Klinik und Genetik des familiären Darmkrebses

Familial clustering of colorectal cancer (CRC) and early disease onset are indicators of an inherited tumour syndrome. Monogenic dispositions account for 3–5% of all CRC cases and are subdivided into hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome) and various gastrointestinal polyposis syndromes. Many of these syndromes are characterised by a broad spectrum of extracolonic tumours. Early detection and accurate classification are essential in providing effective surveillance and treatment. Initial diagnosis is based on endoscopic and histological findings as well as on the presence of extracolonic manifestations and family history. Molecular genetic examination is important for the differential diagnosis, evaluation of recurrence risk, and predictive testing of asymptomatic at risk individuals; it is performed according to largely standardised algorithms. Diagnostic difficulties are common among the hamartomatous polyposes due to their broad phenotypic overlap and frequent uncertainties in histological evaluation, as well as among patients with few adenomas. Risk-adapted surveillance guidelines have been established for HNPCC and for the more frequently observed polyposis syndromes. Beyond established tumour syndromes, familial clustering of CRC (which is often of late onset) or the occurrence of few adenomas is likely to be based upon a multifactorial (complex) etiology. Although identification of the underlying genetic risk factors and biological pathways is still in the early stages, rapid progress is being made due to methodical developments such as genome-wide association studies and CNV analysis.     

Morphogenesis and fate of the residual body in human spermiogenesis

Summary In the human testis the formation of the residual body of the spermatid and its morphological changes during and after spermiation were studied by means of electron microscopy. The caudal cytoplasmic mass of the late spermatid contains a Golgi complex, mitochondria, annulate lamellae, a chromatoid body, flower-like structures, ribosomes, a few large vacuoles, myelin-like membrane profiles and sporadic lipid droplets. When, by detachment of the caudal cytoplasm from the free spermatozoon, the residual body is formed, the chromatoid body has disappeared; the mitochondria are clustered peripherally; the ribosomes appear as a single complex in contact with a large vacuole containing granular material; in place of the Golgi complex aggregations of vesicles are present. The lipid droplets remain unchanged. The residual bodies or their fragments are either extruded via the seminiferous tubular lumen into the excurrent ducts or they are engulfed by Sertoli cells where in the supranuclear region the successive steps of decomposition can be observed. The participation of the various constituents in the disintegration of the residual body is discussed. In contrast to other mammalian species, in man the sporadic lipid droplets seem to be of minor importance in the fate of the residual body.     

Vitellin and vitellogenin in the soldier bug, Podisus maculiventris: identification with monoclonal antibodies and reproductive response to diet

A 171,000 M(r )polypeptide of Podisus maculiventris (Say) (Heteroptera: Pentatomidae) that constituted 16% of the protein in eggs also constituted up to 25% of the protein in hemolymph of fed females. It was identified as the major or sole apoprotein of vitellogenin. Eggs contained major polypeptides of 171, 106, and 51 kDa. The hemolymph polypeptide was identified with a polypeptide (vitellin) in egg extracts by comparing molecular weights, specificity of occurrence in fed females, and immunological reactivities. Females, starved for 5 days after eclosion to assure complete previtellogenic development, produced vitellogenin within a day after feeding on larval Galleria mellonella, and within 4 days after feeding on an artificial diet. Appearance of vitellogenin preceded ovarian growth by 2-3 days. Two monoclonal antibodies raised against egg proteins of P. maculiventris were selected for their strong reaction against egg extract and female hemolymph and null reaction against male hemolymph. Only one 170-kDa band in egg and hemolymph reacted with the antibodies on denaturing Western blots. These monoclonal antibodies are being used to develop an enzyme-linked immunosorbent assay (ELISA) to quantitate reproductive response of females to diets of differing quality.     

Verlust des Sensibilitäts- und Schmerzempfindens

The sensory nervous system detects pressure, touch, stretching, heat, and cold and translates these stimuli into action potentials. To protect the body from tissue damage acute pain is felt when a stimulus gains a critical intensity. The combination of impaired nociception and autonomic dysfunction is the hallmark of hereditary sensory and autonomic neuropathies (HSAN). Sensory loss in HSAN patients results in ulcerations of hands and feet and may necessitate amputations. Congenital onset of HSAN leads to self-mutilating behavior in affected children. Degeneration of motor neurons can complicate the disease. HSAN is divided into five groups according to clinical symptoms. So far, nine genes have been identified as causative for the disorder. The present article reviews the clinical, genetic, and pathophysiological aspects of HSAN.     

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.     

Mosaike bei monogenen Erkrankungen

Mosaicism is defined as the simultaneous presence of cells with different genotypes that originate from a common zygote. Mutations can either be present in germline or somatic cells. Monogenic disorders apparently caused by a de novo mutation may show a recurrence risk due to germline mosaicism in a parent. Duchenne muscular dystrophy is a well investigated example with a high frequency of germline mosaicism and the estimation for the risk of recurrence is based on theoretical models and empirical data. Recently, somatic mutations have been uncovered in various syndromic disorders, such as Proteus syndrome or hemimegalencephaly and respective mutations often show gain-of-function properties. Genetic testing is mainly based on next generation sequencing technologies but still remains challenging; however, detection of somatic mosaicism is expected to be of increasing relevance in the diagnosis of monogenic disorders. Somatic mosaicism may also play a hitherto underestimated role in common disorders.