Classic homocystinuria (CH) is a rare metabolic disorder. It is inherited in an autosomal recessive manner and is caused by cystathionine β-synthase deficiency. CH is associated with significantly increased serum levels of homocysteine and methionine and low concentrations of cysteine. Patients who respond to pyridoxine supplementation have a favorable prognosis. Those who are non-responsive to vitamin B6 need to adhere to strict dietary recommendations to prevent complications involving the central nervous system, skeleton, eye, and cardiovascular system.
CH patients appear normal at birth. Depending on the severity of the disease, first symptoms manifest in infancy or childhood. CH is a multisystem disease and symptoms comprise learning difficulties due to mental retardation, skeletal anomalies, myopia and ectopia lentis, and thrombophilia :
- Besides intellectual disability, CH patients may present with psychiatric and behavioral disorders, seizures, and extrapyramidal signs. The development of receptive and expressive language skills is frequently disturbed .
- Skeletal anomalies characteristic of CH encompass marfanoid features and osteoporosis as well as deformities like pectus excavatum, pectus carinatum, scoliosis, and genu valgum.
- Ectopia lentis may be preceded by progressive myopia, but may also be an isolated finding. It may be associated with glaucoma and/or retinal detachment. In most cases diagnosed after the onset of symptoms, dislocated optic lenses have raised suspicion of CH .
- Thromboembolism has been reported to be the main clinical symptom in CH due to pathogenic mutation I278T; it has also been confirmed as the most common presenting symptom of adult-onset CH   . These observations are in agreement with the hypothesis that mild CH allows for undisturbed mental and physical development and is related to a late onset of clinical disease.
Due to close genotype-phenotype correlations, the intrafamilial variability of age at symptom onset and clinical presentation is low .
Guidelines for the diagnosis and management of cystathionine β-synthase deficiency have been published in 2016 . Here, the analysis of blood samples is mentioned as an initial but essential step to CH diagnosis. The measurement of serum concentrations of homocysteine, methionine, and cysteine is strongly recommended in patients presenting with developmental delay, marfanoid habitus, ectopia lentis, progressive myopia, and other symptoms suggestive of CH. Cystathionine levels may also be assessed. Increased concentrations of homocysteine and methionine associated with decreased levels of cysteine and cystathionine are highly indicative of CH. However, such measurements are not routinely carried out and diurnal fluctuations of amino acid levels may lead to false-negative results, so it may be necessary to repeat biochemical analyses. Furthermore, differential diagnoses such as cobalamin and folic acid deficiency or renal failure should be excluded by measuring the respective serum parameters.
Biochemical results have to be confirmed by means of enzyme activity assessment or genetic analyses. The activity of cystathionine β-synthase can be determined in fibroblasts, but this is a rather cumbersome approach to diagnosis. Today, genetic studies are the gold standard for CH diagnosis. They should be carried out to resolve possible doubts as to the underlying disease and to identify the specific mutation. The latter is of practical interest because of well-defined genotype-phenotype correlations and predictable responses to vitamin B6 supplementation . Additionally, knowledge regarding the CBS mutation carried by a particular patient is valuable for genetic counseling and a possible prenatal diagnosis of the disease. Enzyme activity measurements in fibroblasts don't provide any information as to the specific mutation and may yield results in the reference range in case of mild disease. Still, such assays have to be carried out if CBS mutations cannot be identified despite strong suspicion.
If CH is diagnosed before irreversible tissue damage occurs, severe complications can be avoided. Therefor, therapy should be initiated as early as possible. The oral supplementation of pyridoxine is the mainstay of treatment in case of vitamin B6-responsive CH. In patients suffering from vitamin B6-responsive CH, serum levels of homocysteine should decrease below <100 μmol/l on pyridoxine alone . Ideally, they even diminish to <50 µmol/l. If homocysteine concentrations are kept below that threshold, patients are unlikely to develop any complications at all . Because of potential side effects such as peripheral neuropathy, pyridoxine doses should be as low as possible to maintain acceptable homocysteine levels.
Additionally, CH patients may benefit from betaine. Betaine reduces homocysteine concentrations by enhancing its conversion to methionine in the remethylation pathway. Patients who don't achieve physiological levels of homocysteine on pyridoxine and/or betaine should follow a low-methionine diet. They should be given a cysteine-enriched methionine-free amino acid supplement. All patients should receive folic acid and cobalamin supplementation  .
Serum levels of homocysteine should be monitored and serve as an indicator of response to therapy. It is also recommended to check patients for folic acid and cobalamin deficiencies. Bone density scans should be carried out every 3-5 years from adolescence, and patients should undergo regular ophthalmological examinations. Lifelong treatment is required in all cases.
Enzyme replacement therapy is not yet available but is the focus of intense research efforts .
In general, vitamin B6-responsiveness is related to a milder phenotype and better prognosis . Additionally, long-term morbidity and mortality can be reduced by early treatment. Where CH is not part of the newborn screening profile, diagnosis of the disease is generally delayed by several years and patients thus have a worse prognosis  . Because hyperhomocysteinemia is an independent risk factor for atherosclerosis, ischemic myocardial infarction, and other forms of cardiovascular disease , compliance with the therapeutic regimen is of major importance to improve an individual patient's prognosis regardless of the underlying mutation and their age at the time of diagnosis.
While central nervous system involvement, skeletal anomalies, and ophthalmological complications may account for significant morbidity and long-term disability, thromboembolism is the main cause of CH-associated early mortality . CH-related tissue damage is essentially irreversible. Still, CH patients who are diagnosed early and comply with treatment recommendations are likely to experience normal growth and development and have a normal life expectancy .
CH is an inherited metabolic disorder. Affected individuals are homozygous or compound heterozygous for pathogenic mutations in the CBS gene. This gene is predominantly expressed in liver, pancreas, kidney, and brain and encodes for cystathionine β-synthase, an enzyme catalyzing the conversion of homocysteine and serine to cystathionine . More than 160 CBS mutations have been described to date and certain mutations are associated with vitamin B6-responsiveness and lack of response to pyridoxine, respectively . In the United Kingdom, mutations I278T, G307S, and R336C are most common and genotypes I278T and R336C usually predict responsiveness to vitamin B6. By contrast, patients homozygous for CBS G307S don't generally improve under pyridoxine therapy . The latter also applies to individuals carrying CBS alleles T191M . In sum, these four mutations account for more than half of all CBS cases worldwide .
For the United Kingdom, the incidence of CH has been estimated to <2 in 100,000 live births. Highest incidence rates have been reported for individuals of Irish descent and ethnicities practicing consanguineous marriage   . In Qatar, the frequency of carriers is 2% and the incidence of CH amounts to 1 in 1,800 live births . Of note, recent studies suggest that incidence and prevalence of CH have long since been underestimated. This conclusion is based on a striking discrepancy between heterozygote frequencies and numbers of clinical cases. Presumably, this apparent contradiction can be explained by a relatively high proportion of asymptomatic patients . With regard to symptomatic patients, their age at symptom onset ranges from <1 to >20 years, with more severe variants of the disease manifesting earlier.
The conversion of homocysteine and serine to cystathionine is part of the transsulfuration pathway and requires pyridoxal phosphate as a cofactor for cystathionine β-synthase. Homocysteine itself is synthesized from methionine. While the conversion of homocysteine to cystathionine is irreversible, excess homocysteine can be converted back to methionine in the remethylation pathway . Accordingly, the transsulfuration cascade implicates the elimination of both methionine and homocysteine, and the deficiency of cystathionine β-synthase causes the accumulation of these amino acids in blood and tissues of CH patients.
The pathophysiological events leading to neurological, skeletal, and ocular anomalies in CH patients are incompletely understood. Homocysteine has been suggested to be involved in the modulation of sulfhydryl groups on distinct proteins. Such modulations of sulfhydryl groups may interfere with cross-linking and thus alter the physical and functional properties of the affected protein. Connecting tissue, for instance, may lose stability and resistance. This would explain why CH patients present with marfanoid features and lens dislocation, much like individuals suffering from Marfan syndrome . Thromboembolism is often explained by endothelial dysfunction and impaired thrombolysis. But even though a reduced availability of vasodilator nitric oxide has been proposed as a trigger of endothelial dysfunction and cardiovascular disease in CH patients, evidence regarding the molecular basis of these conditions is still scarce .
Newborn screenings for genetic and inherited metabolic disorders should include CH. The identification of affected individuals before the onset of clinical disease allows for a timely initiation of treatment and is associated with best prognoses . Beyond that, future parents known to carry mutations in the CBS gene should be offered genetic counseling. The prenatal diagnosis of CH is feasible using chorionic villi or amniocytes .
CH is an inherited metabolic disorder. Due to cystathionine β-synthase deficiency, affected individuals suffer from disturbances of amino acid metabolism. This enzyme is required for the elimination of methionine and homocysteine, so CH patients have increased serum and tissue levels of these amino acids. Methionine and homocysteine have been speculated to be involved in the modulation of sulfhydryl groups on different proteins, thereby interfering with the function of multiple proteins . Considering that, it's not surprising that CH presents as a multisystem disease: Central nervous system involvement results in developmental delays, but skeletal growth is also disturbed. CH patients may suffer from progressive myopia and lens dislocation and are at high risks of cardiovascular accidents throughout adulthood.
The prognosis of an individual patient largely depends on the stage of the disease at the time of diagnosis. Compliance with therapeutic regimens is another factor determining the outcome. An early diagnosis allows for the timely initiation of therapy and possibly the avoidance of all complications. By contrast, CH diagnosed in advanced stages is often associated with irreversible tissue damage. Beyond that, an individual patient's genotype determines whether oral pyridoxine supplementation suffices to maintain serum levels of homocysteine below threshold values. If this is not the case, patients have to follow strict dietary recommendations and still have a poorer prognosis.
The term "homocystinuria" refers an increased excretion of homocystine in the urine. This condition is due to elevated serum concentrations of homocysteine, an intermediate amino acid and precursor of homocystine. Abnormally high levels of homocysteine in blood and tissues are associated with a variety of symptoms, namely intellectual disability and psychiatric disorders, marfanoid skeletal features and osteoporosis, myopia and lens dislocation, and an increased risk for thrombotic events.
Under physiological conditions, homocysteine is converted to cystathionine. This reaction is catalyzed by an enzyme named cystathionine β-synthase. However, patients with classic homocystinuria (CH) suffer from cystathionine β-synthase deficiency, i.e., their bodies are unable to synthesize cystathionine β-synthase and to eliminate homocysteine. Cystathionine β-synthase deficiency is a genetic condition and for a person to develop CH, defective alleles have to be inherited from both their parents. The specific mutation in the CBS gene determines whether the disease follows a mild or severe course, and whether symptom onset occurs in infancy, childhood or adolescence.
CH therapy aims at lowering serum levels of homocysteine. In some cases, this may be achieved by the oral supplementation of vitamin B6. If this is not the case, alternative treatment options have to be considered and patients must follow strict dietary recommendations. Compliance with treatment regimens is of utmost importance to avoid CH-associated complications, long-term morbidity, and early mortality. In order to assure a patient's response to therapy, they need to undergo regular follow-ups, in which serum homocysteine levels, bone density, vision, organ function and other parameters are assessed.
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