GenDaB: 1 gene found

HYPOMAGNESEMIA 3, RENAL; HOMG3   248250

INHERITANCE: Autosomal recessive
GROWTH: [Other]; Failure to thrive HEAD AND NECK: [Eyes]; Strabismus; Nystagmus; Hyperopia; Myopia; Astigmatism
ABDOMEN: [Gastrointestinal]; Abdominal pain; Feeding problems
GENITOURINARY: [Kidneys]; Polyuria; Nephrocalcinosis; Progressive renal insufficiency; Renal failure; Nephrolithiasis; Renal magnesium wasting; Renal calcium wasting; [Bladder]; Recurrent urinary tract infections MUSCLE, SOFT TISSUE: Tetany
NEUROLOGIC: [Central nervous system]; Seizures METABOLIC FEATURES: Polydipsia; Incomplete distal renal tubular acidosis LABORATORY ABNORMALITIES: Hypomagnesemia; Normal serum calcium; Elevated parathyroid hormone; Hyperuricemia; Hypermagnesiuria; Hypercalciuria; Hypocitraturia; Hematuria; Abacterial leukocyturia
MISCELLANEOUS: Onset in early childhood; Presenting symptoms - recurrent UTI, polyuria/polydipsia, hematuria, and abacterial leukocyturia; Hypercalciuria and/or nephrolithiasis occurs in heterozygotes MOLECULAR BASIS: Caused by mutation in the claudin 16 gene (CLDN16, 603959.0001)

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A number sign (#) is used with this entry because the disorder is caused by mutation in the claudin-16 gene on chromosome 3 (CLDN16; 603959). A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement. See also Gitelman syndrome (263800), a disorder of combined potassium and magnesium depletion. For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014. CLINICAL FEATURES Friedman et al. (1967) described convulsions in infants in the neonatal period. Primary hypomagnesemia, thought to be due to a defect in intestinal absorption, was present. Associated hypocalcemia was corrected by administration of magnesium alone. The genetic basis of the defect was suggested by its persistence over a period of months and by the fact that the parents were first cousins. Salet et al. (1970) reported the disorder in brother and sister. Manz et al. (1978) described 2 sisters with polyuria, hyposthenuria, hypomagnesemia, hypercalciuria, advanced nephrocalcinosis, low citrate excretion, and low glomerular filtration rates. Acid loading showed incomplete distal tubular acidosis. Hypomagnesium was due to renal magnesium wasting. Their hypothesis that the primary defect was one in renal tubular transport of magnesium was supported by the report by Passer (1976) of 2 adult patients with hypomagnesemia due to intestinal malabsorption combined with incomplete renal tubular acidosis. Both patients responded to Mg supplementation with correction of the renal acidification defect. Manz et al. (1978) suggested that the same disorder was present in the sibs reported by Michelis et al. (1972). Five pairs of affected sibs have been reported, including 2 instances of affected brother and sister (Evans et al., 1981). A parent (Paunier and Sizonenko, 1976) and a child (Freeman and Pearson, 1966) of a patient were said to be affected in other reports. Hennekam and Donckerwolcke (1983) observed Chinese brother and sister with primary hypomagnesemia. The 5-year-old sister, the proband, was admitted to hospital because of tetany following gastroenteritis for several days. She had never before had spasms. Intravenous calcium gluconate had no effect, but after magnesium chloride intravenously, the tetany stopped at once. The affected 17-year-old brother was discovered on family screening. He complained of muscle weakness for more than 2 years and had paresthesias of the fingers and spontaneous spasms. During venipuncture, Trousseau sign was elicited. In the sister and brother, serum magnesium was 0.56 and 0.49 nmol/l, respectively (normal, 0.7-1.0), and serum calcium was 2.09 and 2.31 nmol/l, respectively (normal, 2.25-2.75). The parents denied consanguinity. These authors found a total of 32 reported cases of primary hypomagnesemia of which 10 were in females. Although symptoms usually began in the first 3 months of life, they were delayed to the 36th year in the extreme. Consanguineous parents were reported by Becker et al. (1979) and by Friedman et al. (1967). Secondary magnesium-losing kidney can be caused by diuretics, gentamicin, mercury-containing laxatives, transplanted kidney, urinary tract obstruction, and the diuretic phase of acute renal failure. The disorder may be incorrectly diagnosed as primary hypoparathyroidism because of tetany and hypocalcemia, or as Bartter syndrome because of secondary renal potassium wasting. The diagnosis is made by finding hypomagnesemia with inappropriately high urinary magnesium excretion. Nephrocalcinosis is frequent. Chondrocalcinosis with arthritis is a recognized complication of magnesium depletion. Evans et al. (1981) reported 2 brothers, aged 39 and 29, with infertility and severe oligospermia but normal endocrine function. One of the brothers had sensorineural deafness. Neither deafness nor male infertility had been reported previously in this disorder. Dudin and Teebi (1987) described primary hypomagnesemia with secondary hypocalcemia as a cause of infantile tetany and convulsions in an Arab girl of consanguineous parentage. Praga et al. (1995) used the designation 'familial hypomagnesemia with hypercalciuria and nephrocalcinosis' and cited the patients reported by Michelis et al. (1972), Manz et al. (1978), Evans et al. (1981), Ulmann et al. (1985), and Rodriguez-Soriano et al. (1987) as examples of this disorder. They studied 8 patients from 5 different families. Mean age at diagnosis was 15 years with a range from 5 to 25. All 8 patients had polyuria-polydipsia; 5 had ocular abnormalities (corneal calcifications, chorioretinitis, nystagmus, myopia); 5 had recurrent urinary tract infections; and 2 had recurrent renal colic with passage of stones. Bilateral nephrocalcinosis was observed in all cases. The mean serum magnesium was 1.1 mg/dl with inappropriately high urinary magnesium excretions (70 mg/day). Hypercalciuria was present in every case except in those with advanced renal insufficiency. Serum parathormone levels were abnormally high. Serum Mg and urinary Ca became normal after renal transplantation in 5 patients. None of the 26 members of 4 of the affected families showed hypomagnesemia, renal insufficiency, or nephrocalcinosis; however, 11 (42%) had hypercalciuria and 4 of them presented with recurrent renal stones. Two family members had medullary sponge kidneys. In 1 family, 2 affected individuals were double first cousins. The daughters of 2 sisters married 2 brothers. In another family, the affected brother and sister in one sibship were cousins of an affected female in a first-cousin sibship. Praga et al. (1995) speculated that isolated hypercalciuria might be a heterozygous manifestation. Challa et al. (1994) described 2 female sibs with primary idiopathic hypomagnesemia, born to consanguineous parents. Both presented at 6 weeks of age, with convulsions and persistent hypocalcemia, which could not be controlled with anticonvulsants and/or calcium gluconate. Serum magnesium values of the mother and father were just below the normal range with normal serum calcium. Shalev et al. (1998) described the clinical presentation and long-term outcomes of 15 patients with autosomal recessive primary familial hypomagnesemia. The most common (67%) presenting events were generalized hypocalcemic-hypomagnesemic seizures at a mean age of 4.9 weeks. Thirteen infants who were treated soon after diagnosis with high-dose enteral magnesium developed normally. Their serum calcium returned to normal concentrations, but serum magnesium could not be maintained at normal concentrations. Delay in establishing a diagnosis led to a convulsive disorder with permanent neurologic impairment in 2 infants. Reported complications of prolonged hypomagnesemia such as renal stones, hypertension, arrhythmias, sudden death, or dyslipidemia were not observed. MAPPING Using whole genome scanning in 12 kindreds with typical recessive renal hypomagnesemia, Simon et al. (1999) demonstrated linkage to a segment of chromosome 3q with a lod score of 6.8. The trait was further localized to an approximately 1-cM interval flanked by loci 539-5 and D3S1288. MOLECULAR GENETICS By exon trapping, Simon et al. (1999) identified a gene at the chromosome 3q locus linked to recessive renal hypomagnesemia that they called paracellin-1 (603959). By SSCP and sequencing, they found 10 different mutations in 10 of the kindreds with primary hypomagnesemia. The mutations were found in homozygous state in 8 kindreds and in compound heterozygous state in 2 others.