Phenotypic Expression and Outcomes in Patients with the p.Arg301Gln GLA Variant in Anderson-Fabry Disease.

The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson-Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad-cornea verticillate, neuropathic pain, and angiokeratomas-affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype-phenotype correlation could be useful from a practical clinical point of view and for future decision making.

Val50Met hereditary transthyretin amyloidosis: not just a medical problem, but a psychosocial burden.

BACKGROUND: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a heterogeneous disease with a clinical presentation that varies according to geographical area and TTR mutation. The symptoms of Val50Met-ATTRv are mainly neuropathic and progress to complete disability and death in most untreated patients within 10 to 15 years of diagnosis. The neurological effects may also be accompanied by gastrointestinal impairment, cardiomyopathy, nephropathy and/or ocular deposition. The disease is thus associated with a high degree of patient disability. Accordingly, we aimed to describe the psychosocial burden associated with ATTRv in a group of patients, asymptomatic Val50Met carriers, relatives and caregivers in the endemic focus of the disease in Majorca via a survey addressing various aspects related to psychosocial burden. We performed a an observational, descriptive, cross-sectional and multicentre study in order to analyze the prevalence of self-reported impact of ATTRv disease upon their daily life. In addition to the self-knowledge, fear and burden related to the disease. The survey was disseminated during the regular follow up at the outpatient clinic of the Hospital Universitario Son Llàtzer and during the meetings organized by the Andrade's Disease patients' advocacy group from the Balearic Islands. These meetings were attended also by subjects followed up by the Hospital Universitario Son Espases and their caregivers and relatives. Survey was self-administrated. No intervention was done by the investigators. 85 subjects completed the survey: 61 carrying the TTR-V50M variant and 24 caregivers or relatives. RESULTS: Our study revealed that, although most of the population studied had had prior contact with ATTRv through affected relatives, there was still a lack of information regarding disease diagnosis. Fear of the genetic test result and psychological issues were common in our population. Moreover, the disease had a stronger impact on the daily life of our patients than that of our asymptomatic carriers. Autonomic symptoms were the main source of burden for relatives and caregivers. CONCLUSION: Our survey results show high psychosocial burden associated with Val50Met-ATTRv in our area.