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

Abstract

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.

Gelsolin-Amyloidosis – An Exceptional Cause of Blepharochalasis

“…In a recent study, Schmidt et al presented a comprehensive list of multiple ophthalmological symptoms. Here, they quantify the frequency of drooping eyelids due to cutis laxa and facial nerve paresis in patients in about 86 % (n = 261), yet BC is not explicitly described [9]. With this report we can confirm and highlight BC as a possible lateonset manifestation of AGel amyloidosis.…”

“…Still, a curative therapy is not available yet and repeated surgeries may be needed. Depression is frequently found as a comorbidity in AGel patients, mainly due to the limitation of facial expressions and the appearance of premature aging [9]. Thus, psychological support should also be considered as part of a holistic approach to improve the quality of life of AGel patients.…”

“…A recent comprehensive study of 227 Finnish AGel patients revealed that ophthalmological symptoms are characteristically the first ones to appear [8]. These include keratoconjunctivitis sicca, drooping eye lids, early cataract development, photophobia, corneal ulcers, and secondary glaucoma [8,9]. Although many signs of the involvement of the anterior eye segment have been reported so far, blepharochalasis (BC) as a self-reliant hallmark for the progression of AGel amyloidosis receives only little consideration in the literature.…”

A novel GSN variant outside the G2 calcium‐binding domain associated with Amyloidosis of the Finnish type

“…Ocular and systemic features of Finnish Amyloidosis were evident in both families with individuals manifesting cutis laxa, dermatochalasis, dry eyes, and eczema. Although little data is available on other systemic manifestations of Finnish Amyloidosis in the literature, a recent study reported a high prevalence of hypothyroidism (10%) and cardiac arrhythmias (15%), which were noted in Family 2 (Schmidt et al, 2020). On the basis of lack of GSN staining in lung and canalicular biopsy specimens, we consider it unlikely that the benign inflammatory polyp and chronic dacryocystitis in Case 2 were direct results of pathological GSN deposition.…”

“…Amyloidosis of the Finnish type (MIM# 105120) also known as Finnish Amyloidosis, is a rare autosomal dominant disease characterized by specific systemic and ophthalmic features resulting from pathological tissue deposition of amyloidogenic gelsolin (GSN) proteins (Maury et al, 1990). Although Finnish Amyloidosis is characterized by multiple systemic features caused by extracellular aggregation of aberrant protein fragments, this disease most notably results in ocular features, including sight‐affecting corneal dystrophy, dry eyes, chronic corneal ulceration, and an increased risk of cataracts and glaucoma (Schmidt et al, 2020). The integumentary and nervous systems are also commonly affected, with a high incidence of cutis laxa, dermatochalasis, dry skin, and facial nerve palsies.…”