Publications (181) View all
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Article: Glykogenose Typ IV (Andersen)
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ABSTRACT: Vorgestellt wird der Fall eines Neugeborenen mit Glykogenose TypIV (Andersen), das kurz nach der Geburt verstarb. Die Sicherung der Diagnose erfolgte nach Sektion zunächst lichtmikroskopisch und histochemisch, später auch ultrastrukturell. Aus einer Fibroblastenkultur konnte DNA isoliert werden. Bei der Sequenzierung des für die Erkrankung ursächlichen GBE1-Gens („glycogen branching enzyme 1“) zeigten sich 2Mutationen in jeweils heterozygotem Zustand („Compound-Heterozygotie“). Differenzialdiagnostisch müssen Lafora-Körper-Krankheit und die allelische Polyglukosankörperkrankheit abgegrenzt werden. Da es bisher keine effektive Therapie der Glykogenose TypIV gibt, kommt der pränatalen Diagnostik ein hoher Stellenwert zu. Here we report the case of a newborn with glycogenosis type IV (Andersen disease), who died shortly after birth. The diagnosis was established in the first instance by light microscopy and histochemistry, and subsequently ultrastructurally. DNA could be extracted from a fibroblast cell culture by sequencing the causative GBE1 gene (‘glycogen branching enzyme 1’). Two compound heterozygous mutations in the gene were identified. The differential diagnosis should include Lafora disease as well as polyglucosan body disease. Since there is no effective therapy for glycogenosis type IV to date, prenatal diagnosis is mandatory. SchlüsselwörterGlykogenose TypIV-Andersen-„Glycogen branching enzyme“-Genetik-Polyglukosan KeywordsGlycogenosis type IV-Andersen disease-Glycogen branching enzyme-Genetics-PolyglucosanDer Pathologe 04/2012; 31(4):293-296. · 0.67 Impact Factor -
Article: Klinik und Genetik des Joubert-Syndroms
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ABSTRACT: Das Joubert-Syndrom ist ein überwiegend autosomal-rezessiv und sehr selten X-chromosomal erbliches Krankheitsbild, das durch eine muskuläre Hypotonie, ein irreguläres Atmungsmuster, Augenbewegungsstörungen, eine Ataxie, eine Entwicklungsverzögerung und ein „molar tooth sign“ in der Magnetresonanztomographie (MRT) als Ausdruck einer komplexen Klein- und Mittelhirnfehlbildung charakterisiert ist. Zahlreiche weitere klinische Auffälligkeiten können vorliegen, die häufigsten sind eine Nephronophthise, eine Retinopathie, Kolobome und eine Leberfibrose. Aufgrund der klinischen Variabilität und der Überlappung mit anderen Syndromen wurde der Begriff „Joubert syndrome and related disorders“ (JSRD) eingeführt. Bislang sind 10 Gene bekannt, deren Mutationen zu einem Joubert-Syndrom führen können. Die kodierten Proteine spielen alle eine funktionelle Rolle in Zilien. Joubert syndrome generally represents an autosomal recessive and rarely X-linked disorder characterized by hypotonia, an irregular breathing pattern, abnormal eye movements, ataxia, developmental delay and a complex mid-hindbrain malformation causing the molar tooth sign on magnetic resonance imaging (MRI). Many patients have additional features, with nephronophthisis, retinal dystrophy, coloboma and hepatic fibrosis representing the most frequent features. Due to its clinical variability and overlap with other syndromes, the term “Joubert syndrome and related disorders” (JSRD) was proposed. To date 10 genes are known to cause JSRD. The encoded proteins are localized to cilia, linking JSRD to other human ciliopathies. SchlüsselwörterJoubert-Syndrom-„Molar tooth sign“-Ziliopathie-Nephronophthise-Retinopathie KeywordsJoubert syndrome-Molar tooth sign-Ciliopathy-Kidney diseases, cystic-RetinopathyMedizinische Genetik 04/2012; 22(3):345-350. · 0.06 Impact Factor -
Article: Mikrodeletionssyndrom 9q34 – ein charakteristischer Phänotyp
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ABSTRACT: Das Mikrodeletionssyndrom 9q34 ist ein an Bedeutung zunehmendes Krankheitsbild mit einem charakteristischen Phänotyp. Die Patienten zeigen eine Mikrozephalie, angeborene Herzfehler, muskuläre Hypotonie, eine mäßige bis starke mentale Retardierung und gehäuft Krampfanfälle. Zusätzlich haben sie ein für das Krankheitsbild spezifisches Gesicht mit Synophrys, Mittelgesichtshypoplasie, kurzer Nase mit antevertierten Nasenflügeln, betonter Unterlippe und großer vorstehender Zunge. Das Mikrodeletionssyndrom 9q34 kann zytogenetisch durch Subtelomeranalyse mittels Fluoreszenz-in-situ-Hybridisierung (FISH) sowie molekulargenetisch durch eine Subtelomeranalyse mittels MLPA („multiplex ligation-dependent probe amplification“) nachgewiesen werden. Wir berichten über einen Patienten mit charakteristischen klinischen Merkmalen, bei dem durch FISH-Diagnostik (Subtelomer-Screening) und MLPA ein Mikrodeletionssyndrom 9q34 gesichert werden konnte. Cryptic subtelomeric deletion 9q34 is an increasingly important clinical picture with a recognizable phenotype. Patients are characterised by microcephaly, low muscle tone, congenital heart defects, moderate to severe mental retardation and frequent seizures. In addition, these patients have distinctive facial features with synophrys, midfacial hypoplasia, a short nose with anteverted nares, a thick lower lip and a large, protruding tongue. Cryptic subtelomeric deletion 9q34 can be detected by cytogenetic analysis using the fluorescence in situ hybridisation technique (FISH) or by molecular analysis using a specific MLPA (multiplex ligation-dependent probe amplification) kit. In this paper we present a patient with characteristic clinical features of cryptic subtelomeric deletion 9q34, which we were able to confirm by FISH analysis (subtelomere screening) and MLPA.Monatsschrift Kinderheilkunde 04/2012; 155(8):741-746. · 0.27 Impact Factor -
Article: Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies.
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ABSTRACT: Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.Molecular syndromology 12/2011; 2(1):27-34. -
Article: Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.
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ABSTRACT: Noonan and Cardio-facio-cutaneous (CFC) syndromes are characterized by typical dysmorphic features, cardiac defects, short stature, variable ectodermal anomalies, and intellectual disability. Both belong to the Ras/mitogen-activated protein kinase pathway group of disorders and clinical features overlap other related conditions, notably LEOPARD and Costello syndromes. KRAS mutations account for about 2% of reported Noonan and <5% of reported CFC cases. The mutation spectrum includes recurrent missense changes clustering in particular domains of the KRAS protein and conferring gain-of-function. We report three patients from two unrelated families with novel missense KRAS mutations, p.K147E and p.Y71H. Both mutations affect a residue which is highly conserved in KRAS and other RAS isoforms. One of the families includes a mother and son pair who represent the first report of a vertically transmitted KRAS mutation. In addition, the mother and son pair had peripheral neuropathy, complicated by Charcot arthropathy in the mother. An unusual phenotypic effect of the specific KRAS mutation or a coincidence of two independent disorders may be considered. KRAS mutation-associated phenotypes appear to be subject to considerable clinical heterogeneity. All three cases highlight the challenges of clinical assessment in KRAS mutation-positive patients, and the utility of molecular testing as an adjunct to diagnosis.Clinical Genetics 07/2011; 81(6):590-4. · 3.13 Impact Factor
