Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular, and coronary heart disease. 1-4 Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 1,5-7 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery diseases. 6 We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.

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Primary hypomagnesemia constitutes a rare heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg 2+ ) wasting resulting in generally shared symptoms of Mg 2+ depletion, such as tetany and generalized convulsions, and often including associated disturbances in calcium excretion. However, most of the genes involved in the physiology of Mg 2+ handling are unknown. Through the discovery of a mutation in the EGF gene in isolated autosomal recessive renal hypomagnesemia, we have, for what we believe is the first time, identified a magnesiotropic hormone crucial for total body Mg 2+ balance. The mutation leads to impaired basolateral sorting of pro-EGF. As a consequence, the renal EGFR is inadequately stimulated, resulting in insufficient activation of the epithelial Mg 2+ channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) and thereby Mg 2+ loss. Furthermore, we show that colorectal cancer patients treated with cetuximab, an antagonist of the EGFR, develop hypomagnesemia, emphasizing the significance of EGF in maintaining Mg 2+ balance. IntroductionMagnesium (Mg 2+ ) is established as a central electrolyte in a large number of cellular metabolic reactions, including DNA synthesis, neurotransmission, and hormone receptor binding. It is a component of GTPase and a cofactor for Na,K-ATPase, adenylate cyclase, phosphoinositide kinases, and phosphofructokinase (1). Mg 2+ is also important for the regulation of parathyroid hormone release (2, 3). Accordingly, Mg 2+ deficiency (plasma Mg 2+ concentrations below 0.70 mM) has an effect on multiple body functions. Symptoms of Mg 2+ deficiency are mostly related to muscle dysfunctioning, such as tetany, prolonged QT interval, and cardiac arrhythmias (4). Children with hypomagnesemia often present with tetany and/or convulsions. Hypomagnesemia is a problem frequently observed in more than 10% of hospitalized patients and occurrences can be as high as 65% in intensive care patients (5). A long-term complication seen in many adult patients with chronic hypomagnesemia is chondrocalcinosis, which can lead to impairment of joint function (4). Mg 2+ deficiency can be secondary to systemic diseases (for instance, diabetes mellitus and Crohn disease) or to the use of osmotic agents, diuretics, and drugs such as cyclosporin and cisplatin (6). In addition, primary Mg 2+ deficiency is observed in several monogenetic disorders. Failure of early diagnosis or noncompliance with treatment can be fatal or result in permanent neurological damage.

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.