Homocystinuria is an autosomal recessive metabolic disease characterized by elevated levels of homocysteine. The most common genetic mutation involved in the disease targets cystathionine beta-synthase, an enzyme that catalyzes the conversion of methionine into cysteine.
Patients with homocystinuria can present with a range of findings. Given the genetic nature of the condition, they usually have a positive family history . Signs and symptoms include mental retardation, thromboembolic events that can eventually lead to aphasia, hemiplegia, pseudobulbar palsy or ataxia, features of Marfan's syndrome, ectopia lentis (dislocation of the lens in the downward direction) and abnormalities in thorax and knee anatomy (pectus excavatum and carinatum, genu valgum) .
Classic homocystinuria presents initially with ectopia lentis, mental retardation, seizures and marfanoid features. Other forms of the disorder that involve methylcobalamin synthesis have, in addition, severe methylmalonic acidemia.
Certain factors may aggravate the risk for strokes and these include diabetes, smoking and hypertension. Furthermore, according to one Swedish report, abnormalities in oral health may be prominent. The scientists hypothesized that a diet low in protein, which is generally part of the treatment, may be substituted with diets rich in sugar and carbohydrates, leading to dental decay. Thus, it is recommended for homocystinuria patients to undergo regular dental follow ups and make sure they are performing the necessary preventive measures. The report also found that patients tend to have shortened dental roots, especially roots of the maxillary incisors .
A Spanish study attempted to classify the nature and severity of the symptoms depending on the type of homocystinuria. They found that remethylation defects are associated with the severest symptoms. The majority of cases, however, were characterized by transsulfuration defects. The most common symptoms in the overall population of patients were cognitive impairments and problems with the lens of the eye. Up to half of the patients presented with neurological disorders, with greater involvement of the circulatory system in patients with CBS deficiency.
Other prominent symptoms include fine and brittle hair, decreased pigmentation of the skin, crowding of the teeth, decreased joint mobility, kyphoscoliosis, a high arched palate, myopia, glaucoma and psychiatric disorders. The average IQ of patients with homocystinuria is 80, although 30% of all patients have a normal IQ  .
Homocystinuria refers to excessive excretion of the amino acid homocysteine in the urine, but is also associated with elevated plasma concentration of the same amino acid. CBS deficiency is one of many possible metabolic abnormalities that can lead to homocystinuria. A range of other abnormalities may underlie high homocysteine levels and these include problems with remethyation, deficiency in vitamin B12 (cobalamin), vitamin B9 (folate), vitamin B2 (riboflavin) and vitamin B6 (pyridoxal phosphate). Remethylation defects can be mediated by a number of abnormalities in the synthesis of methionine synthase, MTHFR or cobalamin. Given the large extent of potential causative mechanisms, a broad range of biochemical tests need to be done to narrow the differential diagnosis.
Diagnosis of CBS deficiency may be performed by measuring amino acid levels in the plasma and urine. They will usually show elevation of methionine and presence of homocysteine. These tests are also possible in the metabolic screening programs performed on neonates. Unlike CBS deficiency, other causes of homocystinuria such as MTHFR, methionine synthase deficiency or defects in cobalamin, will not show elevated methionine. Vitamin B12 deficiency and other cobalamin defects can be ruled out through quantitative analyses of methylmalonic acid .
Measurements of homocysteine levels directly may be difficult because of the complex binding of a large portion of the homocysteine present in the blood with other amino acids and proteins. The connection is usually mediated by disulfide bonds such as the one present in cysteine-homocysteine and homocysteine-homocysteine complexes. Although the proportions of free and bound homocysteine are variable, the concentration of total homocysteine is generally constant. Thus, total homocysteine needs to be measured to assess for the precise quantity of homocystinuria. This is done by reducing all disulfide bonds before running the analysis with HPLC and the use of a fluorescent agent for derivatization .
The differential diagnosis of homocystinuria is broad, but Marfan's syndrome should be particularly suspected . Other potential conditions that may explain the presenting symptoms include psoriasis, a postmenopausal status, leukemia, hypothyroidism, intake of certain drugs such as methotrexate and isoniazid and old age.
Homocystinuria is generally treated with 100 to 500 mg per day of pyridoxine. Nonetheless, not all patients are sensitive to the treatment. Those who respond require, in addition to pyridoxine, folic acid and vitamin B12. The three drugs work in combination to reduce levels of homocysteine and may help in ameliorating symptoms. Patients should also undergo preventive measures for strokes and cardiovascular disease, in the form of clopidogrel, aspirin-dipyridamole or aspirin. Studies have not conclusively determined if anticoagulants or other antiplatelet drugs have better or equal efficacy. Treatment response can be followed by assessing serum levels of homocysteine.
Patients who are insensitive to pyridoxine are recommended initially to follow a diet low with methionine. Betaine supplements can also decrease serum homocysteine levels .
Patients with homocystinuria can expect normal life expectancy if the disease is treated. In untreated cases, patients are at greatest risk from thromboembolic events that especially target the cardiac and nervous systems.
Proteins are valuable nutritious materials to the human organism, but need to be properly processed before they can be used. Normally, proteins are broken down to their constituent amino acids. The latter are absorbed in the small bowel and further modified in the tissue where they are used in various functions.
Homocystinuria occurs when there is a defect in an enzyme called cystathionine beta-synthase (CBS). CBS normally helps metabolizing methionine, an important amino acid in the human system. When the enzyme is not working properly either because it's defective or because not enough of it is made, there is a subsequent build up of homocysteine. The concentration of homocysteine and its metabolites rises considerably in the blood and eventually results in dysfunction in various organs.
Genetic mutations in the CBS gene represent the primary etiological factors underlying homocystinuria. The National Institutes of Health has reported up to 150 mutations in the CBS gene that can eventually lead to the development of the condition. The CBS enzyme usually requires vitamin B6 to convert homocysteine. The mutation disrupts the function of the enzyme, with a resulting build up of homocysteine and a number of toxic biochemical elements in the blood. This leads to significant dysfunction in the central and peripheral nervous systems as well as in the vascular system.
Other mutations have been also involved in the disorder particularly mutations in the MTR, MTRR, MMADHC and MTHFR genes. All of these genes function in the biochemical conversion methionine into cysteine. The mode of inheritance is autosomal recessive, meaning that two copies of the mutated gene need to be acquired to express the disorder. Normally, one copy of the gene is transmitted from the mother and the other from the father. Thus, both parents need to have at least one copy of the defective gene for transmission to occur.
In the United States, studies report an incidence of 1 in 100,000 of homocystinuria. These rates vary considerably internationally, with incidence ranging from 1 in 50,000 individuals to 1 in 200,000 individuals.
Mudd et al. conducted a scientific survey to determine morbidity and mortality. They found that 18% of patients with homocystinuria pass away by the time they are 30 years old. The case series involved a total of 629 patients who are deficient in the CBS enzymes . Most cases of mortality are related to cardiovascular or cerebrovascular incidents. Prompt diagnosis and treatment are critical in the prevention of many complications of the disorder, particularly mental retardation, coagulopathy and ectopia lentis.
Homocystinuria can present directly at birth or much later. Mudd et al. found that risk of thromboembolic events significantly rises after patients reach the age of 20. Patients with homocystinuria type I, manifesting with CBS deficiency, are usually normal at birth. On the other hand, abnormal syntheses of methylcobalamin or disrupted tetrahydrofolate metabolism result in a form of the condition that presents very early in infancy.
Homocystinuria is attributed to decreased activity of the enzyme cystathionine beta synthase that normally acts to convert methionine into cysteine. With a deficient enzyme, there is a build-up of homocysteine and other byproducts. The gene responsible for the enzyme is present on locus 21q22.
The accumulation of homocysteine and methionine ultimately leads to damage in tissues by disrupting collagen fibers.
Given the genetic nature of the disease, preventive measures are essentially limited. Any family history of homocystinuria should prompt the patient to visit a genetic counselor. This may help in estimating the likelihood of having an offspring with the disorder. Pregnant women may also undergo a genetic analysis of amniotic cells and villi to detect responsible genetic mutations in the fetus.
Homocystinuria is a genetic metabolic disorder characterized by increased serum and urine concentration of homocysteine, an amino acid involved in the metabolism of methionine. Several genetic mutations are associated with the disease, the most important of which is cystathionine beta-synthase (CBS). This enzyme catalyzes the transformation of methionine to cysteine. Absence or deficient enzyme can lead to a buildup of methionine, homocysteine and other toxic products that can subsequently damage tissue, particularly in regards to collagen cross-linking. Homocystinuria is transmitted in an autosomal recessive fashion.
Symptoms can present early in life or later. Prominent symptoms include a marfanoid habitus, downward dislocation of the lens, pectus excavatum or carinatum, mental retardation and thromboembolic events. Thromboembolic events are responsible for most of the mortality and morbidity, especially when they target the cardiac and nervous systems. Nervous system involvement can lead to strokes, seizures and psychiatric disorder.
Diagnosis is established with extensive metabolic testing. Homocysteine levels in the serum and urine are difficult to estimate because the amino acid is usually bound to other proteins or amino acids with disulfide bonds. Bound and free levels of homocysteine can vary considerably although total homocysteine concentration is generally constant. Thus, evaluation of total homocysteine after reducing all disulfide bonds can determine any particular metabolic abnormalities involving the amino acid. CBS deficiency is also associated with elevated methionine levels. These tests can be performed on newborns for screening purposes.
Homocystinuria is treated with pyridoxine, although not all patients respond. Cobalamin and folic acid are also part of the treatment and help in ameliorating symptoms. Patients who are not sensitive to pyridoxine are started on a low methionine diet with betaine supplements. All patients require prophylaxis against thromboembolic events in the form of aspirin or clopidogrel.
Prognosis for patients with homocystinuria is good if patients are diagnosed early and treated properly, with no decrease in life expectancy.
Homocystinuria is a genetic metabolic disorder characterized by elevated levels of homocysteine. Homocysteine is an amino acid involved in many metabolic reactions in the body. Amino acids are the building blocks of proteins, one of the primary components of the nutritious material the body normally needs.
Homocystinuria is caused by genetic mutations to several genes and are transmitted in an autosomal recessive fashion. That means that the disease has no gender predilection and each offspring requires two copies of the mutated gene to have the disease. Normally, a child receives one copy from every gene from each parent, and generally both parents need to have a copy of the gene to transmit the disease to their child.
Patients with homocystinuria can present at birth or later in life. When not treated, they can suffer from mental retardation, psychiatric disorders, lax joints and clots in their hearts or brain. The latter is the most serious manifestation of the disease and can lead to grave consequences and possibly death.
Homocystinuria is diagnosed with biochemical tests that measure the levels of homocysteine and other biochemical compounds. Newborns can be screened for the disorder. Treatment is administered with pyridoxine, vitamin B12 and folic acid. Some patient may not respond to pyridoxine and would require a diet low in methionine and supplemented with betaine. Patients can expect a normal life expectancy if they are diagnosed early in infancy and treated appropriately.