Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbonic anhydrase (CA) II deficiency is characterized by osteopetrosis, renal tubular acidosis, cerebral calcification, and usually severe mental retardation. We describe an Italian boy with this disease whose mental retardation was relatively mild and whose renal tubular acidosis had only a distal component. A novel mutation of a gt-->tt change of splice donor site at the 5' end of intron 6 was demonstrated. Comparison of this patient with two previous Italian families with different mutations illustrates the clinical and molecular heterogeneity of this disease. The identification of the mutation in this family provided the opportunity for prenatal diagnosis in a subsequent pregnancy.
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PMID:Clinical and molecular heterogeneity in carbonic anhydrase II deficiency and prenatal diagnosis in an Italian family. 958 Jul 77

Deficiency of carbonic anhydrase II (CA II) isoenzyme produces metabolic disorders of bone, kidney and brain. In this report we describe the clinical, radiological, pathological and genetic findings in three brothers who were affected with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis (RTA) and cerebral calcification. The RTA was hybrid type, but urinary concentration ability was intact. Additional features were severe mental retardation, stunted growth, microcephaly, dental malocclusion, high-arched palate, and broad thumbs. Previous reported patients with this syndrome were predominantly from the Middle East and Mediterranean region. This is the first report with CA II deficiency from the Turkish population. The presence of mental retardation and relative infrequency of skeletal fractures in our patients resembles the clinical course of patients with the Arabic mutation of the CA II gene, but this mutation was not found in our patients.
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PMID:Osteopetrosis, renal tubular acidosis without urinary concentration abnormality, cerebral calcification and severe mental retardation in three Turkish brothers. 1179 60

Genetic disorders of acid-base transporters involve plasmalemmal and organellar transporters of H(+), HCO3(-), and Cl(-). Autosomal-dominant and -recessive forms of distal renal tubular acidosis (dRTA) are caused by mutations in ion transporters of the acid-secreting Type A intercalated cell of the renal collecting duct. These include the AE1 Cl(-)/HCO3(-) exchanger of the basolateral membrane and at least two subunits of the apical membrane vacuolar (v)H(+)-ATPase, the V1 subunit B1 (associated with deafness) and the V0 subunit a4. Recessive proximal RTA with ocular disease arises from mutations in the electrogenic Na(+)-bicarbonate cotransporter NBC1 of the proximal tubular cell basolateral membrane. Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II. The metabolic alkalosis of congenital chloride-losing diarrhea is caused by mutations in the DRA Cl(-)/HCO3(-) exchanger of the ileocolonic apical membrane. Recessive osteopetrosis is caused by deficient osteoclast acid secretion across the ruffled border lacunar membrane, the result of mutations in the vH(+)-ATPase V0 subunit or in the CLC-7 Cl(-) channel. X-linked nephrolithiasis and engineered deficiencies in some other CLC Cl(-) channels are thought to represent defects of organellar acidification. Study of acid-base transport disease-associated mutations should enhance our understanding of protein structure-function relationships and their impact on the physiology of cell, tissue, and organism.
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PMID:Genetic diseases of acid-base transporters. 1182 92

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO3-) reabsorption in the renal proximal tubules, characterized by a decreased HCO3- threshold. pRTA commonly occurs as a manifestation of a generalized functional defect in proximal tubules. In contrast, pRTA can occur without other functional defects in proximal tubules (isolated pRTA). Most of the isolated pRTA in children are hereditary. Recent progress in molecular biological analyses is unraveling the molecular basis of hereditary pRTA. Mutations in the kidney type Na+/HCO3- cotransporter gene (SLC4A4) cause permanent isolated proximal RTA with ocular abnormalities. Mutations in carbonic anhydrase II gene lead to osteopetrosis, RTA (pRTA, distal RTA or combined proximal and distal RTA), cerebral calcification, and mental retardation. SLC9A3, encoding the Na+/H+ exchanger, is a candidate gene for pRTA without other manifestations. These results help further understand the molecular basis of hereditary pRTA and characterize the clinical and genetic manifestations of the disorder.
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PMID:Molecular basis of proximal renal tubular acidosis. 1202 12

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H(+)-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H(+)-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.
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PMID:A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. 1256 20

Twenty four patients suffering from osteopetrosis caused by carbonic anhydrase II deficiency are colliged. This pathology seems to be frequent in Tunisia. Mental retardation is present in 52%, 85% of patients have short stature and 25% have optic atrophy. All affected subjects show craniofacial disproportion and dental anomalies. Twenty patients have at least one bone fracture. Metabolic acidosis is constant: it is profound during the first life decade. A severe selective reduction of carbonic anhydrase II in erythrocyte is confirmed in 18 cases. Osteosclerosis and defective skeletal modelling are constant, cerebral calcification can be seen at the scanner approximately at the age of two years and six months. All patients are homozygous for a splice junction mutation in intron 2 of the carbonic anhydrase II gene, this mutation does not seem to protect patients from bone fractures nor induce a severe metabolic acidosis.
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PMID:[Osteopetrosis with carbonic anhydrase II deficiency: report of 24 cases]. 1622 Jun 98

Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. Mutations in CA II in humans lead to osteopetrosis with renal tubular acidosis and cerebral calcifications, a disorder often associated with mental retardation. Recently, new avenues in CA II research have opened as a result of discoveries that the enzyme increases bicarbonate and proton fluxes and may play an important role in brain tissue. In the human brain, CA II was localized to oligodendrocytes, myelin, and choroid plexus epithelium. Because this conclusion was based on a few fragmentary reports, we analyzed in more detail the expression of the enzyme in human telencephalon. By immunoblotting, we found a gradual increase in CA II levels from 17 weeks' gestation to childhood and adolescence. By immunohistochemistry, CA II was found to be present not only in oligodendrocytes and choroid plexus epithelium (declining with aging in both these locations), but also in a subset of neurons mostly with GABAergic phenotype, in a few astrocytes, and transiently during brain development in the endothelial cells of microvessels. The enzyme also occurred in oligodendrocyte processes in contact with myelinating axons, myelin sheaths, and axolemma, but was either absent or appeared in minute amounts in compact myelin. These findings suggest the possible involvement of CA II in a wide spectrum of biologic processes in the developing and adult human brain and may contribute to better understanding of the pathogenesis of cerebral calcifications and mental retardation caused by CA II deficiency.
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PMID:Carbonic anhydrase II in the developing and adult human brain. 1682 53

Carbonic anhydrase II (CAII) deficiency is an autosomal recessive disorder manifest by osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include growth failure and mental retardation. Complications of the osteopetrosis include frequent bone fractures, cranial nerve compression, and dental mal-occlusion. A hyper-chloremic metabolic acidosis, sometimes with hypokalemia, occurs due to renal tubular acidosis that may be proximal, distal, or more commonly, the combined type. Such patients may present with global hypotonia, muscle weakness or paralysis. We report a case of CA II deficiency with recurrent attacks of acute paralysis which was misdiagnosed initially as Guillian-Barre syndrome.
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PMID:Paralysis Episodes in Carbonic Anhydrase II Deficiency. 1765 93

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.
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PMID:Osteopetrosis. 1923 11

Carbonic anhydrase II (CAII) deficiency syndrome characterized by osteopetrosis (OP), renal tubular acidosis (RTA), and cerebral calcifications is caused by mutations in the carbonic anhydrase 2 (CA2) gene. Severity of this disorder varies depending on the nature of the mutation and its effect on the protein. We present here, the clinical and radiographic details along with, results of mutational analysis of the CA2 gene in an individual clinically diagnosed with renal tubular acidosis, osteopetrosis and mental retardation and his family members to establish genotype-phenotype correlation. A novel homozygous deletion mutation c.251delT was seen in the patient resulting in a frameshift and a premature stop codon at amino acid position 90 generating a truncated protein leading to a complete loss of function and a consequential deficiency of the enzyme making this a pathogenic mutation. Confirmation of clinical diagnosis by molecular methods is essential as the clinical features of the CAII deficiency syndrome are similar to other forms of OP but the treatment modalities are different. Genetic confirmation of the diagnosis at an early age leads to the timely institution of therapy improving the growth potential, reduces other complications like fractures, and aids in providing prenatal testing and genetic counseling to the parents planning a pregnancy.
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PMID:Identification of a novel mutation in an Indian patient with CAII deficiency syndrome. 2093 2


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