Neuromuscular diseases in childhood, adolescence and adulthood are rare or very rare diseases and for many of them the prevalence and incidence are unknown. Causal therapies are currently used for ...individual disease entities only. Nevertheless, new genetic methods, a better understanding of the pathophysiology and multidisciplinary treatment concepts help to improve patient life expectancy and quality of life. As a result, more and more patients with an early disease onset reach adulthood and further care in adult medicine is necessary. This imposes new challenges particularly on neurology and the requirements for interdisciplinary cooperation in adult medicine are increased.
How can transition be made meaningful? Where do structural and content problems stand out?
Using the example of Duchenne muscular dystrophy, the content and structural requirements for transition are presented and important aspects and possible problems are pointed out.
The transition process is complex and requires time and personnel resources. If carried out sensibly, it can lead to a better and more efficient care of patients in the long term and thus can also become economically more effective.
Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene ...involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
As the most frequent genetic muscle disease worldwide, Duchenne Muscular Dystrophy affects ∼1:5 000 male births. Caused by a defective DMD gene, the dystrophin protein expression is severely hampered ...and the protein is only partially functional or completely dysfunctional. The constant breakdown of fibres leads to focal necrosis, myophagocytosis and a disease-stage dependent influx of inflammatory cells into the muscle tissue. A further hallmark of the disease is the development of endomysial fibrosis, whereby the amount of fibrosis directly correlates with an adverse outcome and early loss of ambulation. The molecular pathomechanisms underlying development and nature of fibrosis in DMD are not well understood. To study the link between inflammation and fibrosis we analysed macrophage and T cell immunology with regard to development of fibrosis at different time points and identified target molecules involved in this process. We have analysed muscle biopsies derived from DMD patients obtained at different time-points after onset of disease and studied the immune response at protein and mRNA level. Especially the polarisation of macrophages into pro-inflammatory, classically activated M1 phenotype and their switch to an alternatively activated (M2-‘repair phenotype’ during disease progression was investigated. We show a direct link between aaMph’s and fibrogenesis linked to a certain time frame in DMD. An automated whole slide image based quantification of fibrosis showed an increase of fibrosis over time, while the number of macrophages decreased. Polarisation of macrophages showed CD206 positivity. Comparison to patients suffering from Becker muscular dystrophy and female carriers of the defective DMD gene showed less development of fibrosis, and macrophages were only scant. Hopefully the results of this study may add to the development of a time-dependent immune intervention therapy, which can be ideally supplemental to other e.g. gene-therapeutic approaches.
Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, ...hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.
•Female carriers morphologically show increased endo- and perimysial fibrosis.•Increased gene expression of molecules associated with fibrosis is prevalent.•CD206+TGFß+ and CD206+STAT6+ macrophages ...are likely associated with fibrosis.
Female carriers of DMD gene mutations may be symptomatic and show variable skeletal as well as cardiac muscle symptoms. Skeletal muscle can exhibit morphological alterations. However, inflammatory, degenerative and fibrotic changes as seen in Duchenne boys have not been specifically analysed yet, so we addressed the question whether skeletal muscle of female carriers show such alterations. Thirteen carriers with an age range of 3 to 50 years were studied retrospectively. Five out of 13 women had clinically affected relatives. Clinically, most women showed mild muscle weakness, while the CK levels were increased in nine of them. Histomorphological analyses highlighted the typical mosaic pattern of dystrophin-positive and -negative fibres. Regenerating fibres were diffusely scattered and focally pronounced, while endo- and perimysial fibrosis was a variable but constant feature. Infiltration of CD206+TGFß+ macrophages and scattered T cells was noted in the endomysium. TGFb and CCL18, were significantly increased. However, gene expression of markers involved in Th1/Th2 immunity did not reach statistical significance compared to non-diseased controls. In summary, skeletal muscle of clinically manifest female DMD gene mutation carriers shows mild fibrosis and increased regeneration associated with endomysial CD206+TGFβ+ and STAT6+ macrophages, which are most likely involved in fibrotic remodelling.
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and ...high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2·4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.
The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. ...Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
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