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Frequently Asked Questions

What is homocystinuria?
Homocystinuria is a rare clinical condition characterized by severely elevated plasma concentrations of homocysteine (total homocysteine [tHcy] > 100 µM). There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.

Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic).

The signs and symptoms of homocystinuria typically develop within the first year of life, although some people with a mild form of the disease may not develop features until later in childhood or adulthood.

What are the causes of homocystinuria?
Defects in several genes can result in homocystinuria:
  • The CBS gene (trans-sulphuration pathway): CBS deficiency is autosomal recessive. Patients are characterized by elevated homocysteine and methionine levels. They are divided into two major groups according to their response to pyridoxine ( a cofactor of the CBS enzyme): pyridoxine-responsive and pyridoxine non-responsive patients. Approximately 45% of patients are pyridoxine responsive (Yap et al., 2001).
  • The MTHFR gene (remethylation pathway): MTHFR deficiency is an autosomal recessive defect of the MTHFR gene leading to low methylfolate (MTHF) concentrations. The defect of MTHFR results in increased homocysteine levels and low or normal methionine concentrations.
  • The group of cbl genes (remethylation pathway): cbl deficiencies are autosomal recessive. In some cases the synthesis of both methyl and adenosyl cobalamin is impaired, in others the methionine synthase and methionine synthase reductase are deficient. Methionine levels are low or normal while homocyteine levels are increased.

What is the incidence?
The estimated incidence of homocystinuria due to CBS deficiency is 1 in 335,000 births worldwide, with marked regional variations. Based on newborn screening for hypermethioninemia, Ireland shows one of the highest known prevalence with an estimation of 1/65,000 (Naughten et al., 1998). In Japan only 1/1,052,000 live births are CBS deficient (Mudd et al., 1989).

Remethylation deficiencies are estimated as twice less frequent than CBS deficiency.

What are the symptoms?
Homocystinuria results in a variety of symptoms affecting mainly the eyes, the central nervous system, the vascular and skeletal systems as well as the patient’s growth.
While the enzymatic deficiency is present at birth, symptoms may develop in infancy, childhood or as late as adulthood. Developmental delay, severe and fast progressing myopia and ectopia lentis are early warning signs.

Other symptoms include mental deficiency, seizures, psychiatric disturbances, osteoporosis and scoliosis, and Marfanoid features. There is a high risk of thromboembolic complications at any age. These may lead to stroke, seizures, permanent neurological sequelae, increased surgical risk and/or death. The prognosis in the absence of treatment is poor: mortality at the age of 23 years is approximately 20% in pyridoxine non-responsive patients versus < 5% in pyridoxine responsive patients.

How is homosystinuria  diagnosed?
Early diagnosis of homocystinuria is important as many of the symptoms associated with the disease can be prevented by efficient treatment.

Very few of the symptoms described above are specific for homocystinuria making an early diagnosis difficult. Patients are often only diagnosed after a substantial delay. Cruysberg et al., (1996) reported a mean delay of 11 years between the onset of first symptom and the correct diagnosis.

Screening of siblings is recommended upon diagnosis of a homocystinuric patient.

How is homocystinuria being treated?
Patients are treated with one or more of the three following treatment options. The aim of treatment is always the reduction of homocysteine.
  • Methionine restricted diet: Restricted dietary intake of methioinine aims at decreasing the pressure on the metabolic cycle. It is effective in preventing mental deficiency in pyridoxine non-responsive CBS patients detected as newborns and treated early on. However, this form of regimen is one of the most restrictive diets for the treatment of the metabolic diseases, hence many children and late-diagnosis patients have difficulty complying. Furthermore, dietary treatment does not lead to reversal of major pre-existing abnormalities, though it can stop further progression (Mudd et al., 1985).
  • Pyridoxine (Vitamin B6) + Folate( Vitamin B9) + Cobalamin (Vitamin B12): The supplementation of pyridoxine, folate and vitamin B12 ( also referred to as “vitamin treatment”) optimizes the remethylation of homocysteine via the folate dependent remethylation cycle. Patients who are not given folate while on pyridoxine become folate depleted due to the increased flux through the remethylation pathway. To avoid folate refractoriness, it is mandatory to prevent deficiency of vitamin B12, the cofactor in folate-mediated remethylation of homocysteine into methionine. (Boers et al., 2000).
  • Cystadane® ( betaine anhydrous): Cystadane® activates an alternative remethylation for homocysteine via betaine-homocysteine methyltransferase (BHMT). It has been proven to further lower the homocysteine concentration when added to vitamin treatment and/or methionine restricted diet for all homocystinuric patients. In particular in late detected, non-compliant or late treated CBS deficient patients the beneficial effect of betaine with respect to biochemical and clinical features of homocystinuric patients has been extensively documented.