Interstitial deletion of 1p22.2p31.1 and medium‐chain acyl‐CoA dehydrogenase deficiency in a patient with global developmental delay

Abstract

We report on a 6-year-old girl who presented at 6 months of age with seizures, delayed psychomotor development and mild facial dysmorphism. A small muscular ventricular septal defect was documented on echocardiogram and brain MRI showed a frontal brain anomaly. Urine organic acid analysis revealed dicarboxylic aciduria, and plasma acylcarnitine analysis showed marked elevation of octanoyl (C8) and decanoyl (C10) carnitines with C8:C10 ratio of 9:1. These results were indicative of medium chain acyl-CoA dehydrogenase deficiency. ACADM gene sequencing showed an apparent homozygous c.166G > C (Ala31Pro) missense mutation in exon 3; however, only the mother was found to be a carrier of this novel missense mutation. This finding along with non-regressive developmental delay prompted further karyotype and genomic investigations. An interstitial deletion of chromosome 1 was detected by repeat G-banding: 46,XX,del(1)(p22.2p31.1). Parental karyotypes were normal. The deletion was characterized by array CGH analysis using a 1 Mb BAC/PAC array platform. Clones deleted extended from RP11-88B10 (1p31.1) to RP5-1007M22 (1p22.2), a 15.5 Mb deletion which includes the ACADM locus. Clinical review of 6/7 cases of interstitial deletions with breakpoints of 1p22 and 1p31/32, including the patient in this report, indicate a variable phenotype. Thus, although G-band breakpoints are similar, common breakpoints for these alterations are unlikely. This is the first report of a patient with fatty acid oxidation defect caused by a mutation in combination with an interstitial chromosomal deletion.

Monozygotic dichorionic diamniotic twins with large interstitial deletion of chromosome 1p

“…There have been ten published cases of de novo interstitial deletions of the short arm of chromosome 1 involving seven girls and three boys . A comparison of the manifestations of our two patients with previously reported cases is included in the Appendix .…”

“…Terminal deletions of the short arm are more common though a few cases of interstitial deletions have been reported in the literature . Most of the published reports were identified in older children or adults in the setting of developmental delay and minor structural anomalies . In this paper, we present monozygotic twins with a large interstitial deletion of chromosome 1p with more severe phenotypic features than previously described.…”

“…That infant was discharged home with palliative care and survived 44 days. Maegawa et al, published the first report on a child with a fatty acid oxidation defect later also diagnosed with an interstitial deletion of chromosome 1p, which included the medium‐chain Acyl‐CoA dehydrogenase gene locus …”

“…[2][3][4][5] Most of the published reports were identified in older children or adults in the setting of developmental delay and minor structural anomalies. 2,3,[6][7][8][9][10] In this paper, we present monozygotic twins with a large interstitial deletion of chromosome 1p with more severe phenotypic features than previously described.…”

cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain

“…Based on the present observations that cDA at 1 mM significantly decreases state 3 respiration, causes a rapid drop in oxygen consumption in state 4 respiration with succinate and markedly inhibits aconitase activity, as well as CO 2 production and respiratory chain complexes activities (Reis de Assis et al 2004), it is feasible that cDA also behaves as a metabolic inhibitor, therefore compromising mitochondrial energy homeostasis. Therefore, it is tempting to speculate that our present and previous findings indicate that impairment of brain bioenergetics may be involved in the neuropathology of MCAD-deficient patients (Egidio et al 1989;Maegawa et al 2008).…”