Evaluation of von Willebrand factor and protein/creatinine ratio in idiopathic sudden hearing loss / Evaluación del Factor Von Willebraund y la Relación Proteína/Creatinina en la Hipoacusia Súbita Idiopática

Objective The objective of this study was to evaluate the levels of von Willebraund Factor (vWF) in plasma and the protein/creatinine ratio in urine in patients with idiopathic sudden acute hearing loss, which we think to be caused by epithelial dysfunction. Materials-Methods Thirty patients with a sudden hearing loss and thirty healthy individuals were included in the study. Before the treatment, blood and urine were collected from the patients and the control group to investigate the levels of the protein/creatinine ratio and the levels of vWF. The test results of the patients group were compared with those of the control group. Results We found that the levels of vWF increased in the patient group, which was statistically significant (P<.05). The protein/creatinine ratio in the urine increased in the patient group, but this was not statistically significant (P>.05). In addition, we found that the vWF and urine protein/creatin ratio of the patients who benefited from treatment were lower than those who did not benefit. Conclusions This study showed that sudden sensorineural hearing loss may result from endothelial dysfunction. However, more studies that include more patients are needed in order to support this. (AU)

Objetivo El objetivo de este estudio fue evaluar los niveles de factor de von Willebraund (vWF) en plasma y la relación proteína/creatinina en orina en pacientes con hipoacusia aguda súbita idiopática, que creemos que es causada por una disfunción epitelial. Material-Método Treinta pacientes con hipoacusia súbita y treinta individuos sanos fueron incluidos en el estudio. Antes del tratamiento, se recogieron sangre y orina de los pacientes y del grupo de control para investigar los niveles de relación proteína/creatinina y los niveles de vWF. Los resultados de las pruebas del grupo de pacientes se compararon con el grupo de control. Resultados En la literatura, se sabe que la cantidad de proteína en la orina y las elevaciones en los niveles de vWF en plasma son las consecuencias de la disfunción endotelial. Encontramos que los niveles de vWF aumentaron en el grupo de pacientes y esto fue estadísticamente significativo. Sin embargo, la relación proteína/creatinina en la orina aumentó en el grupo de pacientes, pero esto no fue estadísticamente significativo. Además, encontramos que el vWF y la relación proteína/creatina en orina de los pacientes que se beneficiaron del tratamiento fueron más bajos que los que no se beneficiaron. Conclusiones Este estudio muestra que la pérdida auditiva neurosensorial súbita puede resultar de una disfunción endotelial. Sin embargo, se necesitan más estudios que incluyan más pacientes para respaldar esto. (AU)

In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.

Specific combination of compound heterozygous mutations in 17ß-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency.

BACKGROUND: D-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa. METHODS AND RESULTS: Biochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17ß-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable. CONCLUSIONS: We propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.

Mutations in the SLC26A4 (pendrin) gene in patients with sensorineural deafness and enlarged vestibular aqueduct.

Pendred syndrome and the enlarged vestibular aqueduct (EVA) are considered phenotypic variations of the same entity due to mutations in the SLC26A4 (pendrin) gene. Pendred syndrome consists in sensorineural deafness, goiter and impaired thyroid hormone synthesis while in EVA thyroid function seems to be preserved. The aim of this study was to evaluate thyroid function and morphology and to look for mutations in the SLC26A4 gene in patients presented with EVA. Among 57 consecutive patients with sensorineural deafness 15 with EVA, as assessed by magnetic resonance imaging (MRI), were identified and studied. A complete evaluation of thyroid function including thyroid echography and perchlorate discharge test was carried out in all patients with EVA; all exons of the SLC26A4 gene were amplified from peripheral leukocytes and directly sequenced, using specific intronic primers. Out of 15 patients with EVA, goiter was present in 8 (53%), hypothyroidism in 7 (47%), increased serum thyroglobulin levels in 8 (53%) and a positive perchlorate discharge test in 10 (67%). Nine alleles of the SLC26A4 gene were mutated: 2 novel mutations (L465W and G497R) and 4 already known mutations (T410M, R409H, T505N and IVS1001+1G>A) were found. Four subjects were compound heterozygous and 1 heterozygous (G497R/wt). All patients harbouring mutations in the SLC26A4 gene had goiter and a positive perchlorate discharge test: 3 were slightly hypothyroid and 2 euthyroid. The remaining 10 patients had no mutations in the SLC26A4 gene: 4 of them were hypothyroid, 2 with goiter and positive perchlorate discharge test, 2 without goiter and with negative perchlorate discharge test. Two patients without mutations were euthyroid with positive perchlorate discharge test. Patients with mutations in the SLC26A4 gene had larger thyroid volume (p<0.002), higher serum thyroglobulin (Tg) levels (p<0.002) and greater radioiodine discharge after perchlorate (p=0.09) than patients without mutations. The results of the present study lend support to the concept that all patients with mutated SLC26A4 gene have abnormalities of thyroid function tests.

Congenital cytomegalovirus infection: a cause of sensorineural hearing loss.

Prospective studies have suggested that about 108 children with congenital cytomegalovirus (CMV) infection and bilateral sensorineural hearing loss are born each year in England and Wales; this represents about 12% of all children with congenital sensorineural hearing loss. Over a nine year period 1644 children aged between 6 months and 4 years who were attending the Nuffield Hearing and Speech Centre were screened for CMV infection. The prevalence of CMV in the urine of children with sensorineural hearing loss but no immediate family history of deafness was nearly twice that (13%) found in other children with impaired hearing and those with normal hearing (7%). These findings indicate the importance of CMV as a cause of hearing loss.