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Lange M.,University of Regensburg | Kasper B.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bohring A.,University of Munster | Rutsch F.,Muenster University Childrens Hospital | And 20 more authors.
Orphanet Journal of Rare Diseases

Background: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. Methods: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. Results: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. Conclusions: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males. © 2015 Lange et al. Source

Galletti S.,University of Bologna | Nitschke Y.,Muenster University Childrens Hospital | Malavolti A.M.,University of Bologna | Aquilano G.,University of Bologna | And 3 more authors.
Journal of Inherited Metabolic Disease

Generalized arterial calcification of infancy(GACI) is a rare condition characterized by arterial calcificationwithin the internal elastic lamina associated with intimalproliferation, leading to stenosis of great and medium-sizedvessels. This disease, caused by mutations in multiple exonsof ENPP1, frequently results in death in infancy. Nowadays,the most promising therapeutic compounds for this rare diseaseare bisphosphonates. We describe a case of GACI associatedwith the novel mutation c.653A>T (p.D218V) inENPP1 on both alleles. The male infant was delivered prematurelyand developed heart failure, severe hypertension,and diffuse calcifications of all arterial districts. Hewas treated with etidronate (18 mg/kg/day); however, theclinical condition did not improve, and a resolution of calcificationswas not observed. The infant died within the 6thmonth of life of ischemic heart failure. We concludethat even if the diagnosis of GACI is established early andbisphosphonate treatment is started early, the prognosis canbe very poor. © SSIEM and Springer-Verlag Berlin Heidelberg 2011. Source

Nitschke Y.,Muenster University Childrens Hospital | Weissen-Plenz G.,University of Munster | Terkeltaub R.,University of California at San Diego | Rutsch F.,Muenster University Childrens Hospital
Journal of Cellular and Molecular Medicine

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) generates inorganic pyrophosphate (PP i), a physiologic inhibitor of hydroxyapatite deposition. In a previous study, we found NPP1 expression to be inversely correlated with the degree of atherosclerotic plaque calcification. Moreover, function-impairing mutations of ENPP1, the gene encoding for NPP1, are associated with severe, artery tunica media calcification and myointimal hyperplasia with infantile onset in human beings. NPP1 and PP i have the potential to modulate atherogenesis by regulating arterial smooth muscle cell (SMC) differentiation and function, including increase of pro-atherogenic osteopontin (OPN) expression. Hence, this study tested the hypothesis that NPP1 deficiency modulates both atherogenesis and atherosclerotic intimal plaque calcification. Npp1/ApoE double deficient mice were generated by crossing mice bearing the ttw allele of Enpp1 (that encodes a truncation mutation) with ApoE null mice and fed with high-fat/high-cholesterol atherogenic diet. Atherosclerotic lesion area and calcification were examined at 13, 18, 23 and 28 weeks of age. The aortic SMCs isolated from both ttw/ttw ApoE -/- and ttw/+ ApoE -/- mice demonstrated decreased Opn expression. The 28-week-old ttw/ttw ApoE -/- and ttw/+ ApoE -/- had significantly smaller atherosclerotic lesions compared with wild-type congenic ApoE -/- mice. Only ttw/ttw but not ttw/+ mice developed artery media calcification. Furthermore in ttw/+ mice, there was a tendency towards increased plaque calcification compared to ApoE -/- mice without Npp1 deficiency. We conclude that Npp1 promotes atherosclerosis, potentially mediated by Opn expression in ApoE knockout mice. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source

Buers I.,Muenster University Childrens Hospital | Pennekamp P.,Muenster University Childrens Hospital | Nitschke Y.,Muenster University Childrens Hospital | Lowe C.,Muenster University Childrens Hospital | And 2 more authors.
Journal of Cellular and Molecular Medicine

The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl-CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia. LMBRD1 encodes for LMBD1, a predicted lysosomal cobalamin transport protein. In this study, we determine the physiological function of LMBRD1 during embryogenesis by generating Lmbrd1 deficient mice using the Cre/LoxP system. Complete loss of Lmbrd1 function is accompanied by early embryonic death in mice. Whole mount in situ hybridization studies against bone morphogenetic protein 4 and Nodal show that initial formation of the proximal–distal axis is unaffected in early embryonic stages whereas the initiation of gastrulation is disturbed shown by the expression pattern of even skipped homeotic gene 1 and fibroblast growth factor 8 in Lmbrd1 deficient mice. We conclude that intact function of LMBD1 is essential for the initiation of gastrulation. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Source

Buers I.,Muenster University Childrens Hospital | Nitschke Y.,Muenster University Childrens Hospital | Rutsch F.,Muenster University Childrens Hospital
Cytokine and Growth Factor Reviews

Type I interferonopathies are a relatively new class of inherited autoimmune disorders associated with an inborn elevated interferon response. Activation of cytosolic receptors which recognize viral double stranded RNA including the RIG-I (retinoic acid-inducible gene I) like receptors RIG-I and MDA5 (melanoma differentiation-associated gene 5) has been shown to induce the transcription of type I interferon genes. Within recent years, with the help of next generation sequencing techniques in syndromic families, mutations in the genes encoding for RIG-I and MDA5 have been identified to cause rare diseases including Aicardi-Goutières syndrome, Systemic Lupus Erythematosus in certain individuals as well as classic and atypical Singleton-Merten syndrome. Patients carrying mono-allelic mutations in MDA5 and RIG-I show constitutive activation of the RIG-I receptors and downstream signalling associated with increased type I interferon production. Although differing in the degree of phenotypic expression and severity, the phenotype of these "novel" diseases shows a considerable overlap reflecting their common pathogenetic pathway. © 2016 Elsevier Ltd. Source

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