ABSTRACT
BACKGROUND: Congenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far. CASE: Here, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions. RESULTS: We studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C > T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet. CONCLUSION: Although prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.
Subject(s)
Congenital Disorders of Glycosylation/complications , Congenital Disorders of Glycosylation/diagnosis , Congenital Disorders of Glycosylation/genetics , Diet, Ketogenic , Drug Resistant Epilepsy/diet therapy , Mannosyltransferases/genetics , Central Nervous System Neoplasms/etiology , Craniofacial Abnormalities/etiology , Developmental Disabilities/etiology , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/etiology , Female , Hemangioma/etiology , Humans , Infant , Male , Twins , Exome SequencingABSTRACT
Vascular endothelial growth factor (VEGF) is a potent, physiologically relevant, vasodilator of the human term fetoplacental vasculature of placental lobules from normal pregnancy. There is evidence that VEGF and its receptors are dysregulated in preeclampsia (PE). Here, we used dual perfusion of the human placental lobule to test the hypothesis that the VEGF vasodilatory effect on the fetoplacental circulation is altered in PE and examined how vascular responsiveness relates to circulating levels of free VEGF in fetal sera in this disease. Umbilical cord sera and fetal venous perfusate concentrations of free VEGF from pregnancies complicated with PE were significantly lower compared to the normal group (P<0.05 and P<0.01, respectively). There was elevated in vitro placental release of the sequestrating soluble receptor, sVEGFR-1, into the fetal-side perfusate with PE compared to the normal group (P<0.05). The umbilical sera PlGF-1 level was higher by an order of magnitude in the fetal circulation in PE compared to normal pregnancy (P<0.0001), with the placenta appearing to contribute appreciably to these levels. Placental net contribution to maternal systemic free VEGF levels appeared to be negligible in both groups. sVEGFR-1 levels were elevated in the maternal-side venous perfusate with PE compared to the normal pregnancy (P<0.01). Perfused lobules from PE pregnancy exhibited an enhanced fetoplacental vasodilatory response to exogenous VEGF (P<0.001), with a longer recovery time (P<0.05), compared to the normal control group. Extrapolation of our combined functional and biochemical data suggests that a decrease in the in vivo circulating levels of free VEGF in PE is likely to contribute to compromised fetoplacental vascular patency in this disease.
