Treatment of Homocystinuria With a Low-Methionine Diet, Supplemental Cystine, and a Methyl Donor

Perry, ThomasL.; Hansen, Shirley; Love, D. N.; Crawford, LouiseE.; Tischler, Bluma

doi:10.1016/s0140-6736(68)90646-6

Cited by 62 publications

(32 citation statements)

References 8 publications

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“…Similar observations have been made by other investigators [16]. However, other patients with homocystinuria did not respond to the therapy with pyridoxine [26].…”

Section: Discussionsupporting

confidence: 89%

“…Supplementation of a patient's diet with cystine for a prolonged period produced no demonstrable improvement [8]. Methyl donors, such as betaine [17], choline [26], folic acid [7], and B 12 [15] have been used in an attempt to remove homocystine by methylating homocystine to form methionine. It has not been possible to eliminate homocystine by the use of methyl donors alone.…”

Section: Discussionmentioning

confidence: 99%

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Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Wong

Fresco

1972

Pediatr Res

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ExtractMouse brain was demonstrated to concentrate DL-homoserine and L-cysteine from plasma. Simultaneous injection of 7.5 /xmoles DL-homoserine and L-cysteine intraperitoneally to mice resulted in a marked increase of brain cystathionine at the end of 5 hr. The concentration of cystathionine in the experimental group (0.143 ± 0.022 /imole/g) was more than 6 times that of the control group (0.023 d= 0.011 /oriole/g). By using unlabeled DL-homoserine and DL-cysteine-36 S lor injection, cystathionine in brain was found to be labeled, with a specific activity (67,800 dpm/^mole) approximately half that in the radioactive cysteine (115,000 dpm/^mole). These observations suggest that approximately half the cystathionine in brain has been derived from cysteine and, presumably, homoserine. The remaining half is presumed to have been derived from methionine.Chronic feeding of diets containing 5%, 2%, and 1% DL-homoserine and L-cysteine, 5% and 2% DL-homoserine, and 5%, 2%, and 1% L-cysteine to weanling mice resulted in a significant increase in cystathionine in brain compared with controls (0.148 ± 0.016, 0.049 ± 0.002, 0.044 ± 0.002, 0.040 ± 0.001, 0.043 ± 0.003, 0.069 ± 0.003, 0.036 db 0.002, 0.034 ± 0.002, and 0.027 ± 0.003 /miole/g, respectively) .After 34 weeks of dietary experiments, the animals fed with diets containing 5%, 2%, and 1% of both DL-homoserine and L-cysteine, 5% DL-homoserine, and 5% and 2% L-cysteine had significantly lower body weight than that of the controls (22.02 db 0.290, 26.00 ± 0.460, 26.40 ± 0.462, 25.50 db 0.504, 23.10 ± 0.388, 25.82 ± 0.512, and 28.53 ± 0.786 g, respectively). The lower weight gained in the experimental animals was correlated with less food intake.Autopsy on all the experimental animals and light microscopy of their brains, lungs, hearts, livers, spleens, suprarenals, kidneys, and intestines showed no pathology. However, electron microscopy of the livers of animals fed with diets containing 5% cysteine showed subcellular changes compatible with poor nutrition, possibly related to inadequate food intake.Animals on all the experimental diets remained fertile; they conceived and produced normal litters. SpeculationThe observations reported in this paper demonstrated that cystathionine in brain was increased when mice were given cysteine and homoserine either by intraperi-172 Cystathionine in cysteine-and homoserine-treated mice 173 toneal loading or by chronic feeding. It is very probable that tissue cystathionine (particularly that of the brain) may be increased in patients with homocystinuria when adequate amounts of cysteine (or cystine) and homoserine are supplied in the diet. Excessive cysteine may produce unpalatability of the diet. However, this may be corrected by reducing the quantity of cysteine added, flavoring the diet, or by replacing the cysteine with cystine or calcium cystinate. Supplementation of cysteine (or cystine) and homoserine may be the only way to correct cystathionine deficiency in patients with pyridoxine-resistant homocystinuria.Our observations ...

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“…Similar observations have been made by other investigators [16]. However, other patients with homocystinuria did not respond to the therapy with pyridoxine [26].…”

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Wong

Fresco

1972

Pediatr Res

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“…Our team pioneered a low methionine dietary intervention, and working with a family, prevented the mental disability that is the usual tragic result of this condition. We published the results in the Lancet in 1968 [6].…”

Section: My Careermentioning

confidence: 99%

Five Decades: From Challenge to Acclaim

Melina¹

2016

Canadian Journal of Dietetic Practice and Research

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What can make your work as a dietitian so meaningful that you begin each day with enthusiasm, and if you so choose, retain that joy in your work for 5 decades or more? Three themes are: (i) doing work that profoundly makes sense to you, (ii) inspiring others (and yourself) to make healthful choices, and (iii) moving through challenges to success. Initially it can be challenging to make a living through work that is most deeply meaningful or closest to your heart. Yet it is well worth finding the balance between practicality and movement in the desired direction. Other challenges faced by dietitians involve helping others to adopt new, more healthful lifestyle choices. As health professionals, our attitudes towards plant-based diets have changed dramatically during these past decades. This article examines our evolving perspectives of plant-based diets, and uses this as an example of movement through challenges to success and acclaim. Vegetarian and vegan diets that were considered entirely inappropriate for many stages of the life cycle in the 1970s are now seen to confer health benefits. This applies to well-designed plant-based diets, thus offering a significant role for dietitians as creative leaders in this field.(Can J Diet Pract Res. 2016;77:154-158)

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“…To date, the most effective of these has been the use of betaine. Perry et al 17 pioneered the concept of dietary supplementation with a methyl donor compound to promote the BHMT catalyzed remethylation of Hcy to methionine as a treatment for HCU. This group used dietary supplementation with the betaine precursor compound choline, in combination with a methionine-restricted diet.…”

Section: Betainementioning

confidence: 99%

Betaine treatment of cystathionine β-synthase-deficient homocystinuria; does it work and can it be improved?

Maclean¹

2012

ODRR

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Inactivating mutations in cystathionine β-synthase result in classical homocystinuria (HCU) and are typically accompanied by severe elevations of plasma and tissue homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine and significantly decreased cysteine. HCU is usually accompanied by marfanoid skeletal abnormalities, osteoporosis, ectopia lentis and/ or severe myopia, cognitive impairment, and a dramatically increased incidence of atherosclerosis and thromboembolic complications of variable presentation. If untreated, HCU is a serious lifethreatening disease. Betaine (N,N,N-trimethylglycine) is a zwitterionic quaternary ammonium compound that can lower homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and increase cysteine in HCU by serving as a methyl donor for the remethylation of homocysteine in a reaction catalyzed by betaine-homocysteine S-methyltransferase. This review considers the clinical efficacy and safety of betaine treatment of HCU. Possible strategies by which the efficacy of this treatment might be improved are discussed.

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Treatment of Homocystinuria With a Low-Methionine Diet, Supplemental Cystine, and a Methyl Donor

Cited by 62 publications

References 8 publications

Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Five Decades: From Challenge to Acclaim

Betaine treatment of cystathionine β-synthase-deficient homocystinuria; does it work and can it be improved?

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Treatment of Homocystinuria With a Low-Methionine Diet, Supplemental Cystine, and a Methyl Donor

Cited by 62 publications

References 8 publications

Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Tissue Cystathionine in Mice Treated with Cysteine and Homoserine

Five Decades: From Challenge to Acclaim

Betaine treatment of cystathionine &beta;-synthase-deficient homocystinuria; does it work and can it be improved?

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Betaine treatment of cystathionine β-synthase-deficient homocystinuria; does it work and can it be improved?