Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF)

doi:10.1016/0022-510X(94)90092-2

Journal of the Neurological Sciences

Volume 126, Issue 1, October 1994, Pages 40-48

https://doi.org/10.1016/0022-510X(94)90092-2 Get rights and content

Abstract

Familial amyloidosis, Finnish type (FAF), is a gelsolin-related inherited systemic amyloidosis. We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27–74 years: mean 53.9 years). Cardiovascular reflex tests showed a significant decrease in heart rate variation in FAF patients compared with healthy controls. Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls. Signs of amyloid cardiopathy were rare at clinical examination and in radio-, echocardio- and electrocardiographic examinations. Histological and immunohistochemical studies revealed amyloid deposition and immunoreactivity against the gelsolin-related FAF amyloid subunit in autonomic nervous system structures and in cardiac tissue in 3 autopsied FAF patients. The results show that minor autonomic nervous system dysfunction can be found in FAF, while clinically significant amyloid cardiopathy or autonomic neuropathy is not characteristic of this type of amyloidosis.

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AGel amyloidosis is an autosomal-dominant monogenic disease. Symptoms include corneal lattice dystrophy, cranial neuropathy, skin elasticity problems, and renal complications [21–23]. The G2-related mutations occur at different sites: D187 is part of the Ca2+-binding site, both N and Y substitutions impair the ion binding [9,11–16]; the N184K mutant is still able to bind calcium and the geometry of the binding site matches that of wild type (WT) protein [10]; the G167R mutation was shown to promote the dimerization of GSN via a peculiar 3D domain swap mechanism [9].
The second domain of gelsolin (G2) hosts mutations responsible for a hereditary form of amyloidosis. The active form of gelsolin is Ca²⁺-bound; it is also a dynamic protein, hence structural biologists often rely on the study of the isolated G2. However, the wild type G2 structure that have been used so far in comparative studies is bound to a crystallographic Cd²⁺, in lieu of the physiological calcium. Here, we report the wild type structure of G2 in complex with Ca²⁺ highlighting subtle ion-dependent differences. Previous findings on different G2 mutations are also briefly revised in light of these results.
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To analyze the outcome of penetrating keratoplasty (PK) to the first eye for corneal amyloidosis in familial amyloidosis, Finnish type (FAF).
Single-center, retrospective, nonrandomized, interventional, noncomparative case series.
Thirty-one eyes of 31 patients with FAF.
All patients with FAF who had their first PK in Helsinki University Eye Hospital between January 1, 1990, and August 1, 2011, were identified and a retrospective analysis of the patient charts was performed.
Best spectacle-corrected visual acuity (BCVA), intraoperative and postoperative complications, graft survival, reason for graft failure, and frequency of regrafting.
The median follow-up period was 32 months (range, 5–114). After 24 months, the median BCVA was 1.15 on a logarithm of the minimum angle of resolution scale (20/280; mean, 1.1; SD, 0.5) in comparison with the preoperative median BCVA of 1.3 (20/400; mean, 1.3; SD, 0.4). At 24 months, 3 of 18 eyes (17%) had a visual acuity of ≥0.5 (20/63) and 13 of 18 grafts (72%) were clear. Rejection occurred in 6 of 31 primary grafts (19%). Graft failure occurred in 16 of 31 eyes and resulted from surface complications in 11 eyes and additionally from rejection in 5 eyes. Seven eyes needed regrafting (twice in 1 eye). Complications were frequent in the early and late postoperative periods. Presence of preoperative corneal or graft neovascularization was an indicator of a high risk of graft failure and poor visual outcome.
In a minority of FAF patients, PK improves vision. Owing to the high failure risk and guarded visual prognosis after PK, it is important that both the surgeon and the patient have realistic expectations. It may be reasonable to limit PK to cases with bilateral advanced disease. It seems reasonable to optimize ocular surface health and to delay PK.
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If HGA patients manifest with impaired consciousness it is important to consider possible conduction disturbances in the differential diagnosis. Clinically detectable amyloid cardiomyopathy is not common in middle-aged patients (Kiuru et al., 1994). According to French (Chastan et al., 2006) and recent Finnish observations (Laine et al., 2010), cardiac involvement may still be underestimated in HGA.
Hereditary gelsolin amyloidosis (HGA) is an autosomally dominantly inherited form of systemic amyloidosis, characterized mainly by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa. HGA, originally reported from Finland and now increasingly from other countries in Europe, North and South America, and Asia, may still be underdiagnosed worldwide. It is the first and so-far only known disorder caused by a gelsolin gene defect, namely a G654A or G654T mutation. Gelsolin is a principal actin-modulating protein, implicated in multiple biological processes, also in the nervous system, e.g. axonal transport, myelination, neurite outgrowth, and neuroprotection. The gelsolin gene defect causes expression of variant gelsolin, followed by systemic deposition of gelsolin amyloid (AGel) in HGA patients and even other consequences on the metabolism and function of gelsolin. In HGA, specific therapy is not yet available but correct diagnosis enables adequate symptomatic treatment which decisively improves the quality of life in these patients. A transgenic murine model of HGA expressing AGel is available, in anticipation of new treatment options targeted toward this slowly progressive but devastating amyloidosis. Present and future lessons learned from HGA may be applicable even in diagnosis and treatment of other hereditary and sporadic amyloidoses.
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The systemic amyloidoses are an uncommon group of disorders characterized by the extracellular deposition of amyloid in one or more organs. Cardiac deposition, leading to an infiltrative/restrictive cardiomyopathy, is a common feature of amyloidosis. It may be the presenting feature of the disease or may be discovered while investigating a patient presenting with non-cardiac amyloidosis. In this article we review the features of cardiac amyloidosis and its varied manifestations. The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is stressed in light of recent advances in therapy which can, when appropriately used, significantly improve prognosis.
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To define the clinical patterns of peripheral neuropathy and autonomic testing abnormalities in patients with amyloidosis.
A retrospective chart review was conducted of 65 patients who had biopsy-proven amyloidosis and autonomic function testing between January 1, 1985, and December 31, 1997, at Mayo Clinic's site in Rochester, MN. Patients were required to have neurologic evaluation, autonomic reflex screening, and tissue confirmation of amyloidosis.
We identified 5 clinical patterns of peripheral neuropathy: (1) generalized autonomic failure and polyneuropathy with pain (40 patients [62%]), (2) generalized autonomic failure and polyneuropathy without pain (11 [17%]), (3) isolated generalized autonomic failure (7 [11%]), (4) polyneuropathy without generalized autonomic failure (4 [6%]), and (5) generalized autonomic failure and small-fiber (ie, autonomic and somatic C-fiber) neuropathy (3 [5%]). Moderately severe generalized autonomic failure, involving adrenergic, cardiovagal, or sudomotor domains, was found in all patients, including those without clinically manifested autonomic failure. The diagnosis of amyloidosis was delayed in patients who did not have initial symptoms of pain or generalized autonomic failure (48 months to diagnosis in patients with polyneuropathy without autonomic failure vs 12 months to diagnosis in patients with autonomic failure and small-fiber neuropathy; P=.57).
Physicians should test for symptoms of generalized autonomic failure in patients who have peripheral neuropathy of unknown origin. Autonomic testing may give abnormal results in patients without overt symptoms of autonomic failure. Early recognition of autonomic failure may lead to earlier diagnosis of the underlying pathogenesis of amyloidosis, as well as earlier treatment for patients with this condition.
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Research articleAutonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF)

Abstract

Genomics

Clin. Endocrinol. Metab.

Am. J. Med.

Trends Neurosci.

Biochem. Biophys. Res. Commun.

Neurobiol. Aging.

J. Neurol. Sci.

Am. J. Cardiol.

Oncol. Hematol.

Biochim. Biophys. Acta

FEBS Lett.

FEBS Lett.

Genomics

J. Neurol. Sci.

Genomics

Biochem. Biophys. Res. Commun.

Am. J. Cardiol.

J. Biol. Chem.

A peculiar form of peripheral neuropathy: familiar atypical generalized amyloidosis with special involvement of the peripheral nerves

Brain

Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187

Nat. Genet.

Dissociated sensation in amyloidosis: compound action potential, quantitative histologic and teased-fiber, and microscopic studies of sural nerve biopsies

Arch. Neurol.

Gelsolin variant (Asn-187) in familial amyloidosis

Finnish type. Biochem. J.

Amyloidosis due to a mutation of the gelsolin gene in an American family with corneal lattice dystrophy type II

New Engl. J. Med.

Research article
Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF)