Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

Defects in the human Ca(2+)-sensing receptor gene have recently been shown to cause familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. We now demonstrate that a missense mutation (Glu128Ala) in this gene causes familial hypocalcaemia in affected members of one family. Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor. We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.

When EGF is offside, magnesium is wasted.

Our understanding of magnesium (Mg(2+)) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg(2+) homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg(2+) wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg(2+) wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.

Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia.

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.

Neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous Kv1.1 N255D mutation with normal serum magnesium levels.

Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the KCNA1 gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in KCNA1, previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.

A de novo KCNA1 Mutation in a Patient with Tetany and Hypomagnesemia.

Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.

[Severe erythrodermic psoriasis in a patient with 22q11 deletion syndrome]. / Schwere psoriatische Erythrodermie bei 22q11-Deletionssyndrom.

BACKGROUND: Erythrodermic psoriasis is a severe manifestation of psoriasis and can be triggered by several factors. CASE REPORT: A 35-year-old man was admitted with severe, almost generalized exfoliative, oozing erythrodermic psoriasis, fever, and cramping of hands and legs. He was under systemic treatment with acitretin. Laboratory examination revealed a marked hypocalcemia as a consequence of primary hypopara thyroidism as well as hypalbuminemia. After normalization of the serum calcium and albumin levels, cutaneous symptoms and fever rapidly improved. No infectious etiology could be found. Hypoparathyroidism together with a right-sided aorta was caused by a 22q11 deletion syndrome. CONCLUSION: Epidermal cell proliferation and formation of intercellular junctional components of the epidermis are strongly calcium-dependent. Furthermore, carriers like albumin are necessary for the transportation of acitretin in the peripheral tissue. This case report suggests that calcium can be involved in psoriasis pathogenesis at least in a subgroup of patients and that systemic retinoids exhibit insufficient effectiveness under low serum albumin levels.

Normocalcemic tetany. A problem of erethism.

A boy with neonatal and childhood convulsions had prolonged attacks of tetany in adolescence. There was no abnormality of serum calcium or magnesium, and treatment with these cations was ineffective. There was no respiratory alkalosis, and attacks occurred when the patient had not taken anticonvulsant drugs for years. Serum parathormone content and renal responses to the administration of parathormone were normal. "Normocalcemic tetany" seems an appropriate name for the condition, which was probably genetic since the patient's brother and mother had signs of latent tetany and the brother had a convulsive disorder. The cause of the syndrome is not known, but it seems to be an abnormal response of neural membranes rather than an abnormality of calcium homeostasis.

Hypomagnesaemic tetany.

Hypomagnesaemic tetany (hypomagnesaemic tetany with secondary hypocalcaemia) is a rare inherited form of hypomagnesaemia. Initial reports involved affected males only; however, affected females have also been reported. The case of a child with hypomagnesaemic tetany is described, the biochemical and genetic aspects of this condition are reviewed and the importance of the assessment of renal magnesium excretion in patients presenting with hypomagnesaemia is highlighted.

Mistaken diagnoses in continuous muscle fiber activity of peripheral nerve origin.

The syndrome of continuous muscle fiber activity of peripheral nerve origin has manifestations that resemble those of many other more common neurologic disorders during childhood and infancy. This similarity often leads to misdiagnosis when an adequate index of suspicion is not entertained and a comprehensive electromyographic examination is not performed. Two affected patients from 1 family are reported to illustrate the type of diagnostic errors that were made before the establishment of the correct diagnosis.

[Development of tetany in siblings suffered from Bartter's syndrome].

The present authors observed and treated a siblings case of normocalcemic tetany, which is considered as belonging to Bartter's syndrome. As far as we know, there are a number of familial cases of tetany in literature, but none of them spreads over more than two generations, so that the tetany appears to be recessive in hereditary characters including our patients. Both of them presented tetanic seizures in the course of Bartter's syndrome and they were regarded as one of various manifestations of the syndrome. In other words, the Bartter's syndrome or the hypopotassemia should be one of the fundamental disorders for developing tetanic symptom. The tetanic symptoms became extinct during the treatment with spironolactone against hypopotassemia. Of the two patients, younger sister had shown an agitated depression developed on her childish and over-sensitive personality, but the depression was improved in parallel to the recovery from tetany and hypopotassemia. Therefore, it appears to be certain that the patients would have some premorbid deviation of personality traits, where symptomatic psychoses could be attributed, in the case of Bartter's syndrome. Generally speaking the psychic disorders, such as personality deviation and psychotic episode, seem to by very important symptoms in patient with Bartter's syndrome as well as in patient with hypocalcemia or hypoparathyroidism.