Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.

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“…Studies of CBS-deficient mice gave similar results (Gupta et al 2016). This may be because betaine treatment raises the Met concentration.…”

Section: Recommendationssupporting

confidence: 58%

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Morris

Kožich

Santra

et al. 2016

J of Inher Metab Disea

270

360

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“…The original Maeda Cbs −/− mice fail to respond to betaine, while both the HO mice and Tg-I278T Cbs −/− mice showed significant lowering of plasma tHcy [30, 31]. Since the HO and Tg-I278T Cbs −/− mice show much less liver damage compared to the Maeda Cbs −/− animals, it is possible that betaine lowering is dependent on good liver function.…”

Section: Mouse Model Of Cbs Deficiency: Overcoming Neonatal Lethalitymentioning

confidence: 99%

“…Dietary intervention studies show that both the low BMD phenotype and loss of fat mass could be reversed by a low methionine diet, which lowered mean tHcy from 357 to 81 μM [39]. However, betaine supplementation, which only lowered tHcy to 159 μM, was not as effective in reversing the phenotype [31]. These findings suggest that, in mice, there is a tHcy threshold that must be crossed before either osteoporosis or loss of fat mass can occur.…”

Section: Skeletal Fat Mass and Hair Abnormalitiesmentioning

confidence: 99%

Cystathionine β-synthase deficiency: Of mice and men

Kruger

2017

Molecular Genetics and Metabolism

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Cystathionine β-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60 years ago, these is still much we do not understand related to how this specific metabolic defect gives rise to its distinct phenotypes. To try and answer these questions, several groups have developed mouse models on CBS deficiency. In this article, we will review various mouse models of CBS deficiency and discuss how these mouse models compare to human CBS deficient patients.

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“…Diet, genotype, and serum metabolites. Data for this figure were compiled from previously published data . Only growth curves of males are shown, but females behave similarly.…”

Section: Dietary Interventions: Overview and Experimental Designmentioning

confidence: 99%

“…The other animal is Tg‐I278T Cbs +/– . Data for this figure were compiled from previously published data …”

Section: Dietary Interventions: Overview and Experimental Designmentioning

confidence: 99%

The effect of dietary modulation of sulfur amino acids on cystathionine β synthase–deficient mice

Kruger

Gupta

2015

Annals of the New York Academy of Sciences

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Cystathionine β synthase (CBS) is a key enzyme in the methionine and cysteine metabolic pathway, acting as a metabolic gatekeeper to regulate the flow of fixed sulfur from methionine to cysteine. Mutations in the CBS gene cause clinical CBS deficiency, a disease characterized by elevated plasma total homocysteine (tHcy) and methionine and decreased plasma cysteine. The treatment goal for CBS-deficient patients is to normalize the metabolic values of these three metabolites using a combination of vitamin therapy and dietary manipulation. To better understand the effectiveness of nutritional treatment strategies, we have performed a series of long-term dietary manipulation studies using our previously developed Tg-I278T Cbs−/− mouse model of CBS deficiency and sibling Tg-I278T Cbs+/− controls. Tg-I278T Cbs−/− mice have undetectable levels of CBS activity, extremely elevated plasma tHcy, modestly elevated plasma methionine, and low plasma cysteine. They exhibit several easily assayable phenotypes, including osteoporosis, loss of fat mass, reduced life span, and facial alopecia. The diets used in these studies differed in the amounts of sulfur amino acids or sulfur amino acid precursors. In this review, we will discuss our findings and their relevance to CBS deficiency and the concept of gene–diet interaction.

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Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Cited by 21 publications

References 25 publications

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Cystathionine β-synthase deficiency: Of mice and men

The effect of dietary modulation of sulfur amino acids on cystathionine β synthase–deficient mice

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