Homocystinuria Introduction

Introduction
Background
Homocystinuria is an inherited autosomal recessive defect in methionine metabolism that is caused by a deficiency in cystathionine synthase. This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.

In 1960, the first case of homocystinuria was reported from Northern Ireland. The patient was initially described as having an unusual case of Marfan syndrome with renal abnormalities at age 7 years. He had recovered from acute glomerulonephritis at age 6 years and was found to be hypertensive the following year. The patient was mentally slow and thin and had fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, a high arched palate, and bilaterally dislocated lenses. At age 10 years, the patient's urine was found to contain a large quantity of homocysteine; urinalysis results for the nitroprusside cyanide test were positive. The boy's left eye was enucleated because of a staphylococcal infection that occurred after acute pupillary-block glaucoma developed. His right lens became dislocated into the anterior chamber and had to be removed.

The patient's blood pressure readings normalized after his left kidney was removed when he was aged 13 years. Thick-walled internal arteries were noted at histologic examination. When pyridoxine supplementation was initiated at age 18 years, the patient's plasma homocysteine levels decreased below the reference range. Daily folic acid supplementation was added 1 year later because his plasma folate level was low. At age 20 years, the patient had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years. The chest pain was considered to be angina and was successfully treated. At age 50 years, the patient's plasma homocysteine levels still remained low. The patient developed acute gout, which responded to indomethacin therapy.

Pathophysiology
Homocysteine is metabolized by means of 2 pathways: remethylation and transsulfuration.
The remethylation pathway comprises 2 intersecting biochemical pathways and results in the transfer of a methyl group (CH3) to homocysteine from methylcobalamin, which receives its methyl group from S-adenosylmethionine (SAM), from 5-methyltetrahydrofolate (an active form of folic acid), or from betaine (trimethylglycine). Methionine can then be used to produce SAM, the body's universal methyl donor, which participates in several other key metabolic pathways, including the methylation of DNA and myelin.

The transsulfuration pathway of methionine/homocysteine degradation produces the amino acids cysteine and taurine. This pathway is dependent on adequate intake of vitamin B-6 and the hepatic conversion of vitamin B-6 into its active form, pyridoxal-5'-phosphate (P5P). The amino acid serine, which is a downstream metabolite generated from betaine via the homocysteine remethylation pathway is another necessary step.

Folate and vitamin B-12 are required for the remethylation of homocysteine to methionine. Findings from experimental studies have indicated that thyroid hormones affect folate metabolism. The observation that methylenetetrahydrofolate reductase is increased in hyperthyroidism and decreased in hypothyroidism may be relevant to the relationship between plasma homocysteine levels and thyroid status.

Women tend to have lower basal levels of homocysteine than do men, and neither contraceptives nor hormone replacement therapy seems to significantly alter the levels. Homocysteine concentrations are higher in postmenopausal women than in premenopausal women.

On the basis of the type of homocystinuria, the following 3 nosologic units are distinguished:

Homocystinuria can be caused by the deficiency of cystathionine synthase. This is the classic form. The gene for this deficiency is located on chromosomal band 21q22.3. This unit includes the following forms: vitamin B-6 sensitivity (1.5% enzymatic activity), vitamin B-6 resistance (0% enzymatic activity), an intermediate variant, and a benign variant.
Homocystinuria can be caused by insufficient vitamin B-12 synthesis resulting from a defect in the remethylation of homocysteine to methionine; methylmalonic aciduria is present.
Homocystinuria can be caused by a deficiency in methylenetetrahydrofolate reductase. The methionine level is in the reference range.
Urine methionine and homocysteine levels are elevated because of deficient levels of cystathionine beta-synthase. In addition to this, at least 7 causes of homocystinuria are known: (1) defect in vitamin B-12 metabolism, (2) deficiency in N -5,10-methylenetetrahydrofolate reductase, (3) selective intestinal malabsorption of vitamin B-12, (4) homocystinuria responsive to vitamin B-12 (cobalamin [cbl] type E), (5) methylcobalamin deficiency with cbl type G, (6) type 2 vitamin B-12 metabolic defect, and (7) transcobalamin II deficiency.

The basis of the disease is a defect of the gene coding for L-serine dehydratase cystathionine synthase, which converts homocysteine and serine into cystathionine. Deficient activity of this enzyme has been demonstrated in liver extracts, in brain tissue, and in cultured skin fibroblasts and lymphocytes. The deficiency leads to an accumulation of homocysteine and methionine and to its conversion into homocysteine, which is excreted in the urine (Legal test results are positive). Alternatively, methionine is reformed and detectable in appreciable amounts in the urine and serum. The accumulation of homocysteine leads to damage of the collagen and elastic fibers. The binding of homocysteine to lysine residues results in the formation of thiazine bonds.

DL-homocysteine inhibits the production of tyrosinase, which is the major pigment enzyme. Increased concentrations of the methionine metabolite are toxic to the nervous system. Histologic analysis of brain tissue specimens from patients with homocystinuria reveals local foci of gliosis and necrosis.

In 1985, Mudd et al studied hybrid cells of human fibroblasts with normal cystathionine beta-synthase activity and hamster cells without enzyme activity and found that enzyme activity was co-segregated with chromosome 21. Two other enzymes involved in sulfur amino acid metabolism have been mapped: 5-methyltetrahydrofolate and L-homocysteine S-methyltransferase are mapped to chromosome 1, and cystathionase is mapped to chromosome 16. In cases of genetic deletion and partial trisomy, the levels of activity are consistent with the locus of cystathionine beta-synthase (CBS) between chromosomal bands 21q22.1 and 21q21. As reported in the study of fibroblasts, 3 types of cystathionine synthetase deficiency exist; these include types with reduced activity and normal affinity for P5P and types with reduced activity and reduced affinity for the cofactor.

The human CBS gene spans more than 30 kilobases and contains 19 exons. Three different 5' untranslated regions exist in the gene.

Molecular analysis of the methionine synthase reductase (MTRR) gene in one patient reveals compound heterozygosity for a transition c.1459G>A (G487R) and a 2–base pair (bp) insertion (c.1623-1624insTA). Another patient was homozygous for a 140-bp insertion (c.903-904ins140). The insertion is caused by a T>C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. These findings support the concept that this disorder is caused by mutations in the MTRR gene.

Four different mutations were identified in patients in the United Kingdom (c.374G>A, R125Q; c.430G>A, E144K; c.833T>C, I278T; c.919G>A, G307S) and 8 mutations were identified in patients from the United States (c.341C>T, A114V; c.374G>A, R125Q; c.785C>T, T262M; c.797G>A, R266K; c.833T>C, I278T; c.919G>A, G307S; g.13217A>C (del ex 12); c.1330G>A, D444N). The I278T was the predominant mutation in both populations. The spectrum of mutations observed in patients from the United Kingdom and the United States is closer to that observed in Northern Europe and bears less resemblance to that observed in Ireland.

Severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine can be another cause of hypermethioninemia.

To date, 130 pathogenic mutations have been recognized in the CBS gene. In 2004, Orendae examined 10 independent alleles in Polish patients with cystathionine beta-synthase deficiency. They detected 4 already described mutations (c.1224-2A>C, c.684C>A, c.833T>C, and c.442G>A) and 2 novel mutations (c.429C>G and c.1039+1G>T). The pathogenicity of the novel mutations was demonstrated by expression in Escherichia coli. This is the first published communication on mutations leading to cystathionine beta-synthase deficiency in Poland.

Fibrillin-1 is a 350-kd calcium-binding protein that assembles to form 10- to 12-nm microfibrils in the extracellular matrix. The structure of fibrillin-1 is dominated by 2 types of disulfide-rich motifs, the calcium-binding epidermal growth factorlike and transforming growth factor beta binding proteinlike domains. Disruption of fibrillin-1 domain structure and function contributes to the pathogenic mechanisms of homocystinuria.

Methylmalonic aciduria and homocystinuria, cblC type, is the most frequent inborn error of vitamin B-12 metabolism. The gene responsible for cblC, MMACHC, has been identified. Several observations on ethnic origins were noted: the c.331C>T mutation is seen in Cajun and French-Canadian patients and the c.394C>T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype-genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection, and for prenatal diagnosis in families in which mutations are known.

Frequency
United States
Homocystinuria is rare.

International
Homocystinuria rarely occurs. The worldwide frequency is reported to be 1 case per 344,000 population.

In Ireland, the frequency is higher, specifically 1 case per 65,000 population based on newborn screening and clinically detected cases. A surprisingly high prevalence of the CBS 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is known to neutralize the 833T-CV mutation. This finding led some authors to suggest that the incidence of homocystinuria due to homozygosity for the mutation may be at least 1 case per 20,500 live births in Denmark.

Hypermethioninemia was reported in Korea in 2 compound heterozygous siblings with deficient activity of methionine adenosyltransferase (MAT) in their livers (MAT I/III deficiency). Molecular genetic studies demonstrate that each patient is a compound heterozygote for 2 mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III. These mutations include a previously known inactivating G378S point mutation and a novel W387X truncating mutation. W387X mutant protein, expressed in E coli and purified, has about 75% of wild-type activity.

Mortality/Morbidity
The life expectancy of patients with homocystinuria is reduced.
Almost one fourth of patients die as a result of thrombotic complications (eg, heart attack) before they are aged 30 years.
Sex
The disease is more common in males than in females.

Age
This condition is congenital.

Clinical
History
Neurologic features
An infant with homocystinuria is usually healthy, although thromboembolic complications of the CNS and psychomotor delay may occur during the first year of life.
A developmental delay is noted when patients are aged 2-3 years.
Psychiatric symptoms are also described in approximately one half of patients with homocystinuria.
Pyramidal symptoms, including muscle weakness due to an insult to the innervation of the pyramidal motor tract neurons, are occasionally observed in areas such as the leg.
Skeletal and muscular features
The characteristic long thin extremities and arachnodactyly may not appear until late in childhood or during adolescence.
In contrast, osteoporosis, especially that of the spine, may have already been present for some time.
Ophthalmologic features
Severe myopia is the first sign of ectopia lentis and may precede lens dislocation by several months to a year or even longer.
Once established, ectopia lentis progresses, even when good biochemical control is maintained.
Vascular features
Thromboembolic events, such as cerebrovascular occlusions or pulmonary emboli, usually do not occur until adulthood but are reported in childhood and infancy.
Vascular occlusive disease is an important and serious feature.
Other features
Homocystinuria produces high concentrations of amino acids that are competitive inhibitors of tyrosinase.
Accordingly, homocystinuria is associated with pale and pink skin. Occasionally, patients have malar rashes, fine fragile hair, and livedo reticularis.
Physical
Marfan syndrome is the primary differential diagnosis. Clinical features of homocystinuria, such as ectopia lentis, dolichocephalia, and chest and spinal deformities, are similar to the features found in patients with Marfan syndrome, although the cerebral symptoms, the changes in the hair, and the disorders of mental development are absent in patients with Marfan syndrome. Generalized osteoporosis, arterial and venous thrombosis, and mental retardation, which are features of homocystinuria, do not occur in patients with Marfan syndrome. In addition, homocysteine is not detectable in the urine of patients with Marfan syndrome.

Findings in homocystinuria include the following:

Skin findings
Buccal skin shows red macules in children, adolescents, and adults, especially those living in warm environments.
Large pores are evident on the facial skin.
A livedolike pattern of blood vessels and atrophic, small, cigarette paper–like scars may be observed on the arms and hands.
Angiomata may develop in some patients.
DL-homocysteine inhibits tyrosinase, the major pigment enzyme. Hypopigmentation may be reversible in patients with pyridoxine-responsive homocystinuria.
The hair can have a coarse texture. Hair stained with acridine orange produces orange-red fluorescence, whereas healthy hair produces green fluorescence.
Hyperhidrosis, dry skin, and acrocyanosis may be present.
Neurologic findings
Patients may behave aggressively.
Intelligence is slightly diminished, but in approximately one third of patients, intelligence is in the normal range.
Patients' mental capabilities have been reported to be higher in conditions that respond to pyridoxine supplementation than others.
Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may manifest with variable neurologic manifestations. Radiologic features include white matter changes (leukoencephalopathy).
Muscular hypotonia is characteristic.
Increased homocysteine levels have been detected in persons with neurological disorders such as Alzheimer disease, idiopathic Parkinson disease, Huntington disease, primary dystonia, and neural tube defects.
Skeletal and muscular findings
Signs of Marfan syndrome, such as thin and long extremities, arachnodactylia, kyphoscoliosis, and deformations of the thorax, may be present.
Osteoporosis, genua valga, pectus carinatum (excavatum), and deformed teeth can be present.
The homocysteine concentration is an important risk factor for hip fractures in Parkinson disease patients receiving levodopa.
Inguinal and umbilical hernias are observed.
Muscular hypotonia is characteristic.
Spasms may occur.
Ophthalmologic findings
Ophthalmologic findings are similar to those in patients with Marfan syndrome.
Ectopia lentis is an almost universal feature in patients older than 10 years, and it can even be present in newborns.
Other findings include myopia, iridopathy, cataracts, secondary glaucoma, and degeneratio (amotio) retinae.
Atrophy of the optic nerve, strabismus, nystagmus, or diminished convergence can occur in some patients.
Dislocation of the ocular lenses usually occurs in patients aged 4-10 years.
Vascular findings
Vascular changes mainly affect the lower extremities. Fatal arterial and venous thromboses may occur.
Hyperhomocystinemia is an independent risk factor for atherosclerotic heart disease.
Patients with homocystinuria resulting from a deficiency of cystathionine beta-synthase have an increased risk of thrombosis when they also have the Leiden mutation for factor V.
Homocysteine induces tissue factor procoagulant activity in cultured human endothelial cells.
Reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen have been noted in patients with homocystinuria.
Other findings
A slightly foul odor of the urine is typical.
Spontaneous pneumothorax is reported in some adolescents with homocystinuria.
Pancreatitis is described as a complication of homocystinuria.
Increased homocysteine levels are implicated in a variety of other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, diabetic microangiopathy, and premenstrual syndrome.
Children with autism might have lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of S-adenosylhomocysteine (SAH), adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
Cystathionine beta-synthase is encoded on chromosome 21, and deficiency in its activity causes homocystinuria. The most common genetic cause of mental retardation is trisomy 21 or Down syndrome. The levels of cystathionine beta-synthase in the brains of persons with Down syndrome are approximately 3 times greater than those in healthy individuals. The over-expression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down syndrome children and that may lead to Alzheimer-type disease in Down syndrome adults.
Vascular disease is associated with increased plasma asymmetric dimethylarginine and homocysteine, and levels of both are increased in persons with renal failure. The relationship between hyperhomocystinemia and increased plasma asymmetric dimethylarginine may not be direct, but could be secondary do reduced renal function.
Snyderman reports a case of a homocystinuric patient with development of paraparesis and increasing liver failure. A liver transplantation was successful in achieving metabolic control without the need for any dietary restrictions.