Vestibular and audiological findings in the Alport syndrome

Journal of Rare Diseases Research & Treatment

Introduction: Hearing loss is a typical finding in Alport syndrome (sAlport) caused by a genetic defect in the type IV collagen synthesis. Depending on the criteria, these individuals may be diagnosed with normal hearing. Objective: To compare the prevalence of hearing loss according to different criteria-World Health Organization, WHO; Global Burden Disease, GBD and Clark-in patients with sAlport and segmental and focal glomeruloesclerosis (FSGS). Materials And Methods: This is a cross-sectional pilot study. Pure-tone audiometry was carried out in patients with sAlport and FSGS (glomerulopathy which was selected as a control group). Results: We assessed 13 patients (6 with sAlport and 7 with FSGS). Under the WHO criteria, no patient had hearing loss. The prevalence of hearing loss was similar according to GBD criteria (16.67% and 14.29% in the sAlport and FSGS groups, respectively). Clark's criteria, instead, revealed a higher prevalence of hearing loss in the sAlport group (66.67%) vs. FSGS (28.57%). Conclusion: The prevalence of hearing loss in the sAlport group varied depending on the criteria (from nonexistent to 67%). We consider that a critical evaluation of the hearing thresholds may help physicians to early detect minimal hearing impairment even though the report says, "normal hearing".

Archives of Otolaryngology–Head & Neck Surgery, 2005

To determine the distribution of ␣1, ␣3, and ␣5 chains of type IV collagen in the cochlea in Alport syndrome.

Nephrology Dialysis Transplantation, 2012

Alport syndrome (ATS) is a type-IV collagen inherited disorder, caused by mutations in COL4A3 and COL4A4 (autosomal recessive) or COL4A5 (X-linked). Clinical symptoms include progressive renal disease, eye abnormalities and high-tone sensorineural deafness. A renal histology very similar to ATS is observed in a subset of patients affected by mutations in MYH9, encoding nonmuscle-myosin Type IIaa cytoskeletal contractile protein. MYH9-associated disorders (May-Hegglin anomaly, Epstein and Fechtner syndrome, and others) are inherited in an autosomal dominant manner and characterized by defects in different organs (including eyes, ears, kidneys and thrombocytes). We describe here a 6-year-old girl with haematuria, proteinuria, and early sensorineural hearing loss. The father of the patient is affected by ATS, the mother by isolated inner ear deafness. Genetic testing revealed a pathogenic mutation in COL4A5 (c.2605G>A) in the girl and her father and a heterozygous mutation in MYH9 (c.4952T>G) in the girl and her mother. The paternal COL4A5 mutation seems to account for the complete phenotype of ATS in the father and the maternal mutation in MYH9 for the inner ear deafness in the mother. It has been discussed that the interaction of both mutations could be responsible for both the unexpected severity of ATS symptoms and the very early onset of inner ear deafness in the girl.

Orphanet Journal of Rare Diseases, 2018

Objective: To analyze the clinical audiological characteristics of X-Linked Alport syndrome (XLAS) in males and their relationships with genotypes. Methods: The clinical data of 87 male patients with AS were reviewed. Hearing levels were evaluated using pure tone audiometry (PTA) testing, acoustic immittance, and otoacoustic emissions (OAE) testing. The genotypes of COL4A5 and the pathogenic variants were analyzed. The relationships between auditory phenotypes and genotypes were analyzed. Results: Among the 87 patients, the number of patients with normal hearing and hearing loss were 32 and 55, respectively. In all cases, the hearing loss was characterized as bilateral symmetrical sensorineural deafness. Majority of the patients had mild-to-moderate hearing loss. Hearing loss usually started in the middle frequency range and gradually affected high frequencies, at school age and gradually increased with increasing age. However, it maintained a relatively steady level of 50-60 dB HL during the teenage years. The audiometric curves included groove-type in 51 cases (92.73%). Patients were identified to have 60 different COL4A5 pathogenic variants. Of the 49 patients who were followed-up for more than 2 years, 28 cases presented a decreasing trend in the hearing level of about 5 dB per year. The degree of hearing loss was positively correlated with gene mutation type and renal function. Conclusions: Hearing loss in males with XLAS is symmetrical sensorineural, and progressive with increasing age. There is a significant correlation between the degree of hearing loss and genotype, renal function, and age.

International Journal of Pediatric Otorhinolaryngology, 2017

Background: Enlarged Vestibular Aqueduct (EVA) is one of the most common congenital malformations associated with sensorineural or mixed hearing loss. The association between hearing loss and EVA is described in syndromic (i.e. Pendred Syndrome, BOR, Waardenburg) and non-syndromic disorders, as isolate or familiar mutations of the SLC26A4 gene. The audiological phenotype of the EVA syndrome is heterogeneous, the type and entity of hearing loss may vary and vertigo episodes might also be present. Objective: The aim of this retrospective study was to describe the clinical and genetic features of a group of adolescent subjects presenting an EVA clinical profile, considering the presence of SLC26A4 gene mutations. Methods: 14 Caucasian patients were assessed (24 ears in total; 4 patients presented a monolateral EVA), 10 females and 4 males. Their age at the time of diagnosis was between 1 and 6 years (mean age 2.5 years). Subjects were assessed by an ENT microscopy evaluation with a complete audiometric assessment, CT & MRI scans and genetic tests for the evaluation of the pendrin gene mutations (SLC26A4). Results: Considering the presence of SLC26A4 mutations and thyroid function, we could identify three subgroups of patients: group 1, non syndromic EVA (ns EVA, no SLC26A4 mutation and no thyroid dysfunction); group 2, EVA with DFNB4 (single SLC26A4 gene mutation and no thyroid dysfunction); group 3, EVA with Pendred Syndrome (two pathological mutation of SLC26A4 and thyromegaly with thyroid dysfunction). Patients of group 1 (ns-EVA) showed various degrees of hearing loss from mild (55%) to severe-profound (45%). In groups 2 (DFNB4) and 3 (PDS), the degree of hearing loss is severe to profound in 70e75% of the cases; middle and high frequencies are mainly involved. Conclusions: The phenotypic expressions associated with the EVA clinical profile are heterogeneous. From the available data, it was not possible to identify a representative audiological profile, in any of the three subgroups. The data suggest that: (i) a later onset of hearing loss is usually related to EVA, in absence of SLC26A4 gene mutations; and (ii) hearing loss is more severe in patients with SLC26A4 gene mutations (groups 2 and 3 of this study).

The Laryngoscope, 2004

To determine the histopathologic abnormalities within the cochlea in Alport syndrome. Background: Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the ؔ3, ؔ4, and ؔ5 chains of type IV collagen. The ؔ3, ؔ4, and ؔ5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL. Methods: We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen ؔ5 chain gene. Results: By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal. Conclusions: The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.

American journal of human genetics, 1996

Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion of mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and ...

World journal of otorhinolaryngology, 2013

Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct (EVA), and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in ¼ of North American or European EVA populations, one mutant allele is detected in another ¼ of patient populations, and no mutations are detected in the other ½. The presence of two mutant alleles of SLC26A4 is associated with abnormal iodide organification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The presence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not ...

The American Journal of Pathology, 2001

Frontiers in Neurology, 2021

Background: Vestibular disorders (VDs) are a clinically divergent group of conditions that stem from pathology at the level of the inner ear, vestibulocochlear nerve, or central vestibular pathway. No etiology can be identified in the majority of patients with VDs. Relatively few families have been reported with VD, and so far, no causative genes have been identified despite the fact that more than 100 genes have been identified for inherited hearing loss. Inherited VDs, similar to deafness, are genetically heterogeneous and follow Mendelian inheritance patterns with all modes of transmission, as well as multifactorial inheritance. With advances in genetic sequencing, evidence of familial clustering in VD has begun to highlight the genetic causes of these disorders, potentially opening up new avenues of treatment, particularly in Meniere's disease and disorders with comorbid hearing loss, such as Usher syndrome. In this review, we aim to present recent findings on the genetics o...