Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening

Merritt, J. Lawrence; Vedal, Sverre; Abdenur, José E.; Au, Sylvia Mann; Barshop, Bruce A.; Feuchtbaum, Lisa; Harding, Cary O.; Hermerath, Cheryl A.; Lorey, Fred; Sesser, David E.; Thompson, John D.; Yu, Arthur

doi:10.1016/j.ymgme.2014.01.009

Cited by 48 publications

(36 citation statements)

References 30 publications

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“…10,11,27 Our study aimed to develop a tool that predicts the clinical phenotype in individuals with VLCADD detected by NBS. In this article we show a strong correlation between LC-FAO flux in cultured skin fibroblasts and the clinical severity of the phenotype in patients with VLCADD diagnosed before introduction of VLCADD in the Dutch NBS program.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Diekman

Ferdinandusse

Pol

et al. 2015

Genetics in Medicine

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Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity. Methods:We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading. Results:The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05). Conclusion:Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

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Section: Discussionmentioning

confidence: 99%

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Diekman

Ferdinandusse

Pol

et al. 2015

Genetics in Medicine

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“…The tools are applicable to either the diagnosis of one condition or, like the dual scatter plots described in this report, to the differential diagnosis between two conditions with overlapping phenotypes (i.e., true positives versus false positives). 25,27 Briefly, in the dual scatter plot the relationship to reference ranges becomes irrelevant as the comparison now takes place between two disease ranges. The dual scatter plot is also the combination of two tools, one that targets any nonoverlapping result to increase the score for the first condition and decrease the score for the second one, and another that operates in exactly the opposite way.…”

Section: Multivariate Pattern Recognition Softwarementioning

confidence: 99%

Precision newborn screening for lysosomal disorders

Baerg

Stoway

Hart

et al. 2018

Genetics in Medicine

104

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“…Another benefit of a reliable biochemical second-tier test is the avoidance of anxiety and costs associated with the frequent discovery of genotypes of uncertain significance, which eventually turn out to be unaffected individuals with pseudodeficient GAA activities. 8,34,35 It is also possible to begin exploring whether the Cre/Crn ratio alone, the (Cre/Crn)/GAA ratio, or additional permutations of ratios could be relevant to the expansion of the biochemical phenotype of other conditions with prominent skeletal and cardiac myopathy and consequent elevation of creatinine phosphokinase, for example, very long chain fatty acid oxidation disorders 36 and particularly DMD and related disorders. 37 For proof of concept, preliminary testing of blood spotted on filter paper from residual clinical samples of genotyped DMD patients showed consistent elevations of the Cre/Crn ratio ( Figure 3; age 3-11 years, N = 10, range 6.42-8.99; age 25-39 years, N = 10, range 4.71-10.44; controls of age 21-60 years, N = 11, range 2.55-4.96; see Table 1 for neonatal reference percentiles).…”

Section: Discussionmentioning

confidence: 99%