Hearing problems in patients with hereditary gelsolin amyloidosis.

BACKGROUND: Gelsolin amyloidosis (AGel amyloidosis) is a hereditary form of systemic amyloidosis featuring ophthalmological, neurological and cutaneous symptoms. Previous studies based mainly on patients' self-reporting have indicated that hearing impairment might also be related to the disease, considering the progressive cranial neuropathy characteristic for AGel amyloidosis. In order to deepen the knowledge of possible AGel amyloidosis-related hearing problems, a clinical study consisting of the Speech, Spatial and Qualities of Hearing Scale (SSQ) questionnaire, clinical examination, automated pure-tone audiometry and a speech-in-noise test was designed. RESULTS: Of the total 46 patients included in the study, eighteen (39%) had self-reported hearing loss. The mean scores in the SSQ were 8.2, 8.3 and 8.6 for the Speech, Spatial and Qualities subscales, respectively. In audiometry, the mean pure tone average (PTA) was 17.1 (SD 12.2) and 17.1 (SD 12.3) dB HL for the right and left ears, respectively, with no difference to gender- and age-matched, otologically normal reference values. The average speech reception threshold in noise (SRT) was - 8.2 (SD 1.5) and - 8.0 (SD 1.7) dB SNR for the right and left ears, respectively, which did not differ from a control group with a comparable range in PTA thresholds. CONCLUSION: Although a significant proportion of AGel amyloidosis patients experience subjective difficulties in hearing there seems to be no peripheral or central hearing impairment at least in patients up to the age of 60 years.

Cardiac manifestations in Finnish gelsolin amyloidosis patients.

INTRODUCTION: Finnish gelsolin amyloidosis (AGel amyloidosis) is an inherited systemic amyloidosis with well-known ophthalmological, neurological and cutaneous symptoms. Additionally, cardiomyopathies, conduction disorders and need of cardiac pacemakers occur in some patients. This study focuses on electrocardiographic (ECG) findings in AGel amyloidosis and their relation to cardiac magnetic resonance (CMR) changes. We also assessed whether ECG abnormalities were associated with pacemaker implantation and mortality. MATERIALS AND METHODS: In this cohort study, 51 genetically verified AGel amyloidosis patients (mean age 66 years) without cardiac pacemakers underwent 12-lead ECG and CMR imaging with contrast agent in 2017. Patients were followed-up for 3 years. RESULTS: Conduction disturbances were found in 22 patients (43%). Nine (18%) presented with first-degree atrioventricular block, six (12%) with left anterior hemiblock, seven (14%) with left or right bundle branch block and two (4%) with non-specific intraventricular conduction delay. Low QRS voltage was present in two (4%) patients. Late gadolinium enhancement (LGE) concentrating on the interventricular septum and inferior parts of the heart was present in 19 (86%) patients with conduction abnormalities. During the follow-up, only one patient received a pacemaker, and one patient died. DISCUSSION: Conduction disorders and septal LGE are common in AGel amyloidosis, whereas other ECG and CMR findings typically observed in most common cardiac amyloidosis types were rare. Septal pathology seen in CMR may interfere with the cardiac conduction system in AGel amyloidosis, explaining conduction disorders, although pacemaker therapy is rarely required.

Finnish gelsolin amyloidosis causes significant disease burden but does not affect survival: FIN-GAR phase II study.

BACKGROUND: Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. RESULTS: The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70-74 years, for which it was 0.96. CONCLUSIONS: AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.

Myocardial tissue characterization in patients with hereditary gelsolin (AGel) amyloidosis using novel cardiovascular magnetic resonance techniques.

Gelsolin (AGel) amyloidosis is a hereditary condition with common neurological effects. Myocardial involvement, especially strain, T1, or extracellular volume (ECV), in this disease has not been investigated before. Local myocardial effects and possible amyloid accumulation were the targets of interest in this study. Fifty patients with AGel amyloidosis were enrolled in the study. All patients underwent cardiovascular magnetic resonance imaging, including cine imaging, T1 mapping, tagging, and late gadolinium enhancement (LGE) imaging at 1.5 T. Results for volumetry, myocardial feature-tracking strain, rotation, torsion, native T1, ECV, and LGE were investigated. The population mean native T1 values in different segments of the left ventricle (LV) varied between 1003 and 1080 ms. Myocardial mean T1 was 1031 ± 37 ms. T1 was highest in the basal plane of the LV (1055 ± 40 ms), similarly to ECV (30.0% ± 4.4%). ECV correlated with native T1 in all LV segments (p < 0.005). Basal LGE was detected in 76% of patients, and mid-ventricular LGE in 32%. LV longitudinal strain was impaired (- 17.4% ± 2.6%), significantly decreasing apical rotation (p = 0.018) and concurrently myocardial torsion (p = 0.005). LV longitudinal strain correlated with mean T1 and ECV of different LV planes (p < 0.04; basal p < 0.01). Myocardial involvement in AGel amyloidosis is significant, but the effects are local, focusing on the basal plane of the LV.

Common origin of the gelsolin gene variant in 62 Finnish AGel amyloidosis families.

Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326-124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.