Gonosomale Mosaike

With an incidence of approximately 0.2?% in newborns gonosomal chromosome aberrations are of major relevance for clinical genetics. They frequently occur as numerical and/or structural gonosomal mosaicism. The correlation between genotype and phenotype is poor most probably due to different levels of mosaicism in different tissues and they represent a great challenge especially in prenatal diagnostics, requiring genetic counseling by an experienced clinical geneticist. Postnatally, gonosomal mosaicism in females often leads to the clinical symptoms of Turner’s syndrome (especially short stature and infertility) with an potentially increased risk for gonadoblastoma if an XY cell line is present. In males with Klinefelter’s syndrome mosaicism is also frequent (up to 20?%). Mosaicism in 47,XYY and 47,XXX karyotypes is rarely reported perhaps due to the innocuous phenotype seldom being an indication for chromosome analysis.     

Genetische Mosaike in der M 2 bei Oenothera hookeri nach Behandlung mit Meterwellen

Zusammenfassung In der M₂ nach mutagener Behandlung von Pollen und Pflanzen von Oenothera hookeri traten morphologische Chimären auf, die sich als genetische Mosaike erwiesen. Es handelt sich um Abweichungen von Blattform und Blattfarbe. Die abweichenden Sektoren der Pflanzen erwiesen sich durch die Spaltung in der Nachkommenschaft als heterozygot für eine Mutation. Die Mutanten werden beschrieben. Die Mosaikpflanzen lassen Rückschlüsse zu auf die Wachsturnsordnung im Vegetationskegel und bei der Blattbildung. Das verspätete Auftreten der Mutationen wird interpretiert als eine durch die mutagene Behandlung ausgelöste genetische Labilität, die in der M₃ abgeklungen ist.

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Genetic mosaics in the second generation of Oenothera hookeri after treatment with radiowaves

Summary Morphological mosaic plants were observed in the second generation after a mutagenic treatment of pollen and plants of Oenothera hookeri. The abnormal parts showed differences in colour or form of the leaves. The progeny of the normal parts were normal, the abnormal sectors gave rise to several mutants. This proved the plants to be genetic mosaics. The mutants are described. The mosaics lead to conclusions about the growth in the apex and the leaf primordium. The delay in the occurrence of the mutations is interpreted as a genetic lability after the mutagenic treatment.

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Angenommen durch W. Seyffert     

Uniparentale Disomien und Mosaike

Of the various mechanisms of formation of uniparental disomy (UPD) discussed in the literature, the mechanism of trisomy rescue is mostly prone to mosaicism from a trisomy cell line and from a disomy 46, XN uniparental cell line. Therefore, low level or undetected mosaicism has been assumed for a significant number of UPD cases. The clinical consequences of trisomy/UPD mosaicism probably depend on the chromosome involved and the proportional content in individual tissues. As the trisomy cell line of some mosaics might have a disadvantage in biological selection it might not be detected in routine lymphocyte investigations. For evaluation of the clinical relevance in the case of an imprinted chromosome the associated imprinting disorder must also be considered. In a postnatal setting analysis of UPD is indicated in the case of clinical, cytogenetic and molecular data. In the prenatal setting genetic counseling of the parents should be offered prior to any laboratory testing. In total, the impact of mosaicism associated with UPD has to consider the affected chromosome, the associated phenotype, the mechanism of formation and the laboratory method used.     

Genetik der monogenen isolierten Alopezien

The monogenic inherited isolated alopecias comprise a group of clinically and genetically heterogeneous forms of hairlessness or hair loss. Clinical classification of the isolated alopecias is based on the onset of the disorder, the regions affected, and the structure of the hair shaft. Men and women are equally affected, and the mode of inheritance is autosomal dominant or autosomal recessive. Since the identification of the keratin gene KRT86 as a cause of the so-called monilethrix in 1997, mutations in nine other genes have been identified for various isolated alopecias. These include other keratin genes for monilethrix (KRT81 and KRT83), the hairless gene for atrichia congenita/papular atrichia, the corneodesmosin gene for the autosomal dominant form of hypotrichosis simplex, and the genes desmoglein 4, lipase H, and the G-protein-coupled receptor P2RY5 (LPAR6) for the autosomal recessive forms of hypotrichosis. Molecular genetic and pathophysiological studies of these rare disorders of hair development have contributed significantly to our understanding of the basic mechanisms of hair loss as well as the physiological mechanisms of hair growth.     

Mosaike in der Tumorzytogenetik

By definition a tumor disease represents a mosaicism with respect to the entire organism but in addition most tumors also show mosaicism within themselves. This status of mosaicism is usually called intratumoral heterogeneity and is an essential factor which is of relevance for diagnostic as well as for therapeutic strategies. To be able to analyze the genetic changes of a tumor it has to be ensured that a sufficient number of tumor cells is analyzed and not only normal tissue. This is achieved in the diagnostic work-up of the different neoplasias with various approaches depending on the diagnostic method used and the type of neoplasia. Methods are used which either enrich the malignant cells stimulating them to targeted proliferation or the method is carried out with sufficient sensitivity to also detect small clones.     

Mosaike im Gehirn des Menschen

Recently, the human brain has been found to exhibit high levels of somatic mosaicism. On the one hand this has been shown to be age associated, on the other hand mosaicism in the brain was shown to be a mechanism for neurologic and psychiatric disorders (i. e. Alzheimer’s disease and schizophrenia). Thus, a possibility to use this knowledge for the preclinical diagnosis was proposed. Since correlations between patterns of somatic mosaicism in mitotic cells and in post-mitotic neural cells have been described, one can suggest molecular cytogenetic analysis of somatic genome variations in biopsies to have potential diagnostic importance. Finally, detecting alterations to molecular pathways protecting cells from genome or chromosome instability seems to be another promising way for future diagnostic applications in brain diseases.     

Die blutgruppenassoziierten Elektrophoresetypen der alkalischen Serumphosphatase bei Gesunden und bei Patienten mit gastrointestinalen Erkrankungen

Zusammenfassung Mit Hilfe der Stärkegelelektrophorese wurden die phänotypischen Variationen der alkalischen Serumphosphatase bei 746 Gesunden, 62 Patienten mit Ulcus duodeni, 95 Patienten mit Ulcus ventriculi und 65 Patienten mit Magencarcinom untersucht. Die Beziehungen der quantitativen Variationen der langsamer wandernden B-Komponente zum ABO-Blutgruppensystem, zum Lewis-Blutgruppensystem, zum ABH-Ausscheidersystem und ihre Abhängigkeit von der Nahrungszufuhr werden bestätigt.Bei der Untersuchung von 637 nicht nüchternen Gesunden wurde eine positive Korrelation der B-Bande zu den Blutgruppen O, B und Le(a-/b+) und den Ausscheidern von ABH-Substanzen gefunden. Eine negative Korrelation der B-Bande fand sich zu den Blutgruppen A₁, Le(a+/b-) und den Nichtausscheidern von ABH-Substanzen.Bei einem Vergleichskollektiv von 109 nüchternen Gesunden wurde im Prinzip wieder die gleiche Korrelation gefunden. Die Häufigkeit und auch die Intensität der B-Bande war jedoch insgesamt geringer als bei den nicht nüchternen Gesunden.Nach Nahrungsaufnahme kommt es zu einem Anstieg der Intensität der B-Komponente der alkalischen Phosphatase im Serum, wie in einem Diätversuch bei drei Personen gezeigt werden konnte.Bei Patienten mit Ulcus duodeni, Ulcus ventriculi und Carcinoma ventriculi war sowohl die Häufigkeit als auch die Intensität der B-Bande geringer als bei Gesunden. Diese Abweichung wird auf eine Änderung der Ernährungsweise oder eine Störung im Bereich des Gastrointestinaltraktes zurückgeführt. Für einen Zusammenhang zwischen der B-Komponente der alkalischen Serumphosphatase und der bekannten ABO-Blutgruppenassoziation der drei untersuchten gastrointestinalen Erkrankungen ergab sich kein eindeutiger Hinweis.

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The alkaline serum phosphatase has been studied by starch gel electrophoresis in 746 healthy individuals, 62 patients with duodenal ulcer, 95 patients with stomach ulcer, and 65 patients with stomach cancer (Fig. 1, Table 1). The previously reported quantitative variations of the B-component of alkaline phosphatase, which is presumably identical with the intestinal component, has been confirmed. The variations of the B-component are associated with the ABO blood group system, the Lewis blood group system, and the ABH secretor status; they are also influenced by diet.In a sample of 637 healthy, nonfasting persons the B-component was positively correlated to the O, B and Le(a-/b+) blood groups and to ABH secretion. The B-component was negatively associated with the A₁ and Le(a+/b-) blood groups and the ABH non-secretor status (Table 2 and 3).In a sample of 109 fasting healthy individuals the B-component was less frequent and also less intense if present. Nevertheless, the same correlations to the ABO and Lewis blood groups and the ABH secretor status are found as in the non-fasting control (Table 5 and 6).In three persons the increase of the B-component of alkaline phosphatase in serum was followed after intake of a fatty meal (Table 7, Fig. 2 and 3).In patients with duodenal ulcer, stomach ulcer and stomach cancer the B-component is less frequent and less intense than in the control group of fasting healthy individuals. This deviation is related to differences in the diet or to disturbances of the gastrointestinal functions in these patients. There was no clear indication of a connection between the B-component of alkaline phosphatase and the ABO blood groups association with these gastrointestinal diseases (Table 8, 9, and 10).

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft, Bad Godesberg.     

Chromosomale Mosaike in der klinischen Zytogenetik

In contrast to molecular genetics, in cytogenetic analyses single cells are analyzed individually. This affords an opportunity to detect cells with chromosomal mosaicism. This article provides an overview on problems arising in the detection and interpretation of chromosomal mosaicism in cytogenetic diagnostics. A particular challenge in the diagnostics is to distinguish between clinically relevant genuine mosaicism on the one hand and cultured artifacts, pseudomosaics, age effects, maternal contamination and chimerism on the other. The probability of overlooking mosaicism in cytogenetic routine diagnostics is very high, as on average only 15 of the 10¹² cells in the body are examined and usually only a single tissue is analyzed. However, some cytogenetic mosaics are typical for certain syndromes, such as Pallister-Killian syndrome, cat eye syndrome or Ullrich-Turner syndrome and others are characteristic for certain disorders including some hematological malignancies.     

Mitochondriale Erkrankungen

As outlined in other articles of this issue mitochondrial medicine is a complex area in clinical genetics. Due to the wide variability of clinical presentation in both pediatric and adult patients there are frequent constellations of symptoms that may suggest an underlying mitochondrial disorder. This is a challenge in genetic counseling because basically all patterns of inheritance have to be taken into account??including maternal transmission??but a straightforward genetic testing to confirm or exclude the suggested diagnosis is hampered by the immense genetic heterogeneity of the mitochondrial disease spectrum. This article focuses on a diagnostic strategy and specific aspects of genetic counseling in mitochondrial disorders.     

Mitochondriale Erkrankungen

Mitochondrial disorders are clinically, biochemically, and genetically heterogeneous and surprisingly diverse. The clinical spectrum ranges from severe multisystem disorders of early infancy to monosymptomatic mild disorders in late adulthood. Causative for mitochondrial dysfunction are mutations in nuclear genes or/and the proper mitochondrial genome, the mitochondrial DNA. The last years have seen quite remarkable progress in identification of the molecular basis of mitochondrial diseases, which helps in the often difficult process of diagnosis. However, the clinical variability and complexity continue to increase and remain unexplained in many cases.     

Therapie mitochondrialer Erkrankungen

Although there have been major advances in understanding the pathogenesis of mitochondrial disorders, current treatment is largely supportive and there is still no cure. A variety of pharmacological agents, vitamins and cofactors, dietary modifications and interventions are under investigation, including attempts to bypass blocks in the respiratory chain, antioxidative effects, supplementation of deficiencies of specific compounds or the removal of noxious metabolites. There is currently no clear evidence supporting the use of any of these interventions. However, replacement of deficient metabolites or elimination of toxic molecules might be beneficial in specific disorders. Moreover, current data suggest that idebenone might be useful in Leber??s hereditary optic neuropathy (LHON). Only few randomized controlled trials had been conducted to date, and future controlled trials are strongly needed to establish the role of therapeutic approaches in homogeneous study populations. Gene therapy is a challenge, but promising experimental approaches are being pursued.     

Neurodegenerative Erkrankungen des Kindesalters

The understanding of neurodegenerative diseases of childhood has been changing rapidly in recent times: not only is the number of different diseases and underlying genetic defects steadily increasing, approaches to diagnosis and treatment have also developed because of recent technological and therapeutic advances relating to this group of disorders. New gene defects have been identified that provide a basis for understanding the molecular mechanisms underlying this group of diseases, and for the development of targeted therapies. This review focuses predominantly on one of the most common groups of diseases leading to degeneration of the central nervous system, neuronal ceroid lipofuscinosis (NCL). The number of NCL-causing genes and knowledge about genotype–phenotype correlations has been growing over the past few years and the first therapies have been developed. Hence, this group of diseases represents the rapid scientific development in the field of rare neurodegenerative diseases in childhood very well.     

Die Genetik atopischer Erkrankungen

Allergic disorders (atopic dermatitis, asthma, hay fever) are common chronic inflammatory diseases of the skin and airways that are often associated with allergies (formation of specific IgE antibodies) to environmental allergens. They are complex genetic diseases, so that both genetic and environmental factors are involved in their causation. Most of the research effort devoted to the search for genes that might be responsible has so far focused on the mechanisms behind the immune response. More recent work on gene identification, however, documents the decisive importance of epithelial barrier defects in the pathogenesis of AD and allergic airways disease. These findings represent an important milestone in unraveling the genetic mechanisms underlying these complex diseases and allow new insight into the molecular mechanisms that lead illnesses to develop. In addition, they might point the way to novel preventive and therapeutic strategies for atopic disorders.     

Mitochondriale Erkrankungen im Erwachsenenalter

The most frequent manifestation of mitochondrial disease in adults is chronic progressive external ophthalmoplegia (CPEO) that can present with variable multisystemic involvement. Molecular genetically single mtDNA deletions are identified in more than half of the patients associated with mainly sporadic CPEO. There are also autosomal dominant and recessive forms of CPEO due to mutations in nuclear genes that are important for mtDNA replication resulting in multiple mtDNA deletions. Other common multisystemic disorders are MELAS syndrome and MERRF syndrome due to maternally inherited mtDNA point mutations. Leber??s hereditary optic neuropathy is a frequent mitochondrial disorder without multisystemic involvement, which is also due to mtDNA point mutations. In addition to classical mitochondrial disorders there are patients with mitochondrial disease showing non-characteristic sometimes monosymptomic phenotypes (e.g. myopathy or epilepsy) that are difficult to recognize.