Aims-To determine to what extent the Arg 506 to Gln point mutation in the factor V gene and further genetic factors of thrombophilia aVect the risk of porencephaly in neonates and infants. Methods-The Arg 506 to Gln mutation, factor V, protein C, protein S, antithrombin, antiphospholipid antibodies and lipoprotein (a) (Lp(a)) were retrospectively measured in neonates and children with porencephaly (n=24). Results-Genetic risk factors for thrombophilia were diagnosed in 16 of these 24 patients: heterozygous factor V Leiden (n=3); protein C deficiency type I (n=6); increased Lp (a) (n=3); and protein S type I deficiency (n=1). Three of the 16 infants had two genetic risk factors of thrombophilia: factor V Leiden mutation combined with increased familial Lp (a) was found in two, and factor V Leiden mutation with protein S deficiency type I in one. Conclusions-The findings indicate that deficiencies in the protein C anticoagulant pathway have an important role in the aetiology of congenital porencephaly. (Arch Dis Child Fetal Neonatal Ed 1998;78:F121-F124)

Congenital disorder of glycosylation type Id is an inherited glycosylation disorder based on a defect of the first mannosyltransferase involved in N-glycan biosynthesis inside the endoplasmic reticulum. Only one patient with this disease has been described until now. In this article, a second patient and an affected fetus are described. The patient showed abnormal glycosylation of several plasma proteins as demonstrated by isoelectric focusing and Western blot. Lipid-linked oligosaccharides in the endoplasmic reticulum, reflecting early N-glycan assembly, revealed an accumulation of immature Man 5 GlcNAc 2 -glycans in fibroblasts of the patient. Chorion cells of the affected fetus showed the same characteristic lipid-linked oligosaccharides pattern. However, the fetus had a normal glycosylation of several plasma proteins. Some fetal glycoproteins are known to be derived from the mother, but even glycoproteins that do not cross the placenta were normally glycosylated in the affected fetus. Maternal or placental factors that partially compensate for the glycosylation defect in the fetal stage must be proposed and may be relevant for the therapy of these disorders in the future. Inherited defects that affect the biosynthesis of N-or O-glycans are named congenital disorders of glycosylation (CDG) (1). N-linked glycans are attached to asparagine residues of the protein when the Asn occurs within the consensus sequence Asn-X-Ser/Thr. A precursor glycan (Glc 3 Man 9 GlcNAc 2 ) is first assembled in the endoplasmic reticulum on a lipid (dolichol) anchor via a pyrophosphate linkage (Glc 3 Man 9 GlcNAc 2 -PP-dolichol). The glycan is transferred from the anchor to nascent protein and is processed further in the endoplasmic reticulum and Golgi apparatus. O-glycans are attached to serine or threonine residues of the protein via a GalNAc-␣-Ser/Thr linkage and are elongated one sugar at a time; this process occurs in the endoplasmic reticulum and Golgi apparatus. The biochemical compartmentation of the assembly of N-and O-glycans gave rise to the classification of CDG into two subgroups, type I affecting the assembly of the precursor N-glycans on the lipid anchor in the endoplasmic reticulum and type II affecting the processing of the N-glycan after transfer to the protein (2). In recent years, 17 different CDG were characterized, and recently disorders of N-or O-glycosylation that are not yet part of the CDG nomenclature were described (3-5).In 1995, Stibler et al. (6) described two patients with severe psychomotor retardation and an abnormal isoelectric focusing (IEF) pattern of transferrin, suspecting a new subtype of CDG. The biochemical and molecular defect of one patient could subsequently be elucidated by Körner et al. (7), who found a defect in the assembly of lipid-linked oligosaccharides (LLO) in the endoplasmic reticulum of the patient with an accumulation of Man 5 GlcNAc 2 -PP-dolichol. A missense mutation in the human ALG3 gene (8) (synonym: NOT56L, neighbor of tumorous imaginal discs-like protein) coding for doli...

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ABSTRACT. Purpose. Elevated lipoprotein (a) [LP (a)] concentrations are independent risk factors of coronary heart disease or stroke in young adults. To clarify its role in childhood thromboembolism, Lp (a) was measured in 72 children with thromboembolism.Methods. In addition to Lp (a), defects of the protein C anticoagulant system, antithrombin, and antiphospholipid antibodies were investigated in children with arterial (n ‫؍‬ 36) or venous (n ‫؍‬ 36) thrombosis.Results. Enhanced Lp (a) >50 mg/dL was diagnosed in 8 out of 36 children with arterial and 5 out of 36 patients with venous thrombosis. Of the 72 children, 25 showed the factor V Leiden mutation, 10 showed protein C deficiency, 2 showed antithrombin deficiency, and 4 showed primary antiphospholipid syndrome. Three children with increased Lp (a) were heterozygous for the factor V Leiden mutation, and 1 girl showed additional protein C deficiency.Conclusions. Lipoprotein (a) [Lp (a)] is a cholesterol-rich plasma lipoprotein with a lipid composition similar to that of low-density lipoproteins (LDL). The protein composition is different from that of LDL, consisting of two major proteins, apolipoprotein (apo) B and apo (a). 1,2Lp (a) levels vary from person to person but are genetically determined as a dominant trait, minimally affected by race, age, and sex.3,4 Numerous groups agree in their findings that individuals with increased concentrations of Lp (a) have a higher risk of premature coronary heart disease, 5-7 unrelated to the remaining lipoproteins. In addition, the risk of stroke 3,8 -12 as well as for restenosis after coronary artery bypass surgery 13,14 correlates highly with increased Lp (a) concentrations. Little is known, however, about the relation between increased Lp (a) concentrations and childhood thrombosis at various sites. We used a commercially available enzyme-linked immunosorbent assay to measure Lp (a) in a population of children with arterial or venous thrombosis. METHODSSeventy-two infants and children aged from birth to 18 years consecutively recruited between 1992 and 1996 and primarily treated for arterial (n ϭ 36) or venous (n ϭ 36) thrombosis were enrolled in this study. In the majority of cases arterial thrombosis occurred in the central nervous system. Sixteen of 36 infants developed embolic stroke or multiple thrombosis in the neonatal period (attributable to the uncertainty in differentiating between embolic and local stroke in the majority of cases investigated, all children with initial symptoms of stroke were categorized in the arterial group). In addition, 11 children Ͼ1 year of age suffered an ischemic embolic, local, or lacunar stroke. Left intracardial thrombus formation was diagnosed in 4 of 36 patients, the femoral artery was occluded in two children and aortic thrombosis was found in two infants. Venous thromboses were found in the femoral vein (n ϭ 10), renal veins (n ϭ 8), superior caval vein (n ϭ 6), central nervous system (n ϭ 7), and portal vein (n ϭ 5), respectively. In the majority of cases, underlying di...

Summary:Purpose: West syndrome (WS) is still one of the most difficult to treat epilepsies in infancy. Sulthiame (STM), which is commonly used in some countries in the treatment of benign focal epilepsies in childhood, has been suggested to be effective in WS too. This prospective, randomized placebo-controlled study was designed to prove or refute this hypothesis.Methods: Thirty-seven infants aged between 3.5 and 15 months with newly diagnosed WS received baseline therapy with pyridoxine (PDX). The children were randomized in a doubleblind fashion to STM (n = 20) or placebo (n = 17), starting at day 4 at a moderate dose of 5 mg/kg body weight. Without complete cessation of infantile spasms (ISs) and resolution of hypsarrhythmia as the definition criteria of a response, the dose was doubled at day 7. The final examination was undertaken at the end of day 9.Results: Based on the intention to treat, six (30%) of 20 patients responded to STM (p < 0.025), as did six (35%) of 17 infants fulfilling the study criteria (p < 0.01). Patients with tuberous sclerosis did not respond to STM (n = 3) No patient responded to placebo. One patient in the verum group was withdrawn because of reversible somnolence.Conclusions: As no child in the placebo group responded to the baseline PDX therapy, nor did any child in the STM group during the first 3 days of baseline therapy, PDX does not seem to be effective in WS. STM has a positive effect in the primary therapy of WS, comparable to that of vigabatrin.