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New therapies(IEM)   
More than diagnostic procedures, advances in therapy are the most critical aspect for affected patients and their families. Until the mid-20th century, treatment did not exist, destiny would take its course, and genetic counselling about recurrence risks was all that could be offered. Phenylketonuria was then shown by Horst Bickel to be a treatable "genetic" disease in which early diagnosis and dietary treatment prevented mentalretardation. Subsequently, several other inborn errors became manageable in a similar way, i.e., with substratedeprivation strategy-maple syrup urine disease, ureacycle defects, galactosemia, fructosemia, tyrosinemiatype 2, etc. Pharmacological doses of vitamins provedto be useful in dealing with defects of cobalamine and biotin metabolism, distinct forms of homocystinuria,and some others. Avoiding of fasting was recognized as the cornerstone of successful therapy for defects of fatty acid oxidation, ketogenesis and glycogenolysis.The progress in the treatment was initially slow but is beginning to explode as current progress in
understanding the molecular and pathophysiological bases of inborn errors of metabolism funnels into thedevelopment of successful rational therapies: new
treatment protocols, new therapeutic agents (drugs andfoods), improved tissue transplantation, and enzyme replacement by other means.Many inherited metabolic diseases are still not amenable to treatment. Lysosomal storage disorders are particularly hopeless and the outcome is generally determined by the natural course of the illness. About20 years ago, transplantation has become an option for some of them. Bone marrow transplant has partially corrected the defect and positively changed the disease course in some patients with mucopolysaccharidoses
type I (particularly IH) and VI, metachromatic leucodystrophy,Niemann-Pick disease type B, Krabbedisease,and some others. However it failed to prevent
neurological deterioration in mucopolysaccharidoses II,III and IV as well as in Niemann-Pick disease type A. Insome diseases the number of patients who have received transplants is too small to make a reasonable assessment,e.g., in mucopolysaccharidosis type VII. In the future,umbilical-cord blood from unrelated donors may become an attractive alternative to bone marrow from matched
donors as it is more readily available.Liver transplantation has made considerable progress during the last two decades. It was firstrecognized to be life-saving in patients with late-stage Wilson disease, α-1-antitrypsin deficiency, Crigler-Najjarsyndrome type 1 as well as some other progressive
liver diseases. Combined liver-kidney transplantationis needed in patients with hyperoxaluria type 1. Withtime the indications for hepatic transplantation have
constantly widened as contra-indications have decreasedsimultaneously. It can now be considered a rationaloption for definitive therapy in many metabolic diseases,including diseases where the quality of life may beimpaired by time-consuming procedures such as morethan 12 hours of photo therapy for Crigler-Najar disease,bad taste in the mouth, and extremely time-consuming preparation of diets for patients with diseases of aminoacid metabolism including urea cycle defects and organoacidopathies.Other indications would include glycogen storage diseases, whereas most patients withrespiratory chain disorders do not benefit or only for a short time.The possibility to overcome the shortage of available
donor livers makes hepatocyte transplantation one of the most fascinating techniques in the field of transplantationat the present time. Many studies in animal models haveshown that under special circumstances hepatocytestransplanted into the portal vein, the splenic pulpa or the peritoneal cavity may engraft and maintain normalfunction. Since its first use in man in 1992,hepatocyte transplantation has been performed in various conditions such as acute liver failure, liver cirrhosis and somemetabolic diseases.Hepatocyte transplantation is
likely most successful, if only a limited amount of livertissue is needed to compensate for hepatic dysfunction.Being less invasive than whole-liver transplantation, itmay be a promising therapy for poor liver function after extended liver resection, liver graft dysfunction or many inborn errors of metabolism.In most inborn errors of metabolism, only 5%-10% of hepatic enzyme activity is needed to correct the genetic defect. Thus, it is of no surprise that such conditions have been the primary target to consider hepatocyte transplantation or primary gene therapy. In September1999, an 18 year old adolescent suffering from urea cycle disorder or ornithine transcarbamylase (OTC) deficiency participated in a pilot study of adenovirus-mediated gene therapy.Unfortunately, he died from a disseminated adenovirus infection and primary gene therapy studies for monogenic disorders have not been resumed.A landmark progress has been achieved by the development of enzyme replacement therapy, initially in patients with visceral type of Gaucher disease.


 


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