvia; Matern, Dietrich; Highsmith, W. Edward; Oglesbee, Devin

doi:10.1016/j.ymgme.2010.04.001

Cited by 55 publications

(68 citation statements)

References 54 publications

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“…According to Smith, this patient could be considered as having an intermediate phenotype and acylcarnitine results are in agreement with previous descriptions (Smith et al 2010;Maier et al 2005). The average value of C8 in our homozygous patients for the common mutation was 3.9 mmol/L, while the value decreased to 1.28 mmol/L in compound heterozygous.…”

Section: Discussionsupporting

confidence: 91%

“…Similar to other studies, the prevalent mutation in our population is c.985A>G (p.K329E), which was found in 75% of the alleles with MCADD, but was not as high as previously anticipated (Yokota et al 1991;Giroux et al 2007;Waddell et al 2006;Blois et al 2005), although it is rather high if we consider other neonatal screening studies (Andresen et al 2001;Maier et al 2005;Nichols et al 2008;Smith et al 2010) as in the screened individuals it is usual to find milder mutations, while the common mutation c.985A> G is most frequently found in the clinically presenting patients.…”

Section: Discussionsupporting

confidence: 90%

“…Two of the mutations c.245G>C (p.W82S) and c.542A>G (p.D181G) are novel. The c.1247T>C (p.I416T) has very recently been reported in a US newborn identified by MS/MS-based routine screening (Smith et al 2010), and we have furthermore observed this mutation in another US newborn identified by MS/MS-based routine screening (personal communication). Among our MCADD individuals (20 alleles), the prevalence of the common allele is 75%.…”

Section: Resultssupporting

confidence: 77%

“…This mutation has never been identified in patients with a clinical phenotype, but in several newborns identified by neonatal screening in the United States, Australia, and Germany Smith et al 2010;Zschocke et al 2001). These newborns had a relatively mild acylcarnitine profile, like our patient 8, that was compound heterozygous for this and for the common mutation and only presented a slight elevation of metabolites.…”

Section: Discussionmentioning

confidence: 55%

“…It seems that there is no clear relationship between genotype and phenotype (Andresen et al 1997;Lehotay et al 2004;Waddell et al 2006;Hsu et al 2008), but patients homozygous for the common mutation have higher levels of C8 (Andresen et al 2001;Waddell et al 2006;Smith et al 2010), and it is associated with a greater predisposition to suffer decompensation in situations of metabolic stress (Arnold et al 2010). Thus, compound heterozygous for the prevalent c.985A>G mutation and a milder mutation in the other allele may have a risk reduction due to their greater residual enzyme activity (Lehotay et al 2004).…”

Section: Discussionmentioning

confidence: 99%

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Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

et al. 2011

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Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.The common mutation, c.985A>G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G>C (p.W82S) and c.542A>G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A>G mutation, died at the age of 2 years due to a severe infection. This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Resultssupporting

confidence: 77%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

et al. 2011

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Protein Interaction and Genetic Disease

Gregersen

Bross

Olsen

et al. 2011

Encyclopedia of Life Sciences

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The function of proteins is dependent on other proteins. Proteins function as oligomers, complexes, super‐complexes or higher order networks, in which they interact with each other, either temporarily when they exert their function or ‘permanently’ in functional units. Genetic defects in single proteins may therefore, in addition to disturbing the specific function of the defective protein, disturb other functions that are dependent on it. In this review we will discuss how the two main types of defects in genetic disease, truncating variations (stop‐codon introductions and small out‐of‐frame deletions/insertions) and in‐frame variations (missense variations and small in‐frame deletions/insertions), may disturb normal interactions. Depending on the importance (location) of the missing or aberrant protein, the effect on the cellular pathway or interacting network may be severe or mild. Protein interactions and disturbances therein may be determined by protein mass spectrometry after immuno‐precipitation or other fractionation and separation methods. Key Concepts: Cellular proteins interact in oligomer and complex structures as well as in higher order networks. Protein interactions may be permanent in the lifetime of proteins or temporary during their function. Genetic defects may disturb interactions between proteins depending on the nature of the defect and type of interaction. Missing proteins due to truncation, comprising big deletions, small out‐of‐frame deletions/insertions and severe splice alteration, may abolish the function of oligomers, complexes, pathways and networks. Aberrant proteins due to missense variations and in‐frame deletions/insertions may disturb interactions with protein partners in oligomers, complexes and networks. Missing and aberrant proteins in branch‐points (nodes) have as a role severe consequences, resulting in genotype–phenotype association. Missing and aberrant proteins in redundant pathways have variable consequences, resulting in poor genotype–phenotype association. Missing and aberrant proteins in molecular machines, such as the chaperonin Hsp60, may elicit pleotropic effects due to defective processing of client proteins. Protein interactions and disturbances therein may be determined experimentally by protein mass spectrometry (MS), preceded by immunoprecipitation of target proteins, either directly or after cross‐linking, or indicated after mild solubilisation followed by extensive separating procedures and MS. The challenge is to design experiments that can determine qualitative and quantitative disturbances of proteins interactions in cells and tissue from patients, model animals and model cells compared to interactions in normal cells and tissue.

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Expanded Newborn Screening: Articulating the Ontology of Diseases with Bridging Work in the Clinic

Timmermans¹,

Buchbinder

2012

The Sociology of Medical Screening

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Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5years of ACADM sequencing

Cited by 55 publications

References 54 publications

Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

Protein Interaction and Genetic Disease

Expanded Newborn Screening: Articulating the Ontology of Diseases with Bridging Work in the Clinic

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