Hearing loss in fabry disease: A 16 year follow-up study of the Danish nationwide cohort.

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide (Gb3) causing multi-organ dysfunction. The audiologic involvement in FD has been neglected in previous studies; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life. Objective: To investigate hearing loss from baseline through 16 years follow-up of the Danish FD cohort and to compare audiometric data to other clinical variables. Methods: Data was collected prospectively and assessed retrospectively during a period of 16 years from 83 patients (age: 9-72 years; sex: 29 males and 54 females). 55 patients underwent treatment. Air conduction thresholds was assessed at six frequencies between 0.25 and 8 kHz bilaterally. Data was analyzed using multilinear models. Results: Mean follow-up period for patients undergoing a FD specific treatment was 7.8 years (0-12.8 years, SD 3.8 years, n = 55). Hearing thresholds for FD patients deviated from healthy individuals at all frequencies for both sexes (p < 0.001). Males had more profound hearing loss than females at high frequencies (4,8 kHz) (p = 0.025). There was no improvement in hearing with treatment (p = 0.343♂, p = 0.256♀). No associations between hearing loss and measured glomerular filtration rate, left ventricular wall thickness or cerebral white matter lesions were found. Lower plasma Gb3 concentration correlated with better hearing (p = 0.046) in males. Conclusion: Our findings demonstrated significant hearing loss in FD patients compared to audiologically healthy individuals at all frequencies, and no change in hearing during treatment. Lower plasma Gb3 concentrations correlated with better hearing in males.

Non-diagnostic autopsy findings in sudden unexplained death victims.

BACKGROUND: Several inherited cardiac diseases may lead to sudden cardiac death (SCD) a devastating event in the families. It is crucial to establish a post mortem diagnosis to facilitate relevant work-up and treatment of family members. Sudden unexplained death (SUD) victims constitute roughly one third of all SCD cases in Denmark. METHODS: This was a single center, retrospective study investigating SUD cases. Victims who died unexplained due to suspected or confirmed cardiac disease were consecutively referred to a third line referral center established in 2005. All autopsy reports were investigated. Victims were divided into two groups: non-diagnostic cardiac findings and normal cardiac findings. None of the included victims had findings consistent with a diagnosis based on existing criteria. RESULTS: In total, 99 SUD cases were referred. The mean age of the victims was 37 years (range 0-62 years, 75% males). A total of 14 (14%) victims had a cardiovascular diagnosis pre-mortem. Thirty-seven cases had normal cardiac findings and non-diagnostic cardiac findings were found in 62 cases (63%). The five most common findings included ventricular hypertrophy and/or enlarged heart (n = 35, 35%), coronary atheromatosis (n = 31, 31%), myocardial fibrosis (n = 19, 19%), dilated chambers (n = 7, 7%) and myocardial inflammation (n = 5, 5%). CONCLUSION: One third of SUD victims had normal cardiac findings and non-diagnostic cardiac findings were seen in almost two thirds of the SUD victims. These non-diagnostic findings may be precursors or early markers for underlying structural cardiac disorders or may be innocent bystanders in some cases. Further studies and improved post-mortem examination methods are needed for optimization of diagnostics in SUD.

Significant hearing loss in Fabry disease: Study of the Danish nationwide cohort prior to treatment.

BACKGROUND: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide resulting in multi-organ dysfunction e.g. cerebral, cardiac, renal and audiologic complications. The audiologic involvement in FD has often been neglected; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life. OBJECTIVES: To investigate baseline hearing status of the Danish Fabry cohort prior to treatment, compared to sex- and age-expected hearing levels and correlating hearing to renal and cerebral findings. MATERIAL AND METHODS: Retrospective study of baseline hearing status of the Danish Fabry cohort (n = 83, 9-72 years). Air conduction and speech discrimination scores were assessed at 6 frequencies between 0.25-8 kHz bilaterally. Data were collected between 2001-2014 and compiled in STATA using multilinear mixed modelling for statistical evaluation. RESULTS: Hearing thresholds at all frequencies deviated from the expected thresholds of an otologically normal cohort (p<0.001) and ranged 0.5 to 1.5 standard deviations below expected values. In total 29 males and 54 females were included. Hearing loss was more pronounced in the higher frequencies. There was a trend of association between hearing loss and measured glomerular filtration rate (mGFR) (p = 0.084). No association was present between hearing loss and albuminuria (p = 0.90), Fabry related cerebral abnormalities (p = 0.84) and cardiac left ventricular mass index, (LVMi) (p = 0.67) independent of sex. Hearing thresholds were poorer for men compared to women (p = 0.001). Sex differences were present at 0.25, 4 and 8 kHz. CONCLUSION: Our findings demonstrated significant hearing loss in Danish FD patients before treatment initiation, being more profound than in otologically healthy individuals at all frequencies. Additionally, we observed no association between hearing loss and LVMi, albuminuria or FD cerebral abnormalities, with a trend of association to mGFR. SYNOPSIS: Patients with Fabrys disease have hearing loss of all frequencies and most prominently at high frequencies (4-8 kHz), with no association between the hearing loss and cerebral abnormalities, and cardiac mass but with a trend of association to measured glomerular filtration rate.