BACKGROUND: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers. AIMS: To evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools. METHODS: We retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations. RESULTS: VLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed the variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen. CONCLUSIONS: These results emphasize the importance of functional investigation of abnormal NBS or clinical testing suggestive but not diagnostic of VLCADD. A larger prospective study is necessary to better define the clinical and metabolic ramifications of the defects identified in such patients.
BACKGROUND: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers. AIMS: To evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools. METHODS: We retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations. RESULTS:VLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed the variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen. CONCLUSIONS: These results emphasize the importance of functional investigation of abnormal NBS or clinical testing suggestive but not diagnostic of VLCADD. A larger prospective study is necessary to better define the clinical and metabolic ramifications of the defects identified in such patients.
Authors: Tien V Nguyen; Brage S Andresen; Thomas J Corydon; Sandro Ghisla; Nasser Abd-El Razik; Al-Walid A Mohsen; Stephen D Cederbaum; Diane S Roe; Charles R Roe; Nicolas J Lench; Jerry Vockley Journal: Mol Genet Metab Date: 2002 Sep-Oct Impact factor: 4.797
Authors: Manuel Schiff; Birgit Haberberger; Chuanwu Xia; Al-Walid Mohsen; Eric S Goetzman; Yudong Wang; Radha Uppala; Yuxun Zhang; Anuradha Karunanidhi; Dolly Prabhu; Hana Alharbi; Edward V Prochownik; Tobias Haack; Johannes Häberle; Arnold Munnich; Agnes Rötig; Robert W Taylor; Robert D Nicholls; Jung-Ja Kim; Holger Prokisch; Jerry Vockley Journal: Hum Mol Genet Date: 2015-02-26 Impact factor: 6.150
Authors: B Merinero; P Alcaide; E Martín-Hernández; A Morais; M T García-Silva; P Quijada-Fraile; C Pedrón-Giner; E Dulin; R Yahyaoui; J M Egea; A Belanger-Quintana; J Blasco-Alonso; M L Fernandez Ruano; B Besga; I Ferrer-López; F Leal; M Ugarte; P Ruiz-Sala; B Pérez; C Pérez-Cerdá Journal: JIMD Rep Date: 2017-07-29
Authors: Loren D M Pena; Sandra C van Calcar; Joyanna Hansen; Mathew J Edick; Cate Walsh Vockley; Nancy Leslie; Cynthia Cameron; Al-Walid Mohsen; Susan A Berry; Georgianne L Arnold; Jerry Vockley Journal: Mol Genet Metab Date: 2016-05-13 Impact factor: 4.797