Hereditary Gelsolin Amyloidosis Research Articles

Dynamic Reconstruction Using Bilateral Lengthening Temporalis Myoplasty for Facial Palsies in Patients with Hereditary Skin Laxity.

Hereditary skin laxity is a rare condition, some cases of which are also referred to as cutis laxa, and those involving facial skin are considered a target for treatment by plastic surgery as patients present with an aged face, which can reduce their quality of life. In some of these patients, the facial nerve and muscles may be affected, and cause weakness of mimetic muscles. We performed one-stage bilateral lengthening temporalis myoplasty reanimation, followed by lower facial contouring with partial lower lip excision and hammock-shaped fascia grafting in two patients with hereditary facial skin laxity coexisting with facial palsy. The patient was a 63-year-old woman with hereditary gelsolin amyloidosis and a 64-year-old man who was diagnosed with oculopharyngeal muscular dystrophy. Postoperatively, a symmetrical facial contour was achieved in repose, and smiling with and without biting was possible. To our knowledge, there are no reports of dynamic smile reconstruction for facial weakness in patients with hereditary facial skin laxity. Although these patients may experience progressive loss of function of the trigeminal nerve and its innervating muscles, the static suspension effect of lengthening temporalis myoplasty can be expected to continue even if the temporal muscles lose their function in the future. We believe that, with careful patient selection, dynamic reconstruction is an option for progressive facial paralysis. In this article, we present the chronological history of two patients who underwent multiple plastic surgery procedures and discuss the importance of the role of plastic surgery in improving the quality of life under these conditions.

Slowly progressive descending facial nerve paralysis indicates hereditary gelsolin amyloidosis

A 63-year-old woman attended our oculoplastic clinic with a 10-year history of progressive weakness of the muscles of her forehead, and drooping eyebrows and eyelids that were affecting her field of vision (figure).

Hereditary gelsolin amyloidosis: a rare cause of cranial, peripheral and autonomic neuropathies linked to D187N and Y447H substitutions

Introduction Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States. Methods Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews. Results Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis. Discussion We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.

Hearing problems in patients with hereditary gelsolin amyloidosis

BackgroundGelsolin 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.ResultsOf 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.ConclusionAlthough 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.

Severe ocular involvement in hereditary gelsolin amyloidosis.

Hereditary gelsolin amyloidosis is a rare subtype of hereditary systemic amyloidosis. An old male presented with the characteristic triad of symptoms, including bilateral facial palsy, cutis laxa, and corneal lattice amyloidosis. The diagnosis was confirmed by the detection of the mutation in gelsolin gene located on chromosome 9. Although the presenting symptoms were highly suggestive of the disease, reports of severe ocular involvement are scarce in the literature.

Retinitis pigmentosa associated with systemic light chain amyloidosis (AL amyloidosis)

Retinitis pigmentosa (RP) or hereditary retinal dystrophy is a rare disease that can be isolated (non-syndromic RP) or associated with other systemic signs (syndromic RP). Kidney damage is exceptionally reported in patients with RP, particularly in syndromic forms. Association with renal amyloidosis remains unusual with only one reported case of RP and hereditary gelsolin amyloidosis due to a G654A gelsolin mutation defining the new syndrome of Ardalan-Shoja-Kiuru. Apart from this publication, no case associating RP and AL amyloidosis has been found. We report an original case of renal damage revealing kappa-type systemic light chains amyloidosis (AL amyloidosis) in 35-year-old man with sporadic RP. Our observation is, to our knowledge, the first to report this association.

Amyloid in parenchymal organs in gelsolin (AGel) amyloidosis

Objectives: Previous clinical studies have shown frequent cardiac symptoms in patients with hereditary gelsolin (AGel) amyloidosis, possibly related to amyloid deposition in the heart and other internal organs. Previous studies on internal organ amyloid deposition in AGel amyloidosis have been based on small patient series.Methods: Paraffin-embedded tissue sections from 25 autopsied individuals (age at death 44.4–88.6 years) with AGel amyloidosis were stained with HE, Congo red and Herovici stains and immunohistochemistry against the low molecular weight gelsolin fraction was performed. The amount of amyloid was estimated semi-quantitatively.Results: AGel-based amyloid deposits were found in the myocardium and cardiac blood vessels in every patient. The deposits were mainly small and co-localized with regions with excess fibrosis in the myocardium. The lungs were positive for amyloid in 79%, renal parenchyma in 54% and renal blood vessels in 71% of the cases. The amount of myocardial, renal and hepatic amyloid correlated with age at death of the patients.Conclusions: We show the constant presence of AGel amyloid in the hearts of patients with AGel amyloidosis. Although the deposits were mainly small, the co-localization of amyloid with fibrosis may amplify the effect of pure amyloid deposition, possibly leading to clinical signs and symptoms.

IS DOXYCYCLINE AN ANSWER TO PREVENT PROGRESSION OF FAMILIAL GELSOLIN TYPE AMYLOIDOSIS INVOLVING THE HEART?

Hereditary gelsolin amyloidosis (HGA) is an autosomal dominant form of systemic amyloidosis, characterized mainly by cranial and sensory peripheral neuropathy and corneal lattice dystrophy. Currently no specific treatment is established for this condition. We present a case of HGA involving the

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.

Expression, purification, and characterization of recombinant 8 kDa gelsolin fragment

A mutation (D187N/Y) in human plasma gelsolin (GSN) leads to the generation of an 8 kDa GSN fragment (8 kDa-GSN), and consequently causes the familial amyloidosis of Finnish type. Because of its faster kinetics of amyloid formation under physiologically relevant conditions, 8 kDa-GSN is used to explore gelsolin amyloidosis and screen small molecules that can disaggregate amyloids. However, the synthetic 8 kDa-GSN is expensive, and substantial quantities of 8 kDa-GSN are needed for the screen. Here we report a study to obtain recombinant 8 kDa-GSN with high yield from Escherichia coli. Firstly, 8 kDa-GSN in fusion with Mxe GyrA intein was purified by Ni-affinity chromatography. Then 8 kDa-GSN was released by intein-mediated protein cleavage, and separated from intein by ion-exchange chromatography. The yield of 8 kDa-GSN was only 1.5 mg/L from bacterial culture in the previous report, while it was improved to 4.25 mg/L in our study. Finally, the amyloidogenic property of 8 kDa-GSN was validated by circular dichroism spectrometry and dynamic light scattering.

Increasing amount of amyloid are associated with the severity of clinical features in hereditary gelsolin (AGel) amyloidosis

Background: Patients with hereditary gelsolin (AGel) amyloidosis (HGA) present with hanging skin (cutis laxa) and bilateral cranial neuropathy, and require symptomatic plastic surgery. Our clinical observation of tissue fragility prompted us to design a prospective study.Methods: Twenty-nine patients with HGA undergoing surgery were interviewed and clinically examined. The height and thickness of skin folds in standard anatomical localizations were measured. The presence and distribution of amyloid in skin samples were analyzed using Congo red staining and immunohistochemistry using antibodies against gelsolin amyloid (AGel) subunit.Results: The measured skin folds stretched more in patients with HGA (e.g. skin over olecranon, p < 0.001). The skin folds were thinner in patients with HGA (e.g. forehead skin, p < 0.001). The skin and subcutaneous fat were abnormally fragile during surgery. The total amount of AGel amyloid, and its presence in the deep layers of the skin and subcutaneous fat correlated with the measurements of skin folds, age and extent of cranial neuropathy.Conclusions: The AGel amyloid in the skin and subcutis, together with morphologic changes in the dermal stroma and skin adnexa contribute to the atrophied and fragile structure of HGA skin. This is the first study to demonstrate the correlation between AGel amyloid accumulation and clinical disease severity.

Gelsolin amyloid angiopathy causes severe disruption of the arterial wall

Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi-quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA.

Causes of death and life span in Finnish gelsolin amyloidosis

Background: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients’ life span.Methods: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients’ underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs.Results: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6–149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31–0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13–5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0–75.6) and 78.0 years for female patients (95% CI: 76.4–79.5) compared to 72.1 and 80.1 years for the general population.Conclusions: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers.Key MessagesAGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients’ life span is comparable to that of the general population.

Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis

Hereditary gelsolin amyloidosis (GA) is a rare condition caused by the gelsolin gene mutation. The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa. Detailed information on facial paralysis in GA and the extent of cranial nerve injury is lacking. 29 GA patients undergoing facial corrective surgery were interviewed, examined, and studied electroneurophysiologically. All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve. Clinical involvement of frontal, zygomatic, and buccal facial nerve branches was seen in 97%, 83%, and 52% of patients, respectively. Electromyography showed marked motor unit potential loss in facial musculature. Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings. We describe a grading method for bilateral facial paralysis in GA, which is essential for evaluation of disease progression and the need for treatment.

Natural course of Finnish gelsolin amyloidosis

Background. Finnish type of hereditary gelsolin amyloidosis (FGA) is one of the most common diseases of Finnish disease heritage. Existing FGA knowledge is based only on smaller patient series, so our aim was to elucidate the natural course of the disease in a comprehensive sample of patients and to build up a national FGA patient registry.Methods. An inquiry about the known and suspected signs of FGA, sent to the members of Finnish Amyloidosis Association, telephone contacts, and hospital records were utilized to create the registry.Results. A total of 227 patients were entered to the database. The first symptom was ophthalmological for 167 patients (73.6%) at the mean age of 39 years. Corneal lattice dystrophy (CLD) was reported at the mean age of 43 years. Impaired vision, polyneuropathy, facial nerve paresis, and cutis laxa appeared on average between 52 and 57 years. Carpal tunnel syndrome (CTS) was reported by 86 patients (37.9%). Nine patients (4.0%) had a pacemaker, and 12 (6.1%) had cardiomyopathy.Conclusions. The first symptom was ophthalmological in most cases. Except for CLD no prominent difference in the age of appearance was found between the major symptoms. CTS, cardiac pacemakers, and cardiomyopathy were remarkably more common compared to the general population.

An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model.

Hereditary gelsolin amyloidosis is an autosomal dominantly inherited amyloid disorder. A point mutation in the GSN gene (G654A being the most common one) results in disturbed calcium binding by the second gelsolin domain (G2). As a result, the folding of G2 is hampered, rendering the mutant plasma gelsolin susceptible to a proteolytic cascade. Consecutive cleavage by furin and MT1-MMP-like proteases generates 8 and 5 kDa amyloidogenic peptides that cause neurological, ophthalmological and dermatological findings. To this day, no specific treatment is available to counter the pathogenesis. Using GSN nanobody 11 as a molecular chaperone, we aimed to protect mutant plasma gelsolin from furin proteolysis in the trans-Golgi network. We report a transgenic, GSN nanobody 11 secreting mouse that was used for crossbreeding with gelsolin amyloidosis mice. Insertion of the therapeutic nanobody gene into the gelsolin amyloidosis mouse genome resulted in improved muscle contractility. X-ray crystal structure determination of the gelsolin G2:Nb11 complex revealed that Nb11 does not directly block the furin cleavage site. We conclude that nanobodies can be used to shield substrates from aberrant proteolysis and this approach might establish a novel therapeutic strategy in amyloid diseases.

Clinical characteristics and SAP scintigraphic findings in 10 patients with AGel amyloidosis

The clinical features of hereditary gelsolin (AGel) amyloidosis include corneal lattice dystrophy, distal sensorimotor, cranial neuropathy and cutis laxa. To date, four mutations of the gelsolin (GSN) gene encoding the following variants have been identified as the cause of this malady; p.D214N, p.D214Y, p.G194R and p.N211K (this nomenclature includes the 27-residue signal peptide). Interestingly, the latter two variants are associated exclusively with a renal amyloidosis phenotype. Here we report the clinical features in 10 patients with AGel amyloidosis associated with the p.D214N mutation, all of whom underwent whole body 123I-SAP scintigraphy and were followed up in a single UK Centre for a prolonged period. Two patients, from the same kindred presented with proteinuria; eight subjects had a characteristic AGel amyloidosis phenotype including cranial neuropathy and/or corneal lattice dystrophy. 123I-SAP scintigraphy revealed substantial renal amyloid deposits in all 10 patients, including those with preserved renal function, and usually without tracer uptake into other visceral organs. 123I-SAP scintigraphy is a non-invasive technique that aids early diagnosis of patients with this rare disease, especially those who lack a family history and/or present with an unusual clinical phenotype.

WHY THE LONG FACE?

We report a 63 year old lady with decreased visual acuity, no wrinkles and difficulty sucking drinks through a straw. Neurological examination revealed bilateral lower motor neuron facial weakness. There was normal tone and power in the limbs and pinprick, temperature and proprioception were intact but vibration sensation was absent to the level of the sternum. Gait was normal but there was mild clumsiness of the hands. No prior family history of neurological disease was known. Electrophysiology revealed normal sensory action potentials. Ophthalmological examination prompted the diagnosis of hereditary gelsolin amyloidosis which is recognized by the triad of corneal lattice dystrophy, progressive cranial neuropathy and cutis laxa. This was confirmed on finding a heterozygous D241N Gelsolin mutation. The unusual pattern of dissociated vibration and proprioceptive loss has been described in this condition with histopathological amyloid deposition providing eloquent demonstration of the involved anatomy. We present this rare case as an interesting and educational lesson in spinal cord anatomy.

Relation of gelsolin amyloidosis and periodontal health

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a rare, dominantly inherited systemic disease with worldwide distribution, caused by a gelsolin gene mutation. We studied the periodontal conditions and microbiological plaque composition of AGel amyloidosis patients. A voluntary study group of 36 AGel amyloidosis patients (mean age 61) filled in a questionnaire. A thorough periodontal examination included periodontal pocket depth and attachment level measurements, registrations of visible plaque, bleeding on probing and panoramic radiographs. The presence of oral Candida was studied by fungal culture method. Bacterial samples from deepened pockets (≥4mm) were analyzed with checkerboard DNA-DNA hybridization method. VPI (15.3%) and BOP (11.2%) of the patients were modest reflecting relatively adequate oral self-care. Still 89% of the patients had at least one PPD of ≥4mm; 78.5% of the PPDs ≥6mm were found in molars. Patients had lost one third of the molars due to periodontitis and/or tooth decay. Half of the patients (53%) were Candida carriers. Bacterial analysis of subgingival plaque samples revealed bacterial species common to chronic periodontitis. AGel amyloidosis may increase the risk for periodontitis even when the oral self-care is adequate. Molar teeth appear to be mostly affected, leading to tooth loss. AGel amyloidosis as a systemic disease is related with a vast variety of symptoms with variable severity. Even though a causal relationship of the systemic disease and periodontitis has not yet been proven, increased risk for periodontal problems should be considered when examining AGel amyloidosis patients.

Novel gelsolin variant as the cause of nephrotic syndrome and renal amyloidosis in a large kindred

Familial Amyloidosis of Finnish type (FAF) is a rare type of autosomal dominant hereditary amyloidosis associated with genetic variants of gelsolin. Three amyloidogenic mutations have previously been reported characteristically presenting with ophthalmologic abnormalities, progressive cranial neuropathy and cutis laxa. We report a novel gelsolin variant in a 62-year-old man with nephrotic range proteinuria of 13.2 grams/day as the only presenting symptom. Renal biopsy followed by laser micro-dissection and mass spectrometry showed amyloidosis derived from gelsolin. DNA sequencing revealed the novel gelsolin mutation (c.633C > A) encoding p.N211K protein variant. Four of 13 asymptomatic family members were found to be heterozygous for the p.N211K mutation, three of whom had proteinuria of varying degree including one who proceeded to renal biopsy and was confirmed to have renal amyloidosis. Follow-up of these cases might give us more insight into pathogenicity and potential treatment strategy of this atypical presentation of gelsolin amyloidosis.