Long-Term Assessment of Treatment Is Critical

 For treating monogenic diseases, long-term evaluation of cohorts of treated individuals, often over decades, is critical for several reasons. First, treatment initially judged as successful may eventually be revealed to be imperfect; for example, although well-managed children with PKU have escaped severely impaired intellectual development and have normal or nearly normal IQs (see later), they may manifest subtle learning disorders and behavioral disturbances that impair their academic performance in later years.

Second, successful treatment of the pathologic changes in one organ may be followed by unexpected problems in tissues not previously observed to be clinically involved because the patients typically did not survive long enough for the new phenotype to become evident. Galactosemia, a well-known inborn error of carbohydrate metabolism, illustrates this point. This disorder results from an inability to metabolize galactose, a component of lactose (milk sugar), because of the autosomal recessive deficiency of galactose-1-phosphate uridyltransferase (GALT).

Affected infants are usually normal at birth but develop gastrointestinal problems, cirrhosis of the liver, and cataracts in the weeks after they are given lactose containing milk. The pathogenesis is thought to be due to the negative impact of galactose-1-phosphate accumulation on other critical enzymes. If not recognized, galactosemia causes severe intellectual disability and is often fatal. Complete removal of milk from the diet, however, can protect against most of the harmful con sequences, although learning disabilities are now recognized to be common, even in well-treated patients. Moreover, despite conscientious treatment, most females with galactosemia have ovarian failure that appears to result from endogenously produced galactose toxicity.

Another example is provided by hereditary retinoblastoma due to germline variants in the retinoblastoma (RB1) gene. Patients successfully treated for the eye tumor in the first years of life are unfortunately at increased risk for development of other independent malignant neoplasms, particularly osteosarcoma, after the first decade of life. Ironically, therefore, treatment that successfully pro longs life provides an opportunity for the manifestation of a previously unrecognized phenotype.

In addition, therapy that is free of side effects in the short term may be associated with serious problems in the long term. For example, clotting factor infusion in hemophilia sometimes results in the formation of antibodies to the infused protein, and blood transfusion in thalassemia invariably produces iron overload, which must then be managed by the administration of iron-chelating agents, such as deferoxamine.

Genetic Heterogeneity and Treatment

 The optimal treatment of single-gene defects requires an unusual degree of diagnostic precision; one must often define not only the biochemical abnormality but also the specific gene that is affected. For example, as we saw in Chapter 13, hyperphenylalaninemia can result from variants in either the phenylalanine hydroxylase (PAH) gene or in one of the genes that encodes the enzymes required for the synthesis of tetra hydrobiopterin (BH4 ), the cofactor of the PAH enzyme (see Fig. 1). The treatment of these two different causes of hyperphenylalaninemia is entirely different, as shown in Table 1.

Fig1. The biochemical pathways affected in the hyperphenylalaninemias. BH4 , tetrahydrobiopterin; 4αOHBH4 , 4α-hydroxytetrahydrobiopterin; qBH2 , quinonoid dihydrobiopterin, the oxidized product of the hydroxylation reactions, which is reduced to BH4 by dihydropteridine reductase (DHPR); PCD, pterin 4α-carbinolamine dehydratase; phe, phenylalanine; tyr, tyrosine; trp, tryptophan; GTP, guanosine triphosphate; DHNP, dihydroneopterin triphosphate; 6-PT, 6-pyruvoyltetrahydropterin; l-dopa, l dihydroxyphenylalanine; NE, norepinephrine; E, epinephrine; 5-OH trp, 5-hydroxytryptophan.

Table1. Locus Heterogeneity in the Hyperphenylalaninemias

Allelic heterogeneity may also have critical implications for therapy. Some alleles may produce a protein that is decreased in abundance but has some residual function, so strategies to increase the expression, function, or stability of such a partially functional mutant protein may correct the biochemical defect. This situation is again illustrated by some patients with hyperphenylalaninemia due to variants in the PAH gene; the variants in some patients lead to the formation of a mutant PAH enzyme whose activity can be increased by the administration of high doses of the BH4 cofactor. Of course, if a patient carries two alleles with no residual function, nothing will be gained by increasing the abundance of the mutant protein. One of the most striking examples of the importance of knowing the specific mutant allele in a patient with a genetic disease is exemplified by cystic fibrosis (CF); the drug ivacaftor (Kalydeco) was approved for treating CF patients carrying any one of only nine of the many hundreds of CFTR missense alleles. Further work has resulted in identification of a three-drug regimen that can treat over 90% of CF patients.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يقيم مهرجان الماء المعين السنوي الثالث في بغداد

على هامش المؤتمر التمهيدي لألفية الحوزة العلمية.. الهيأة العليا تقيم جلسة حوارية عن تراث الشيخ الطوسي

العتبة العباسية المقدسة تستعد لإقامة حفل التكليف الشرعي لتلميذات مدارس كربلاء

لليوم الثاني.. قسم التطوير يواصل تقديم دورة إعداد المدربين (TOT) لملاكات مديرية تربية كربلاء

المزيد

الآخبار الصحية

اللحظات الأخيرة قبل الموت.. هذا هو تسلسل "فقدان الحواس"

وخز الأطراف وضعف الذاكرة.. علامات على نقص فيتامين هام

عادة صباحية بسيطة.. تأثيرها قد يحسن ضغط الدم

عادات يومية تدمر قلبك بصمت.. خبراء يطلقون التحذير

المزيد

الآخبار التكنلوجية

الذكاء الاصطناعي يفك لغز آثار أقدام الديناصورات

القمر أولا.."سبيس إكس" تؤجل خططها الخاصة بالرحلات إلى المريخ

الذكور أم الإناث؟ دراسة "تنسف الشائع" بشأن التوحد

خبير يكشف عن اقتراب العلماء من فك شفرات "لغات الحيوانات" !

المزيد

مواضيع ذات صلة

Familial Occurrence of Cancer

Testing for Germline Pathogenic Variants Causing Hereditary Cancer

Pathogenic Variants in Tumor Suppressor Genes Causing Autosomal Recessive Pediatric Cancer Syndromes

Pathophysiology of Fanconi Anemia

The Current State of Treatment of Genetic Disease

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