Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.
Title: Current Medical Diagnosis & Treatment, 46th Edition
Copyright 2007 McGraw-Hill
> Table of Contents > 41 - Genetic Disorders
Reed E. Pyeritz MD, PhD
Acute Intermittent Porphyria
Essentials of Diagnosis
Unexplained abdominal crisis, generally in young women.
Acute peripheral or central nervous system dysfunction.
Recurrent psychiatric illnesses.
Porphobilinogen in the urine during an attack.
Though there are several different types of porphyrias, the one with the most serious consequences and the one that usually presents in adulthood is acute intermittent porphyria, which is inherited as an autosomal dominant, though it remains clinically silent in the majority of patients who carry the trait. Clinical illness usually develops in women. Symptoms begin in the teens or 20s, but onset can begin after menopause in rare cases. The disorder is caused by partial deficiency of porphobilinogen deaminase activity, leading to increased excretion of aminolevulinic acid and porphobilinogen in the urine. The diagnosis may be elusive if not specifically considered. The characteristic abdominal pain may be due to abnormalities in autonomic innervation in the gut. In contrast to other forms of porphyria, cutaneous photosensitivity is absent in acute intermittent porphyria. Attacks are precipitated by numerous factors, including drugs and intercurrent infections. Harmful and relatively safe drugs for use in treatment are listed in Table 41-1. Hyponatremia may be seen, due in part to inappropriate release of antidiuretic hormone, though gastrointestinal loss of sodium in some patients may be a contributing factor.
A. Symptoms and Signs
Patients show intermittent abdominal pain of varying severity, and in some instances it may so simulate acute abdomen as to lead to exploratory laparotomy. Because the origin of the abdominal pain is neurologic, there is an absence of fever and leukocytosis. Complete recovery between attacks is usual. Any part of the nervous system may be involved, with evidence for autonomic and peripheral neuropathy. Peripheral neuropathy may be symmetric or asymmetric and mild or profound; in the latter instance, it can even lead to quadriplegia with respiratory paralysis. Other central nervous system manifestations include seizures, psychosis, and abnormalities of the basal ganglia. Hyponatremia may further cause or exacerbate central nervous system manifestations.
B. Laboratory Findings
Often there is profound hyponatremia. The diagnosis can be confirmed by demonstrating an increased amount of porphobilinogen in the urine during an acute attack. Freshly voided urine is of normal color but may turn dark upon standing in light and air.
Most families have a different mutation in the porphobilinogen deaminase gene causing acute intermittent porphyria. Mutations can be detected and used for presymptomatic and prenatal diagnosis.
Avoidance of factors known to precipitate attacks of acute intermittent porphyria especially drugs (sulfonamides and barbiturates, or drugs listed in Table 41-1) can reduce morbidity. Starvation diets also cause attacks and so must be avoided.
Table 41-1. Some of the unsafe and probably safe drugs used in the treatment of acute porphyrias.
Treatment with a high-carbohydrate diet diminishes the number of attacks in some patients and is a reasonable empiric gesture considering its benignity. Acute attacks may be life-threatening and require prompt diagnosis, withdrawal of the inciting agent (if possible), and treatment with analgesics and intravenous glucose and hematin. A minimum of 300 g of carbohydrate per day should be provided orally or intravenously. Electrolyte balance requires close attention. Hematin therapy is still evolving and should be undertaken with full recognition of adverse consequences, especially phlebitis and coagulopathy. The intravenous dosage is up to 4 mg/kg once or twice daily. Liver
Desnick RJ et al: Inherited porphyrias. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2006.
Foran SE et al: Guide to porphyrias. A historical and clinical perspective. Am J Clin Pathol 2003;119(Suppl):S86.
Kauppinen R: Molecular diagnostics of acute intermittent porphyria. Expert Rev Mol Diagn 2004;4:243.
Norman RA: Past and future: porphyria and porphyrins. Skinmed 2005;4:287.
Soonawalla ZF et al: Liver transplantation as a cure for acute intermittent porphyria. Lancet 2004;363:705.
Alkaptonuria is caused by a recessively inherited deficiency of the enzyme homogentisic acid oxidase. This acid derives from metabolism of both phenylalanine and tyrosine and is present in large amounts in the urine throughout the patient's life. An oxidation product accumulates slowly in cartilage throughout the body, leading to degenerative joint disease of the spine and peripheral joints. Indeed, examination of patients in the third and fourth decades shows a slight darkish blue color below the skin in areas overlying cartilage, such as in the ears, a phenomenon called ochronosis. In some patients, a more severe hyperpigmentation can be seen in the sclera, conjunctiva, and cornea. Accumulation of metabolites in heart valves can lead to aortic or mitral stenosis. A predisposition to coronary artery disease may also be present. Although the syndrome causes considerable morbidity, life expectancy is reduced only modestly. Symptoms are more often attributable to spondylitis with back pain, leading to a clinical picture difficult to distinguish from that of ankylosing spondylitis, though on radiographic assessment the sacroiliac joints are not fused in alkaptonuria.
The diagnosis is established by demonstrating homogentisic acid in the urine, which turns black spontaneously on exposure to the air; this reaction is particularly noteworthy if the urine is alkaline or when alkali is added to a specimen. Molecular analysis of the homogentisic acid oxidase gene, recently mapped to chromosome 3, is available but not necessary for diagnosis.
Treatment of the arthritis is similar to that for other arthropathies. Though in theory rigid dietary restriction might reduce accumulation of the pigment, this has not proved to be of practical benefit.
Keller JM et al: New developments in ochronosis: review of the literature. Rheumatol Int 2005;25:81.
La Du BN: Alcaptonuria. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001.
Mannoni A et al: Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum 2004;33:239.
Phornphutkul C et al: Natural history of alkaptonuria. N Engl J Med 2002;347:2111.
Down syndrome is usually diagnosed at birth on the basis of the typical facial features, hypotonia, and single palmar crease. Several serious problems that may be evident at birth or may develop early in childhood include duodenal atresia, congenital heart disease (especially atrioventricular canal defects), and leukemia. The intestinal and cardiac anomalies usually respond to surgery, and the leukemia generally responds to conservative management. Intelligence varies across a wide spectrum. Many people with Down syndrome do well in sheltered workshops and group homes, but few achieve full independence in adulthood. An Alzheimer-like dementia usually becomes evident in the fourth or fifth decade and, for those who survive childhood, accounts for a reduced life expectancy. Studies addressing the risk and severity of dementia in relation to the apolipoprotein E genotype have had conflicting results. Cytogenetic analysis should always be performed even though most patients will have simple trisomy for chromosome 21 to detect unbalanced translocations; such patients may
The presence of a fetus with Down syndrome can be detected in many pregnancies in the early second trimester through screening maternal serum for -fetoprotein and certain hormones ( multiple marker screening ) and by detecting increased nuchal thickness on fetal ultrasound.
The risk of bearing a child with Down syndrome increases exponentially with the age of the mother at conception and begins a marked rise after age 35. By age 45 years, a mother has one chance in 40 of having an affected child. The risk of other conditions associated with trisomy also increases, because of the increased predisposition of older oocytes to nondisjunction during meiosis. There is little risk of trisomy associated with increased paternal age. However, older men do have an increased risk of fathering a child with a new autosomal dominant condition. But because there are so many distinct conditions, the chance of fathering an offspring with any given one is extremely small.
Andriolo RB et al: Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome. Cochrane Database Syst Rev 2005;(5):CD005176.
Baliff JP et al: New developments in prenatal screening for Down syndrome. Am J Clin Pathol 2003;120(Suppl):S14.
Galley R: Medical management of the adult patient with Down syndrome. JAAPA 2005;18:45.
Roizen NJ: Down's syndrome. Lancet 2003;12:1281.
Tolmie JL: Down syndrome and other autosomal trisomies. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2006.
Tyler C et al: Down syndrome, Turner syndrome, and Klinefelter syndrome: primary care throughout the life span. Prim Care 2004;31:627.
Fragile X Mental Retardation
This X-linked condition accounts for more cases of mental retardation in males than any condition except Down syndrome; about one in 4000 to 6000 males is affected; the condition also affects intellectual function in females about 50% less frequently than in males. The first marker for this condition was a small gap, or fragile site, evident near the tip of the long arm of the X chromosome. Subsequently, the condition was found to be due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1. All individuals have some CGG repeats in this location, but as the number increases beyond 52, the chances of further expansion during spermatogenesis or oogenesis increase. Being born with one FMR1 allele with 200 or more repeats results in mental retardation in most men and in about 60% of women. The more repeats, the greater the likelihood that further expansion will occur during gametogenesis; this results in anticipation, in which the disorder can worsen from one generation to the next. Affected (heterozygous) women show no physical signs other than early menopause, but they may have learning difficulties or frank retardation. Affected males show macroorchidism (enlarged testes) after puberty, large ears and a prominent jaw, a high-pitched voice, and mental retardation. Some show evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse.
Men who are not retarded but carry an increased number of CGG repeats in the FMR1 locus (premutation carriers) are at increased risk for developing intention tremor, ataxia, or both. Likewise, women who are premutation carriers (55 200 CGG repeats) are at increased risk for premature ovarian failure and mild cognitive or behavioral abnormalities. Male and female premutation carriers are at risk for developing tremor and ataxia beyond middle age. Because of the relatively high prevalence of premutation carriers in the general population, older people in whom any of these problems develop should undergo testing of the FMR1 locus.
DNA diagnosis for the number of repeats has supplanted cytogenetic analysis for both clinical and prenatal diagnosis. This should be done on any male or female who has unexplained mental retardation.
Hagerman PJ et al: The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004;74:805.
Hatton DD et al: Problem behavior in boys with fragile X syndrome. Am J Med Genet 2002;108:105.
Jacquemont S et al: Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460.
Kenneson A et al: The female and the fragile X reviewed. Semin Reprod Med 2001;19:159.
Sutherland GR et al: Fragile X syndrome and other causes of X-linked mental handicap. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2006.
Terracciano A et al: Fragile X syndrome. Am J Med Genet C Semin Med Genet 2005;137:32.
Gaucher disease has an autosomal recessive pattern of inheritance. A deficiency of -glucocerebrosidase causes an accumulation of sphingolipid within phagocytic cells throughout the body. Anemia and thrombocytopenia are common and may be symptomatic; both are due primarily to hypersplenism, but marrow infiltration with Gaucher cells may be a contributing factor. Cortical erosions of bones, especially the vertebrae and femur, are due to local infarctions, but the mechanism is unclear. Episodes of bone pain (termed crises ) are reminiscent of those in sickle cell disease. A hip fracture in a patient with a palpable spleen especially in a Jewish person of Eastern European origin suggests the possibility of Gaucher disease. Bone marrow aspirates reveal typical Gaucher cells, which have
Two uncommon forms of Gaucher disease, called type II and type III, involve neurologic accumulation of sphingolipid and a variety of neurologic problems. Type II is of infantile onset and has a poor prognosis.
Over 200 mutations have been found to cause Gaucher disease, and some are highly predictive of the neuronopathic forms. Thus, mutation detection, especially in a young person, is of potential value. Only four mutations in glucocerebrosidase account for more than 90% of the disease among Ashkenazic Jews, in whom the carrier frequency is 1:15.
Heterozygotes for Gaucher disease may be at increased risk for developing Parkinson disease.
For many years, treatment was supportive and included splenectomy for thrombocytopenia secondary to platelet sequestration. A recombinant form of the enzyme glucocerebrosidase (imiglucerase) for intravenous administration on a regular basis now permits a reduction in total body stores of glycolipid and improvement in orthopedic and hematologic manifestations. Unfortunately, the neurologic manifestations of types II and III have not improved with enzyme replacement therapy. The major drawback is the exceptional cost of imiglucerase, which can exceed $350,000 per year for a severely affected patient. Administration of less enzyme (30 units/kg per month) is effective for most adults and reduces the cost to about $100,000 150,000 annually.
Aharon-Peretz J et al: Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2004;351:1972.
Beutler E et al: Gaucher disease. In: The Metabolic Basis of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001.
Charrow J et al: The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 2000;160:2835.
Germain DP: Gaucher's disease: a paradigm for interventional genetics. Clin Genet 2004;65:77.
Hollak CE et al: Clinically relevant therapeutic endpoints in type I Gaucher disease. J Inherit Metab Dis 2001;24(Suppl 2):97.
Wenstrup RJ et al: Skeletal aspects of Gaucher disease: a review. Br J Radiol 2002;75(Suppl 1)A2.
Disorders of Homocysteine metabolism
Homocystinuria in its classic form is caused by cystathionine -synthase deficiency and exhibits an autosomal recessive pattern of inheritance. This results in extreme elevations of plasma and urinary homocystine levels, a basis for diagnosis of this disorder. Homocystinuria is similar in certain superficial aspects to Marfan's syndrome, since patients may show a similar body habitus and ectopia lentis is almost always present. However, mental retardation is often present, and the cardiovascular events are those of repeated venous and arterial thromboses whose precise cause remains obscure. Life expectancy is reduced, especially in untreated and pyridoxine-unresponsive patients; myocardial infarction, stroke, and pulmonary embolism are the most common causes of death. This condition is diagnosed in some states by newborn screening for hypermethioninemia; however, pyridoxine-responsive infants may not be detected. The diagnosis should be suspected in patients in the second and third decades of life who show evidence of arterial or venous thromboses and have no other risk factors. Although many mutations have been identified in the cystathionine -synthase gene, amino acid analysis of plasma remains the most appropriate diagnostic test. Patients should be studied after they have been off folate or pyridoxine supplementation for at least 1 week. The plasma should be separated promptly from the fresh venous blood specimen.
About 50% of patients have a form of cystathionine -synthase deficiency that improves biochemically and clinically through pharmacologic doses of pyridoxine and folate. For these patients, treatment from infancy can prevent retardation and the other clinical problems. Patients who are pyridoxine nonresponders must be treated with a dietary reduction in methionine and supplementation of cysteine, also from infancy. The vitamin betaine is also useful in reducing plasma methionine levels by facilitating a metabolic pathway that bypasses the defective enzyme. Patients who have suffered venous thrombosis receive anticoagulation therapy, but there are no studies to support prophylactic use of warfarin or antiplatelet agents.
Over the past 5 years, considerable evidence has accumulated to support the 20-year-old observation that patients with clinical and angiographic evidence of coronary artery disease tend to have higher levels of plasma homocysteine than controls without coronary artery disease. The relationship has been extended to cerebrovascular and peripheral vascular diseases. Although this effect was initially thought to be due at least in part to heterozygotes for cystathionine -synthase deficiency (see above), there is little evidence for this. Rather, the major factor leading to hyperhomocysteinemia is folate deficiency. Pyridoxine (vitamin B6) and vitamin B12 are also important in the metabolism of methionine, and deficiency of any of these vitamins can lead to accumulation of homocysteine. A number of genes influence utilization of these vitamins and can predispose to deficiency. For example, having one and especially two copies of an allele that causes thermolability of methylene tetrahydrofolate reductase predisposes patients to elevated fasting homocysteine levels. However, both nutritional and most genetic deficiencies of these vitamins can be corrected by dietary supplementation of folic acid and, if serum levels are low, vitamins B6 and B12. In the United States, cereal grains are now fortified with folic acid. Studies are ongoing to determine the
Relatively few laboratories currently provide highly reliable assays for homocysteine. Processing of the specimen is crucial to obtain accurate results. The plasma must be separated within 30 minutes; otherwise, blood cells release the amino acid and the measurement will then be artificially elevated.
Carmel R et al (editors): Homocysteine in Health and Disease. Cambridge University Press, 2001.
Kelly PJ et al: Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology 2003;28:275.
Knekt P et al: Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med 2001;161:1589.
Mudd H et al: Disorders of transsulfuration. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001.
Refsum H et al: Birth prevalence of homocystinuria. J Pediatr 2004;144:830.
Schnyder G et al: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593.
Soinio M et al: Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med 2004;140:94.
Undas A et al: Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 2005;94:907.
Yap S et al: Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 2001;21:2080.
Boys with an extra X chromosome are normal in appearance before puberty; thereafter, they have disproportionately long legs and arms, a female escutcheon, gynecomastia, and small testes. Infertility is due to azoospermia; the seminiferous tubules are hyalinized. The diagnosis is often not made until a couple is evaluated for inability to conceive. Mental retardation is somewhat more common than in the general population. Many men with Klinefelter syndrome have learning problems. However, their intelligence usually tests within the broad range of normal. As adults, detailed psychometric testing may reveal a deficiency in executive skills. The risk of breast cancer is much higher in men with Klinefelter syndrome than in 46,XY men, as is the risk of diabetes mellitus.
Treatment with testosterone after puberty is advisable but will not restore fertility. However, men with Klinefelter syndrome have had mature sperm aspirated from their testes and injected into oocytes, resulting in fertilization. After the blastocysts were implanted into the uterus of a partner, natural children resulted. However, men with Klinefelter syndrome do have an increased risk for aneuploidy in sperm, and chromosome analysis of a blastocyst before implantation should be considered.
Allanson J et al: Sex chromosome abnormalities. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2006.
Ferlin A et al: Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities. Cytogenet Genome Res 2005;111:310.
Lanfranco F et al: Klinefelter's syndrome. Lancet 2004;364:273.
Swerdlow AJ et al: Mortality and cancer incidence in persons with numerical sex chromosome abnormalities. Ann Hum Genet 2001;65:177.
Temple CM et al: Executive skills in Klinefelter's syndrome. Neuropsychologia 2003;41:1547.
Wattendorf DJ et al: Klinefelter syndrome. Am Fam Physician 2005;72:2259.
Essentials of Diagnosis
Disproportionately tall stature, thoracic deformity, and joint laxity or contractures.
Ectopia lentis and myopia.
Aortic dilation and dissection.
Mitral valve prolapse.
Marfan syndrome, a systemic connective tissue disease, has an autosomal dominant pattern of inheritance. It is characterized by abnormalities of the skeletal system, ocular system, and cardiovascular system. Spontaneous pneumothorax, dural ectasia, and striae atrophicae can also occur. Of most concern is disease of the ascending aorta, which is associated with a dilated aortic root. Histology of the aorta shows diffuse medial abnormalities. Aortic and mitral valve leaflets are also abnormal and mitral regurgitation may be present as well, often with elongated chordae tendineae, which on occasion may rupture.
A. Symptoms and Signs
Affected patients are typically tall, with particularly long arms, legs, and digits (arachnodactyly). However, there can be wide variability in the clinical presentation. Commonly, joint dislocations and pectus excavatum are found. Ectopia lentis may lead to severe myopia
B. Laboratory Findings
Mutations in the fibrillin gene on chromosome 15 cause Marfan syndrome. Nonetheless, no simple laboratory test is available to support the diagnosis in questionable cases because related conditions may also be due to defects in fibrillin. The pathogenesis of Marfan syndrome involves aberrant regulation of transforming growth factor (TGF)b activity. Mutations in either of two receptors for TGFb can cause conditions that resemble Marfan syndrome in terms of aortic aneurysm and dissection and autosomal dominant inheritance.
There is prenatal and presymptomatic diagnosis for patients in whom the molecular defect in fibrillin has been found and for large enough families in whom linkage analysis using polymorphic markers around the fibrillin gene can be performed.
Children with Marfan syndrome require regular ophthalmologic surveillance to correct visual acuity and thus prevent amblyopia, and annual orthopedic consultation for diagnosis of scoliosis at an early enough stage so that bracing might delay progression. Patients of all ages require echocardiography at least annually to monitor aortic diameter and mitral valve function. All patients should use standard endocarditis prophylaxis. Chronic -adrenergic blockade, titrated to individual tolerance but enough to produce a negative inotropic effect (atenolol, 1 2 mg/kg), retards the rate of aortic dilation. Restriction from vigorous physical exertion protects from aortic dissection. Prophylactic replacement of the aortic root with a composite graft when the diameter reaches 50 55 mm (normal: < 40 mm) prolongs life. A procedure to reimplant the patient's native aortic valve and replace just the aneurysmal sinuses of Valsalva shows promise and also avoids the need for lifelong anticoagulation.
People with Marfan syndrome who are untreated commonly die in the fourth or fifth decade from aortic dissection or congestive heart failure secondary to aortic regurgitation. However, because of earlier diagnosis, lifestyle modifications, -adrenergic blockade, and prophylactic aortic surgery, life expectancy has increased by several decades in the past 25 years.
de Oliveira NC et al: Results of surgery for aortic root aneurysm in patients with Marfan syndrome. J Thorac Cardiovasc Surg 2003;125:789.
Dietz HC et al: Marfan syndrome and related disorders. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001.
Erkula G et al: Growth and maturation in Marfan syndrome. Am J Med Genet 2002;109:100.
Judge DP et al: Marfan's syndrome. Lancet 2005;366:1965.
Miller DC: Valve-sparing aortic root replacement in patients with Marfan syndrome. J Thorac Cardiovasc Surg 2003;125:773.
Pyeritz RE: The Marfan syndrome. Annu Rev Med 2000;51:481.