Myotonic Dystrophy Type 1 or Steinert's disease.

Myotonic Dystrophy Type 1 (DM1) is the most common worldwide autosomal dominant muscular dystrophy due to polynucleotide [CTG]( n ) triplet expansion located on the 3'UTR of chromosome 19q13.3. A toxic gain-of-function of abnormally stored RNA in the nuclei of affected cells is assumed to be responsible for several clinical features of the disease. It plays a basic role in deregulating RNA binding protein levels and in several mRNA splicing processes of several genes, thus leading to the multisystemic features typical of DM1. In DM1, the musculoskeletal apparatus, heart, brain, eye, endocrine, respiratory and gastroenteric systems are involved with variable levels of severity. DM1 onset can be congenital, juvenile, adult or late. DM1 can be diagnosed on the grounds of clinical presentation (distal muscular atrophy and weakness, grip and percussion myotonia, ptosis, hatchet face, slurred speech, rhinolalia), EMG myotonic pattern, EKG (such as AV-blocks) or routine blood test abnormalities (such as increased CK values or hypogamma-globulinemia) and history of cataract. Its confirmation can come by DNA analysis. At present, only symptomatic therapy is possible and is addressed at correcting hormonal and glycemic balance, removing cataract, preventing respiratory failure and, above all, major cardiac disturbances. Efficacious therapies targeted at the pathogenic mechanism of DM1 are not yet available, while studies that seek to block toxic RNA intranuclear storage with specific molecules are still ongoing.

[Hans Steinert: 100 years of myotonic dystrophy]. / Hans Steinert: Zum 100. Jahrestag der Erstbeschreibung der myotonen Dystrophie.

This study includes for the first time detailed biographical facts about Hans Steinert (1875-1911), who in 1909 first described myotonic dystrophy (Steinert's disease) as an independent syndrome. Of utmost importance are Steinert's years at the medical hospital of Leipzig University, where in 1901 he became the assistant of his mentor Heinrich Curschmann (1846-1910). Shortly after being appointed Extraordinary Professor there, Steinert died at the age of 36. As early as 1912 Hans Curschmann (1875-1950) fully recognized the importance of Steinert's pioneering work. Referring to key passages in his 1909 investigation, this study demonstrates how, on the basis of precise observation, subtle neurologic examination, and great clinical experience, Steinert succeeded in identifying a syndrome that to this day plays an important role in neurologic practice.

Distrofia miotónica de Steinert en un retrato del Museo del Padro / Steinert's myotonic dystrophy in a portrait in the Prado Museum

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[Gustave Roussy's (1874-1948) contribution to neuroendocrinology]. / Gustave Roussy (1874-1948): sa contribution à la neuroendocrinologie.

Gustave Roussy (1874-1948) is remembered as a distinguished French neuropathologist and a leader in the field of oncology. However, his original contribution to the study of hypothalamic functions and neuroendocrinology remains ignored. Among Roussy's discoveries is the first experimental demonstration of the hypothalamic origin of diabetes insipidus and adiposo-genital dystrophy. Also, based on his own histological work, he pioneered the concept of neurosecretion, which was termed by him "neuricrinie".

RNA pathogenesis of the myotonic dystrophies.

Myotonic dystrophy (dystrophia myotonica, DM) is the most common form of muscular dystrophy in adults. The presence of two genetic forms of this complex multisystemic disease (DM1 and DM2) was unrecognized until the genetic cause of DM1 was identified in 1992. The fact that the DM1 mutation is an untranslated CTG expansion led to extended controversy about the molecular pathophysiology of this disease. When the DM2 mutation was identified in 2001 as being a similarly untranslated CCTG expansion, the molecular and clinical parallels between DM1 and DM2 substantiated the role of a novel mechanism in generating the unusual constellation of clinical features seen in these diseases: the repeat expansions expressed at the RNA level alter RNA processing, at least in part by interfering with alternative splicing of other genes. For example, in both DM1 and DM2, altered splicing of chloride channel and insulin receptor transcripts leads to myotonia and insulin resistance, respectively. Although other mechanisms may underlie the differences between DM1 and DM2, the pathogenic effects of the RNA mechanism are now clear, which will facilitate development of appropriate treatments.

Myotonic dystrophy in Ancient Egypt.

Amenhotep IV, better known as Akhenaton, the heretical pharaoh, was a king of the New Kingdom of Ancient Egypt. Statues and reliefs of him show an unhealthy man whose body has abnormal features. By studying the pictures of Akhenaton (the mummy has not yet been found), we conclude that he may have been affected by myotonic dystrophy (MD). Moreover, the available data on his family suggest that MD may have caused the end of the royal bloodline of the Eighteenth Dynasty.

Anticipation in myotonic dystrophy: new light on an old problem.

The concept of anticipation, the occurrence of a genetic disorder at progressively earlier ages in successive generations, has been debated from the early years of this century, with myotonic dystrophy as the most striking example. Throughout most of this period there has been controversy as to whether the phenomenon resulted from observational and ascertainment biases or reflected a more fundamental mechanism. The recent discovery of inherited unstable DNA sequences, first in fragile-X mental retardation and now in myotonic dystrophy, not only confirms that anticipation indeed has a true biological basis but provides a specific molecular mechanism for it; this discovery can explain many of the puzzling anomalies in the inheritance of myotonic dystrophy and may prove relevant to comparable problems in other genetic disorders.