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Biomedical subjects

Robert Kleta

Publications and source records attributed to Robert Kleta.

At least 19 recordsLinked to original sources
PubMed2006

Bartter syndromes and other salt-losing tubulopathies.

Genetic studies into rare inborn errors of renal tubular sodium handling in man have brought many interesting, sometimes surprising insights into how we can maintain our bodies' electrolytes and fluids homeostasis. The cloning and identification of sodium transporting genes and proteins like NHE3, NKCC2, ROMK, CLCNKB, NCC, and EnaC has considerably improved our understanding of renal salt handling. Subsequently, studies of genetically engineered animals provided even more insight into the complex renal physiology. The recent discovery of the WNK kinases as regulators and integrators of specific renal transport pathways helped elucidate this further and lets us start to appreciate the full complexity of renal sodium handling. We summarize recent findings in the field in the context of human diseases and a pathophysiologic basis for their treatment.

Animals↗
PubMed2006

Nodular regenerative hyperplasia and severe portal hypertension in cystinosis.

BACKGROUND & AIMS: Cystinosis is a rare autosomal-recessive disorder characterized by the intralysosomal accumulation of cystine, which is responsible for widespread tissue destruction. Liver biopsy specimens of patients with cystinosis show cystine crystal formation in Kupffer cells. However, significant liver disease and portal hypertension is not a common complication of cystinosis. We report the case histories of 2 young men with poorly treated nephropathic cystinosis who developed noncirrhotic portal hypertension with evidence of nodular regenerative hyperplasia (NRH). METHODS: Liver biopsy examinations, upper and lower endoscopy with biopsy examination, imaging studies, venous pressure measurements, and laboratory investigations were used to evaluate the causes of the liver disease and portal hypertension. RESULTS: Histologic examination of liver biopsy specimens from both patients showed changes characteristic of NRH with portal hypertension documented by measurement of pressure gradients. In addition, endoscopy in the first patient showed varices and portal hypertensive gastropathy. CONCLUSIONS: NRH was confirmed by histologic examination of the liver in both patients and is the likely cause of their portal hypertension. NRH may represent a rare, late complication of cystinosis, although the mechanism remains undefined.

Adult↗
PubMed2005

Clinical and molecular findings in a family with the carbonic anhydrase II deficiency syndrome.

Carbonic anhydrase II (CA2) deficiency syndrome is an autosomal recessive disorder leading to osteopetrosis, renal tubular acidosis, and cerebral calcifications. Affected members of an Arab family with the CA2 deficiency syndrome carried the "Egyptian mutation" in CA2, i.e., c.191 del A, H64fsX90. One affected member, homozygote for the mutation, developed primary pulmonary hypertension. Primary pulmonary hypertension was never described before in patients with this unique syndrome. The likelihood of both occurring randomly in a single individual is very low. We therefore speculate that there might be a possibility of an etiologic link between these entities.

Acidosis, Renal Tubular↗
PubMed2005

Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C>T, CGA>TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein's BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT.

Blood Platelets↗
PubMed2005

Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy.

Nephropathic cystinosis is a rare, autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene that codes for a cystine transporter in the lysosomal membrane. Affected patients store 50-100 times the normal amounts of cystine in their cells, and suffer renal tubular and glomerular disease, growth retardation, photophobia, and other systemic complications, including a myopathy and swallowing dysfunction. Using videofluoroscopy and ultrasound examinations, we assessed the swallowing function of 101 patients with nephropathic cystinosis on their most recent admission to the National Institutes of Health Clinical Center between 1987 and 2004. These patients ranged in age from 6 to 45 years; more than half had significant complaints of swallowing difficulty. On examination of barium swallow, the oral, pharyngeal, and esophageal phases of swallowing were abnormal in 24%, 51%, and 73% of patients, respectively. The frequency of dysfunction increased with age for each phase of swallowing. Both the Swallowing Severity Score (a measure of dysfunction on barium swallow) and the Oral Muscle Composite Score (a reflection of vocal strength, oral-facial movement, and tongue and lip function) increased (that is, worsened) with the number of years that a patient was not receiving treatment with cysteamine, the cystine-depleting agent of choice in cystinosis. The severity scores decreased with the number of years on cysteamine therapy. The Swallowing Severity Score varied directly with the severity of muscle disease, but was not correlated with the presence or absence of the 57-kb CTNS deletion that commonly occurs in nephropathic cystinosis patients. We conclude that swallowing dysfunction in cystinosis presents a risk of fatal aspiration, correlates with the presence of muscle atrophy, and, based on cross-sectional data, increases in frequency with age and number of years without cysteamine treatment. Cystine-depleting therapy with cysteamine should be considered the treatment of choice for both pre- and posttransplant cystinosis patients.

Adolescent↗
PubMed2005

Novel form of intermediate salla disease: clinical and neuroimaging features.

The objective of this article is to describe the clinical, radiographic, and molecular genetic features of a new intermediate form of free sialic storage disease. Free sialic storage disease is a rare autosomal recessive lysosomal disorder that results from mutations in SLC17A5, a gene that codes for sialin, a lysosomal membrane sialic acid transporting protein. Infantile sialic acid storage disease has a severe phenotype, and Salla disease (Finnish variant) is generally milder in phenotype; intermediate forms have also been described. There have been few reports of magnetic resonance imaging (MRI) in the sialic acid storage disorders; leukodystrophy has been the characteristic finding, along with hypoplasia of the corpus callosum. An 8-month-old non-Finnish child presented with hypotonia and global developmental delay. Serial MRIs with magnetic resonance spectroscopy at 9 and 16 months revealed severe hypomyelination and hypogenesis of the corpus callosum. There was mild elevation of urinary sialic acid (4.5 times above normal). Electron microscopy of a skin biopsy showed lysosomal enlargement with oligosaccharide storage, and confirmatory molecular genetic testing revealed compound heterozygosity for two new SLC17A5 mutations. Free sialic storage disease of the intermediate type is an important part of the differential diagnosis of a hypotonic, delayed child with abnormal white matter on MRI. Intermediate types of free sialic acid overlap in phenotype with infantile sialic acid storage disease and the milder Salla disease and thus might be more difficult to identify clinically; the lack of Finnish ethnicity should not preclude testing for this probably under-recognized disorder. White-matter abnormalities appear to be characteristic of the entire phenotypic spectrum.

Brain↗
PubMed2004

FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. The most prevalent CTNS mutation, a 57-kb deletion, occurs in approximately 60% of patients in the United States and northern Europe and removes exons 1-9, most of exon 10, the CTNS promoter region, and all of an adjacent gene of unknown function called CARKL. CTNS codes for the lysosomal cystine transporter, whose absence leads to intracellular cystine accumulation, widespread cellular destruction, renal Fanconi syndrome in infancy, renal glomerular failure in later childhood, and other systemic complications. Because treatment with oral cysteamine can prevent or delay these complications significantly, early and accurate diagnosis is critical. This study describes the generation of fluorescence in situ hybridization (FISH) probes for the 57-kb deletion in CTNS, enabling cytogenetics laboratories to test for this common mutation. The probes would also be able to detect a less frequent 11.7-kb deletion. A blinded study was performed using multiplex PCR analysis as the gold standard to determine the presence or absence of the 57-kb deletion. The FISH probes, evaluated on 12 lymphoblastoid cell lines from singly deleted, doubly deleted, and nondeleted patients, made the correct diagnosis in every case. This appears to be the first FISH-based diagnostic method described for any lysosomal storage disorder. It can assist in the antenatal and perinatal diagnosis of cystinosis and promote earlier salutary therapy with cysteamine.

Alleles↗
PubMed2004

Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.

Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B(0)AT1 (ref. 4). We isolated the human homolog of B(0)AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter.

Amino Acid Sequence↗
PubMed2004

Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report.

BACKGROUND: Triple-A syndrome (Allgrove syndrome) is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and - occasionally - autonomic instability. Mutations have been found in the AAAS gene on 12q13. CASE PRESENTATION: We present the case of a 12 year-old boy with classic systemic features of triple-A syndrome and several prominent ophthalmic features, including: accommodative spasm, dry eye, superficial punctate keratopathy, and pupillary hypersensitivity to dilute pilocarpine. MRI showed small lacrimal glands bilaterally. DNA sequencing of PCR-amplified fragments from the 16 exons of the AAAS gene revealed compound heterozygosity for a new, out-of-frame 5-bp deletion in exon 15, c1368-1372delGCTCA, and a previously-described nonsense mutation in exon 9, c938C>T, R286X. CONCLUSIONS: In addition to known ophthalmic manifestations, triple-A syndrome can present with accommodative dysregulation and ocular signs of autonomic dysfunction.

Accommodation, Ocular↗
PubMed2004

Long-term follow-up of well-treated nephropathic cystinosis patients.

We report the excellent clinical outcomes of siblings with nephropathic cystinosis treated diligently with cysteamine starting at 20 months and 2 months of age. Now 15 and 8 years old, they have glomerular filtration rates of 78 and 105 mL/min/1.73m 2 , respectively. These cases illustrate the critical importance of early diagnosis and treatment.

Cysteamine↗
PubMed2004

Renal glucosuria due to SGLT2 mutations.

Isolated renal glucosuria results from mutations in SGLT2, which codes for an active transporter specific for d-glucose and expressed in the luminal membrane of the renal proximal tubule. In affected individuals, glucosuria leads to pursuit of hyperglycemia to exclude defects in glucose metabolism, and to investigation of renal proximal tubular function to exclude renal Fanconi syndrome. Here we present clinical and molecular data regarding a 19-year-old woman with isolated glucosuria. She was compound heterozygous for two SGLT2 mutations, i.e., a new missense mutation, T200K, and a known missense mutation, N654S.

Adult↗
PubMed2004

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity.

The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3-4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide storage. Free sialic acid in fibroblasts was 3.8+/-0.9 nmol/mg protein (concurrent normal controls, 0.5+/-0.1); differential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child's clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical findings. The differential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease.

Base Sequence↗