Genetic disease can be treated at any level from the mutant gene to the clinical phenotype (Fig. 1). Treatment at the level of the clinical phenotype includes all the medical or surgical interventions that are not unique to the management of genetic disease. Throughout this chapter we describe the rationale for treatment at each of these levels. The current treatments are not necessarily mutually exclusive and many are used in conjunction to treat certain disorders; however, only gene therapy, gene editing, or cell transplantation can potentially provide cures.

Fig1. The various levels of treatment that are relevant to genetic disease, with the corresponding strategies used at each level. For each level, a disease discussed in the book is given as an example. All the therapies listed are used clinically in many centers, unless indicated otherwise. Hb F, Fetal hemoglobin; mRNA, messenger RNA; PKU, phenylketonuria; RNAi, RNA interference; SCID, severe combined immunodeficiency. (Modified from Valle D: Genetic disease: an overview of current therapy, Hosp Pract 22:167–182, 1987.)

Although powerful advances are being made, the overall treatment of single-gene diseases is presently deficient. Nevertheless, advances in the number of approaches to diagnosis and treatment of inborn errors of metabolism are accelerating (Fig. 2). Note, however, that inborn errors are a group of diseases for which treatment is advanced, in general, compared to most other types of genetic disorders such as those due, for example, to chromosomal abnormalities, imprinting defects, or copy number variation. An encouraging trend over past decades is that treatment is more likely to be successful if the basic biochemical defect is known. In one study, for example, although treatment increased life span in only 15% of all single-gene diseases studied, life span was improved by ~50% in the subset of 57 inborn errors in which the cause was known; significant improvements were also observed for other phenotypes, including growth, intelligence, and social adaptation. Thus research to elucidate the genetic and biochemical bases of hereditary disease has a major impact on the clinical outcome.

Fig2. Timeline of major developments in the treatment and diagnosis of inborn errors of metabolism (IEM) from 1955 to present. ADA-SCID, Adenosine deaminase-severe combined immunodeficiency, LC-FAO, long chain fatty acid oxidation defects; MoCDa, molybdenum cofactor deficiency type A; NAGS, N-acetylglutamate synthetase; UCD, urea cycle defects; levocarnitine and medical foods are used to treat many IEMs. (Adapted from Vernon HJ, Manoli I: Milestones in treatments for inborn errors of metabolism: reflections on where chemistry and mediine meet, Am J Med Genet 185a:3350–3358, 2021.)

The improving but still unsatisfactory state of treatment of monogenic diseases is due to numerous factors, including the following:

• Gene not identified or pathogenesis not understood. Although more than 4500 genes have been associated with monogenic diseases, there are still ~16,000 protein coding genes not yet linked to a disease phenotype, and over half of patients undergoing clinical exome sequencing do not receive a diagnosis. This fraction will improve over the next decade because of the impact of whole genome sequencing and other -omic technologies. However, even when the gene is known, knowledge of the pathophysiologic mechanism is often inadequate and can lag well behind gene discovery. In phenylketonuria (PKU), for example, despite decades of study, the mechanisms by which the elevation in phenylalanine impairs brain development and function are still poorly understood.

• Prediagnostic fetal damage. Some variants act early in development or cause irreversible pathologic changes before they are diagnosed. These problems can sometimes be anticipated if there is a family history of the genetic disease or if carrier screening identifies couples at risk. In some cases, prenatal treatment is possible (e.g., maternal dexamethasone [a cortisol analog] to prevent virilization in female fetuses known to have congenital adrenal hyperplasia).

 • Severe phenotypes are less amenable to intervention. The initial cases of a disease to be recognized are usually the most severely affected, but they are often less amenable to treatment. In such individuals, the variant frequently leads to the absence of the encoded protein or to a severely compromised mutant protein with no residual activity. In contrast, when the variant is less disruptive, the mutant protein may retain some residual function, and it may be possible to increase the small amount of function sufficiently to have a therapeutic effect, as described later.

• The challenge of dominant negative alleles. For some dominant disorders, the mutant protein interferes with the function of the normal allele. The challenge is to decrease the expression or impact of the variant allele or its encoded altered protein specifically, without disrupting expression or function of the normal allele or its normal protein.

اخر الاخبار

اخبار العتبة العباسية المقدسة

سماحة السيد الصافي يؤكّد أن القرآن عظّم شخصية النبي (صلّى الله عليه وآله) وكشف زيف ما أُلصِق بسيرته

العتبة العباسية المقدسة تفتح باب الاشتراك في مسابقة مراقي المجتبى للقصيدة العمودية السادسة

المجمع العلمي يختتم دورته التطويرية الثالثة لإعداد أساتذة الدورات القرآنية الصيفية في صلاح الدين

يضم أكثر من 25 ألف قطعة موثّقة.. متحف الكفيل ينجز الجرد السنوي لمخزن النفائس

المزيد

الآخبار الصحية

عرض شائع على الأصابع.. قد يكشف سرطان الرئة مبكرا

7 مشروبات طبيعية لتقليل التوتر والقلق

دراسة: "خطر مبكر" يهدد صحة الأطفال

الجوز أو الفول السوداني.. أيهما يتفوّق في حماية القلب؟

المزيد

الآخبار التكنلوجية

مفاجأة علمية عن الإنجاب.. كم طفلا يطيل عمر المرأة؟

استطلاع يكشف "الأكثر قلقا" من تأثر الوظائف بالذكاء الاصطناعي

هل يمنحك تناول الجزر يوميا سمرة طبيعية؟

إنجاز طبي تاريخي.. جراحة قلب بلا شق في الصدر

المزيد

مواضيع ذات صلة

Diseases Due to the expansion of Unstable Repeat Sequences

Normal Collagen Structure and Its Relationship to Osteogenesis Imperfecta

Cystic Fibrosis

Familial Hypercholesterolemia: A Genetic Hyperlipidemia

A Loss of Glycosylation: Mucolipidosis II or I-Cell Disease

Congenital Disorders of Glycosylation

The Example of Diseases Related to the X Chromosome: Hemophilia A and B

The Example of an Autosomal Recessive Disease: Cystic Fibrosis

Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The β- Thalassemias

The α- Thalassemias

Hemoglobin Structural Alterations