Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations of the Ca(2+)-sensing receptor (CaR) gene cause autosomal dominant hypoparathyroidism. Functional expression studies have been reported for several mutations, but have produced conflicting results. Thus, the mechanism by which these mutations activate the receptor is unclear. We describe here a new family with autosomal dominant hypoparathyroidism. The mother and three daughters experienced muscle spasms and/or seizures from early childhood. They were treated with oral calcium and vitamin D analogs, and all four patients developed hypercalciuria, nephrocalcinosis, and renal insufficiency. In this family, we identified a heterozygous missense mutation (F612S) involving the extracellular region of the CaR. The mutation cosegregated with disease. It was not present in 50 normal control individuals. We used site-directed mutagenesis to introduce this mutation into the CaR cDNA, and then expressed the mutant receptor in human embryonic kidney (HEK)-293 cells. In these cells, the accumulation of inositol phosphates was measured as a function of extracellular Ca2+ concentration. Compared with the wild-type receptor, the mutant receptor showed a left-shift in the concentration-response curve and an increase in the maximal response to high Ca2+ concentration. These effects did not appear to be mediated by changes in levels of receptor expression, as judged by ELISA, or by changes in receptor glycosylation, as judged by Western analysis. We conclude that this CaR mutation causes hypoparathyroidism by a dual increase in receptor sensitivity to extracellular Ca2+ and maximal signal transduction capacity.
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PMID:A Ca(2+)-sensing receptor mutation causes hypoparathyroidism by increasing receptor sensitivity to Ca2+ and maximal signal transduction. 938 Apr 34

Gain-of-function mutations of the calcium-sensing receptor (CaR) gene cause autosomal dominant and/or sporadic hypocalcemia with hypercalciuria. Because treatment of the hypocalcemia with vitamin D and/or calcium in patients with such mutations results in increased hypercalciuria, nephrocalcinosis, and renal impairment, its use should be limited to alleviating the symptoms of symptomatic patients. Because thiazide diuretics have been successfully used to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CaR gene. In this study, we report on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in two Japanese patients with gain-of-function mutations of the CaR gene. Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia (serum calcium values: 1.1 mmol/liter and 1.3 mmol/liter, respectively). Despite treatment with the standard dose of 1,25-dihydroxyvitamin D(3) in one patient and 1alpha-hydroxyvitamin D(3) in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) doses to be reduced, and it alleviated their symptoms. A heterozygous missense mutation was identified in both patients. In one patient, the mutation was A843E in the seventh transmembrane domain of the CaR, and in the other it was L125P in the N-terminal extracellular domain. In vitro transient transfection of their mutant CaR cDNAs into HEK293 cells shifted the concentration-response curve of Ca(2+) to the left. In conclusion, two sporadic cases of hypercalciuric hypocalcemia were due to de novo gain-of-function mutations of the CaR gene. Hydrochlorothiazide with vitamin D(3) successfully reduced the patients' urinary calcium excretion and controlled their serum calcium concentrations and symptoms. Thiazide diuretics are effective in patients with gain-of function mutations of the CaR gene.
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PMID:Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. 1210 2

Autosomal dominant hypocalcaemia with hypercalciuria (ADHH) is an intriguing syndrome, in which activating mutations of the calcium sensing receptor (CaSR) have recently been recognised. We describe a kindred with seven affected individuals across three generations, including patients affected in the first decade of life. Age at diagnosis varied from birth to 50 years. Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia. Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia. Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals. Symptomatic individuals were treated with calcium and calcitriol to reduce the risk of hypocalcaemic seizures. DNA sequence analysis, identified a mutation in exon 3, codon 129 (TGC-->TAC) of the CaSR gene of seven affected family members, resulting in loss of a conserved cysteine residue, potentially disrupting CaSR receptor dimerisation. Thus, a novel mutation was identified in this family, who demonstrate variability of ADHH phenotype and also illustrate the complexities of clinical management. Optimal management of ADHH is difficult and we recommend judicious treatment to avoid an increased risk of nephrocalcinosis.
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PMID:A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges. 1612 46

Pseudohypoparathyroidism (PHP) is a rare inherited syndrome with several types. We reviewed the cases of 7 PHP patients seen between 1990 and 2003, and analyzed their clinical, biochemical data and long-term medical outcomes. Six boys and one girl were included. Two siblings showed Albright's hereditary osteodystrophy (AHO) and PHP Ia was impressed. The rest were suspected of PHP Ib. Their mean diagnosed age was 10.8 years and most had symptoms onset for several years before diagnosis. The most frequent initial presentations were seizure, followed by extremity muscle spasm, short stature, learning disability and psychomotor retardation. Mild thyrotropin elevation was noted in two patients of PHPIa. Early puberty onset, combined with bone age advancement was noted in the boy with PHP Ia, who had the shortest predicted adult height (PAH) (139.5 cm). The other 5 boys had normal PAH, mean 171.42 cm, and 4 male patients reached final height with a mean of 163.25 cm, close to their target heights. During treatment, 2 patients developed nephrocalcinosis. In conclusion, subtypes of PHP present heterogeneous phenotypes. Non-Ia subtypes might not be rare in Taiwan. Therefore, in hypocalcemic patients with mild high or normal parathyroid hormone (PTH), even in the absence of AHO, PHP should be ruled out. Regular renal sonography follow-up is recommended during therapy.
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PMID:Pseudohypoparathyroidism: report of seven cases. 1664 41

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation. Due to their location within the primary structure of Claudin-16, both mutations are suggested to interfere with renal paracellular magnesium conductance.
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PMID:Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene. 1734 84

Pyridoxine-responsive seizures (PRS) and the role of pyridoxine (PN, vitamin B(6)) in hypophosphatasia (HPP) are incompletely understood. Typically, PRS and HPP are rare, independent, metabolic disorders. In PRS, seizures resist standard anticonvulsants apart from PN, yet have a good prognosis. In HPP, inactivation of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP) impairs skeletal mineralization and causes rickets in infants that can be fatal. Here, we report a 7-month-old girl, newly diagnosed with infantile HPP, who presented as a neonate with PRS but without bony abnormalities. Analysis of biogenic amines in cerebrospinal fluid (CSF) suggested brain pyridoxal 5'-phosphate (PLP) deficiency, although PLP in CSF was not decreased. She had normal cognitive milestones but failure to thrive and rickets. Nearly undetectable serum ALP activity, elevated plasma PLP and urinary phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi) levels, hypercalcemia, hypercalciuria and nephrocalcinosis were consistent with infantile HPP. Only prednisolone reduced serum calcium levels. Despite improved growth and weight gain, she developed rib fractures and died from respiratory failure at age 9 months. Sequence analysis of the TNSALP gene revealed novel missense mutations in exon 7 (c.677T>C, p.M226T) and exon 10 (c.1112C>T, p.T371I). Our patient demonstrated that PRS in neonates may not necessarily be "idiopathic"; instead, such seizures can be caused by severe HPP that becomes clinically apparent later in infancy. The pathophysiology of PRS in HPP differs from the three other genetic defects known to cause PRS, but all may lead to brain PLP deficiency reducing seizure thresholds. All reported HPP patients with neonatal seizures died within 18 months of birth, suggesting that PRS is an indicator of HPP severity and lethal prognosis. We recommend that assessment of any neonate with PRS should include measurement of serum ALP activity.
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PMID:Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. 1739 61

Hypoparathyroidism is one of the recognized causes of late-onset neonatal hypocalcemia. Maternal hypercalcemic hyperparathyroidism has been shown to suppress fetal parathyroid glands, causing transient neonatal hypoparathyroidism. We report two siblings (6 years apart) with transient hypoparathyroidism presented with hypocalcemic seizures during the first 2 weeks of life. Subsequent investigation revealed an unrecognized normocalcemic hyperparathyroidism with nephrocalcinosis in the mother. Maternal hyperparathyroidism was caused by two parathyroid adenomas. In conclusion, our report highlights the importance of careful evaluation of neonatal hypoparathyroidism in uncovering an unrecognized, asymptomatic hyperparathyroidism in the mother.
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PMID:Transient neonatal hypoparathyroidism in two siblings unmasking maternal normocalcemic hyperparathyroidism. 1756 90

Subcutaneous fat necrosis in a newborn is a rare, benign and self-limiting panniculitis. Hypercalcemia may develop and has been implicated as the cause of serious complications including seizures, nephrocalcinosis, and death. We report a case of subcutaneous fat necrosis in a newborn associated with asymptomatic and uncomplicated hypercalcemia, which resolved spontaneously.
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PMID:Subcutaneous fat necrosis in a newborn associated with asymptomatic and uncomplicated hypercalcemia. 1941 78

Hypophosphatasia (HPP) is a rare metabolic disease with the hallmark finding of deficient serum tissue nonspecific alkaline phosphatase (TNSALP) activity. TNSALP is primarily known for its role in mineralization; hence, HPP is characterized by defective mineralization of bone and/or teeth. TNSALP is also necessary for proper vitamin B6 metabolism and its participation as a cofactor for neurotransmitters in the central nervous system. Defective TNSALP activity in the brain can result in intractable seizures responsive to pyridoxine. The pathophysiology of pyridoxine-responsive seizures (PRS) in severe HPP remains to be clearly defined. We review the case of a 2-month-old Caucasian boy presenting with seizures refractory to conventional antiepileptic medications. Empiric treatment with favorable response to pyridoxine in conjunction with severe metabolic bone disease, extremely low serum alkaline phosphatase, elevated phosphoethanolamine, hypercalcemia, hypercalciuria, and nephrocalcinosis led to a clinical diagnosis of infantile HPP. Sequence analysis revealed compound heterozygosity of the TNSALP gene with a novel mutation in exon 9 and a previously reported mutation in exon 12. This case reminds the physician that severe infantile HPP can present with PRS as its major initial manifestation and should alert clinicians to consider HPP in their differential of PRS. In addition, despite this severe genotype, the clinical diagnosis of our patient was delayed because of minimal phenotypic features initially. This highlights that the phenotype-genotype correlation could be variable even in severe disease. This case also demonstrates that HPP should be classified as PRS and not a form of pyridoxine-dependent epilepsy (PDE) as our patient was able to stop the pyridoxine supplementation without seizure recurrence once enzyme replacement was initiated. With the advent of enzyme replacement therapy, this once fatal disease may have improved morbidity and mortality.
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PMID:Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures. 2347 1

Hypophosphatasia (HPP) is a rare, inherited, potentially life-threatening metabolic disorder that arises from loss-of-function mutations in the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). As a result of these mutations (as many as 260 genetic mutations have been associated with HPP), patients have disordered bone mineralization leading to rickets, osteomalacia, fractures and other skeletal abnormalities as well as other systemic complications such as seizures, respiratory compromise, dental anomalies, nephrocalcinosis and/or weakness and chronic pain. HPP may appear across the age spectrum, from in utero, to infancy, childhood, adolescence and/or adulthood. More severe cases tend to be seen in utero and infancy, and in these instances, mortality may be as high as 50%. In surviving or older patients, disability and poor quality of life may be seen. Based on clinical presentation, HPP can be mistakenly diagnosed as other skeletal diseases, but a low alkaline phosphatase is an important, distinguishing sign of this condition. While patients with HPP may benefit from supportive measures, at the present time, there is no approved specific therapy for HPP.
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PMID:Hypophosphatasia. 2385 21


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