1/15. bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase ii deficiency syndrome.carbonic anhydrase ii (CAII), found in renal tubules, brain, and osteoclasts, is critical in acid-base homeostasis and bone remodeling. Deficiency of CAII gives rise to a syndrome of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification with associated developmental delay. It is inherited in an autosomal recessive fashion and found most frequently in the mediterranean region and the middle east. We report 2 related Irish families with clinically severe CAII deficiency in whom the gene mutation has been fully elucidated. Two children, one from each family, have undergone allogeneic bone marrow transplantation because of severe progressive visual and hearing loss. The older 2 children had already developed cerebral calcification and marked visual loss at the time of diagnosis and were treated symptomatically. Post-transplantation evaluation at 2 and 3 years demonstrates histologic and radiologic resolution of their osteopetrosis with stabilization of hearing and vision. Both children remain developmentally delayed and continue to have RTA, and the older child has now developed cerebral calcification. Allogeneic bone marrow stem cell replacement cures the osteoclast component of CAII deficiency and retards the development of cerebral calcification, but it appears to have little or no effect on the renal lesions. (blood. 2001;97:1947-1950)- - - - - - - - - - ranking = 1keywords = acid (Clic here for more details about this article) |
2/15. Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis.Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease. The TNFRSF11A gene encodes the receptor activator of nuclear factor-kappaB (RANK), which has been demonstrated to be essential in bone remodeling and osteoclast differentiation. Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds. The mutation is an 18 base pair tandem duplication in the sequence coding for the signal peptide of RANK, which causes an increase in NF-kappaB signaling. We report the identification and mutational analysis of two unrelated FEO patients. One had no family history of FEO, but presented with bilateral hearing loss at an early age, deterioration of teeth, and severe pain and swelling in the distal tibia before the age of 20. The second patient had a family history of FEO and exhibited an extensive expansile tibial lesion and lesions in one humerus and a phalanx. She also had early hearing loss and dental disease. Mutational analysis of the TNFRSF11A gene in our patients demonstrated an 18 base pair tandem duplication, one base proximal to the duplications previously reported. This novel mutation results in addition of the same six amino acids to the RANK signal peptide that has been observed previously. Further analysis of the exon 1 sequence demonstrated that it has the ability to form a stable secondary structure that may facilitate the generation of tandem duplications.- - - - - - - - - - ranking = 0.5keywords = acid (Clic here for more details about this article) |
3/15. P1 latency as a biomarker for central auditory development in children with hearing impairment.We used the latency of the P1 cortical auditory-evoked potential (CAEP) as a biomarker for the development of central auditory pathways in three children who received intervention through hearing aids and/or cochlear implants. Our goal was to examine the clinical feasibility of using the latency of the P1 CAEP as an objective tool to evaluate whether acoustic amplification for hearing-impaired children has provided sufficient stimulation for normal development of central auditory pathways. If clinicians have such a marker, then they can more confidently make a decision about whether to provide a child with a cochlear implant following an appropriate hearing-aid trial. Using the same marker, clinicians will also be able to monitor the maturation of central auditory pathways once electrical stimulation is initiated.- - - - - - - - - - ranking = 2837.7752820313keywords = amplification (Clic here for more details about this article) |
4/15. liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-coa mutase deficiency.Methylmalonic acidopathy resulting from severe methylmalonyl-coa mutase deficiency causes acute, potentially lethal ketoacidotic episodes, renal failure, and acute and chronic neurologic disease. As dietary and alkali therapy is suboptimal, liver transplantation during infancy has been touted as a potential cure. However, reports in liver transplant recipients about new onset neurologic disease, in the absence of ketoacidosis, and progressive renal insufficiency have cast doubt about its effectiveness. We report the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the USA and provide new biochemical data that indicate why transplanted patients are still susceptible to "metabolic strokes". In our 10-year-old male patient, there is clear evidence that the de novo synthesis of propionyl-CoA within the CNS leads to brain methylmalonate (MMA) accumulation that is largely unaffected by transplantation. Liver replacement is not a cure for methylmalonic acidopathy.- - - - - - - - - - ranking = 4.5keywords = acid (Clic here for more details about this article) |
5/15. point mutation tRNA(Ser(UCN)) in a child with hearing loss and myoclonus epilepsy.We report on a family with a 12-year-old boy who suffered from a maternally inherited syndrome characterized by a combination of sensorineural hearing loss, myoclonus epilepsy, ataxia, severe psychomotor retardation, short stature, and diabetes mellitus. First, he showed a muscular hypotonia with hearing loss; later, he developed a myoclonus epilepsy, growth failure, and severe psychomotor retardation. At the age of 10 years, he developed diabetes mellitus. After initiation of combined ubiquinone and vitamin C treatment, we observed a progression in psychomotor development. Lactate and pyruvate levels in blood and cerebrospinal fluid were normal. No ragged red fibers or ultrastructural abnormalities were seen in a skeletal muscle biopsy. Biochemical assays of respiratory chain complex activities revealed decreased activity of complexes I and IV. By sequence analysis of mitochondrial dna encoding transfer ribonucleic acids (RNAs), a homoplasmic T to C substitution at nucleotide position 7512 was found affecting a highly conserved base pair in the tRNA(ser(UCN)) acceptor stem. Asymptomatic family members of the maternal line were heteroplasmic for the mutation in blood samples. Analysis of mitochondrial dna in patients with hearing loss and myoclonus epilepsy is recommended, even in the absence of laboratory findings. Therapeutically, ubiquinone and antioxidants can be beneficial.- - - - - - - - - - ranking = 0.5keywords = acid (Clic here for more details about this article) |
6/15. Deficient membrane integration of the novel p.N14D-GJB2 mutant associated with non-syndromic hearing impairment.Mutations in GJB2, the gene encoding for the Gap Junction protein Connexin 26 (Cx26), have been established as the major cause of hereditary, non-syndromic hearing impairment (HI). We report here the identification of a novel point mutation in GJB2, c.40A>G [p.N14D], detected in compound heterozygosity with the c.35delG mutation in two brothers with moderate non-syndromic sensorineural HI. The mother who carried one wildtype and a p.N14D allele displayed normal hearing. The mutation leads to substitution of the neutral amino acid asparagine (N) by the negatively charged aspartic acid (D) at amino acid number 14, a position that is conserved among Cx26 of different organisms and among many other connexin isoforms. To investigate the impact of this mutation on protein function, Cx26 activity was measured by depolarization activated hemichannel conductance in non-coupled xenopus laevis oocytes. oocytes injected with the p.N14D mutant cRNA showed strongly reduced currents compared to wildtype. Coinjection of wildtype and mutant cRNA at equimolar levels restored the conductive properties supporting the recessive character of this mutation. Total Cx26 protein expression and cell surface abundance examined by western blotting and by quantitative immunoassays revealed that the hemichannel was properly synthesized but not integrated into the plasma membrane. In this study we have shown that the GJB2 mutation p.N14D is associated with recessively inherited HI and exhibits a defective phenotype due to diminished expression at the cell surface.- - - - - - - - - - ranking = 1.5keywords = acid (Clic here for more details about this article) |
7/15. Nager syndrome: an update of speech and hearing characteristics.Nager acrofacial dysostosis is a rare syndrome of unknown etiology combining mandibular and thumb/radial hypoplasia. Seven patients evaluated in this study had histories of early respiratory and feeding problems, micrognathia and absent velum, atretic ear canals and conductive hearing loss, upper and lower limb malformations, normal intelligence, and speech/language delays and disorders. These findings, with few exceptions, were consistent with the findings in previously published and unpublished case histories of patients with Nager syndrome. Recommended rehabilitative strategies include prespeech feeding activities (especially if gastrostomy tubes are present), oral language stimulation, individualized speech/language therapy, and early audiologic evaluation and amplification.- - - - - - - - - - ranking = 2837.7752820313keywords = amplification (Clic here for more details about this article) |
8/15. Multichannel syllabic compression for severely impaired listeners.Two listeners with congenital hearing losses characterized by flat audiograms and dynamic ranges of 18-33 dB were tested with three compression systems and one (reference) linear amplification system. The compression systems placed progressively larger amounts of speech energy within the listener's residual dynamic range, by raising to audibility and compressing 25, 50, and 90 percent of the short-term input amplitude distribution in each of 16 frequency bands. The comparison linear system was defined by adjusting six octave-wide bands of speech to comfortable levels. System performance was evaluated with nonsence CVC syllables presented at a constant input level and spoken by two talkers. Extensive training was provided to ensure stable performance. The results were notably speaker-dependent, with compression consistently providing better performance for one speaker, linear amplification for the other. Averaged over speakers, however, there was no net advantage for any of the compression systems for any listener. The use of high compression ratios and large input ranges tended to degrade perception of initial consonants and vowels. Under some conditions, however, final consonant scores were higher with compression than with linear amplification. Compression generally enhanced the distinction between stops and fricatives, but degraded spectral-concentration and relative-intensity cues required to identify place of articulation.- - - - - - - - - - ranking = 8513.3258460938keywords = amplification (Clic here for more details about this article) |
9/15. Long-term auditory and visual complications of biotinidase deficiency.The biochemical, dermatological and neurological motor disorders of biotinidase deficiency (multiple carboxylase deficiency) show a dramatic response to pharmacological doses of biotin. This condition is characterised by the accumulation of biocytin and depletion of biotin. Neuromuscular function returns to normal with the reversal of the characteristic organic acidaemia. It would appear that the optic and auditory nerves or their related neurological structures may suffer damage from the excess biocytin and deficient biotin. Despite reversal of the dermatological and psychomotor abnormalities children are likely to be left with auditory and/or visual handicaps if diagnosis and treatment is delayed beyond the first year of life. Treatment with biotin was commenced 6, 18, and 13 months after onset of symptoms. Two children subsequently were found to have visual impairment (acquired retinal dysplasia) and two had sensori-neural deafness. In one patient both defects were present.- - - - - - - - - - ranking = 0.5keywords = acid (Clic here for more details about this article) |
10/15. Identification of amyloid A protein in a sporadic Muckle-Wells syndrome. N-terminal amino acid sequence after isolation from formalin-fixed tissue.The amyloid of a patient (WAL) with a sporadic Muckle-Wells syndrome was analyzed in tissue sections and after it had been isolated from formalin-fixed tissue. The predominant amyloid fibril protein was the amyloid A (AA) type determined by the following criteria. (a) Only antiserum against protein AA gave a strong specific reaction, whereas the other antisera with specificity against amyloid of immunoglobulin origin, i.e., A-lambda and A-kappa, did not stain using the indirect immunoperoxidase technique on formalin-fixed, paraffin-embedded tissue sections. (b) In immunodiffusion, the predominant amyloid fibril protein from WAL isolated in pure form from formalin-fixed tissues precipitated in a line of identity with anti-AA and a purified and chemically identified protein AA from another patient. (c) Amyloid fibril protein from WAL had a molecular weight of 8000 to 9000 in sodium dodecyl sulfate polyacrylamide gel electrophoresis and, thus, is in the same range as the commonly found protein AA. (d) The N-terminal amino acid sequence analysis was that of protein AA. In addition to the pure amyloid fibril protein AA (WAL), proteins of higher molecular weights with AA-antigenic determinants were also isolated. These proteins may represent protein AA in a complex form or protein AA linked to other proteins. Since an inflammation is the most likely cause of amyloidosis complicating the Muckle-Wells syndrome an antiinflammatory therapy (as in other AA-type amyloidoses) is recommended.- - - - - - - - - - ranking = 2.5keywords = acid (Clic here for more details about this article) |
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