Familial amyloidosis of the Finnish type: clinical and neurophysiological features of two index cases
- Inês Antunes Cunha ,
- Ana Brás ,
- Fátima Silva and
- Anabela Matos
- Neurology Deparment, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal
- Correspondence to Dr Inês Antunes Cunha; ines.antcunha@gmail.com
Abstract
Familial amyloidosis of the Finnish type (FAF) is a rare multisystemic disorder caused by mutations in the gelsolin gene. The clinical presentation is typically characterised by a triad of ophthalmic, neurological and dermatological findings. FAF has been reported in several countries, primarily in Finland and recently in Portugal. We report the first genetically confirmed cases of FAF from two unrelated families in our neuromuscular outpatient clinic. Gelsolin gene sequencing revealed the heterozygous gelsolin mutation (c.640G>A). The clinical features and the neurophysiological studies of two index patients and their relatives are presented. Obtaining an early diagnosis can be challenging, but FAF should be considered in the differential diagnosis of progressive bilateral facial neuropathy, even if there is no known Finnish ancestor.
Background
Familial amyloidosis of the Finnish type (FAF), also called hereditary gelsolin amyloidosis (AGel amyloidosis),1 is a rare autosomal dominantly inherited form of systemic amyloidosis, which was first described in 1969 by the Finnish ophthalmologist Meretoja.2 FAF is a disease caused by single-point mutations in the gene coding for gelsolin. The c.640G>A and >T are the most common and better characterised substitutions2 3 but others have been recently reported.4–8 The mutated protein becomes susceptible to aberrant proteolysis and the generated fragments aggregate and deposit in several tissues.1 The main clinical manifestations are progressive cranial and peripheral neuropathy, corneal lattice dystrophy and skin changes (cutis laxa).9 Heterozygous patients often present ophthalmological disturbances in the third or fourth decade of life, while homozygous have greater severity of clinical findings at an earlier age of onset.10
Although it has initially been described in Finland,2 new cases have been gradually reported in other countries11–15 and it was recently reported in Portugal.16 We, here, describe the clinical and neurophysiological features of the two first families of FAF diagnosed in our clinical centre.
Case presentation
Patient 1. A woman in her 70s presented with slowly progressive facial weakness and gait imbalance since her 60s, accompanied by changes in visual acuity for 6 years. Her mother and two maternal aunts had similar complaints. When examined, she presented cutis laxa, facial diplegia with facial myokymia, labial dysarthria, bilateral Babinski sign but no motor deficit and normal deep tendon reflexes, generalised hypopalesthesia, axial and appendicular ataxia (video 1). No other neurological abnormality was detected on clinical examination.
Patient 2. A man in his 60s presented with a 20-year history of progressive visual loss and facial weakness. Symptoms started after an episode of facial paralysis, associated with herpes zoster infection. The infection resolved, but he noted progressive visual loss and progressive drooping of the face. Over the last years, he reported gait difficulties and ultimately became wheel-chair bound. The patient had a history of a left corneal transplant, a bilateral blepharoplasty of upper eyelid and a lumbar herniated disc surgery. His familiar history was positive for ophthalmological problems and facial palsy. On examination, he presented cutis laxa (figure 1), facial diplegia with facial myokymia, limitation of eye movements, marked labial dysarthria, symmetrical tetraparesis, generalised hyper-reflexia, axial and appendicular ataxia (video 2). No other abnormality on neurological examination was observed.
Cutis laxa of patient 2.
Investigations
At time of referral to neuromuscular disorders clinic, patient 1 had already undergone extensive investigation. Blood serologies and autoimmune panel, cerebrospinal fluid (CSF) analysis (including oligoclonal bands), search for occult malignancy, brain and cervical MRI were all unremarkable. The ophthalmological evaluation showed a corneal lattice dystrophy. Facial nerve investigation was suggestive of axonal lesion, with decreased compound muscle action potential amplitude and electromyography (EMG) of orbicularis oculi and oris muscles revealed signs of moderately severe chronic denervation (reduced recruitment and high amplitude, long duration motor unit potentials) and acute denervation signs (fibrillations and increased insertional activity). Electrophysiological signs of right carpal tunnel syndrome (CTS) (prolonged distal motor and sensitive latencies of the median nerve) were found. Motor (ulnar and peroneal nerves) and sensory nerve conduction studies (ulnar and sural nerves) showed normal amplitudes, distal latencies, conduction velocities and F waves (latencies and frequency). The sensory evoked potential (SEP) study showed no cortical response obtained by tibial nerve stimulation and a normal response was elicited by median nerve stimulation. H-reflex study was not done. Gelsolin gene sequencing was requested and found a heterozygous c.640G>A mutation. Two of her daughters were clinically observed (video 3) and the same mutation was identified.
Outcome and Follow-up
After 5 years of follow-up, patient 1 had developed chronic heart failure, presenting dyspnoea, fatigue and peripheral oedema. She was referral to the cardiac outpatient clinic. Before that appointment, she became progressively more symptomatic and she was admitted for decompensated heart failure following SARS-CoV-2. Unfortunately, she has died few days later. Her both daughters have remained independent for activities of daily living, under no treatment, and they have been in our hospital outpatient follow-up (once per year).
During more than 10 years of follow, patient 2 had been wheelchair-bound because of his disease, requiring help with feeding and personal hygiene. In his 70s, his cough reflex was very poor and the cough-assist device was tried. The patient tolerated it well and it was able to assist him bringing thick secretions into his mouth from his chest. Unfortunately, the patient got a severe SARS-CoV-2 pneumonia, his respiratory condition gradually worsened and he has died few days later.
Discussion
We present the first two index cases, from unrelated families, diagnosed with FAF in our neuromuscular outpatient clinic, confirmed by molecular genetic testing.
Although its molecular spectrum is being expanded,4–8 FAF is invariably associated with two substitutions of the same nucleotide, namely c.640G>A and c.640G>T, resulting in amino acid substitution p.Asp214Asn and p.Asp214Tyr, respectively.2 3 The most common mutation (p.Asp214Asn) has already been identified in two other families in Portugal16 but our cases had no known familiar or geographic relation to the previously described ones.16
The clinical picture in our two index patients is similar to that of the Finnish and Portuguese families, concerning the neurological, ophthalmological and dermatological findings.2 16 Although not confirmed with molecular genetic analysis, it is reasonable to believe that the mother and two maternal aunts of the patient 1, as well as patient 2’ grandmother, mother and brother were affected by the same disorder as suggested by the history and photographs, which is consistent with an autosomal dominantly inherited disease, as described by Meretoja.2
In heterozygous individuals, FAF often manifests at age 25–30 years with corneal lattice dystrophy, followed by slowly progressive cranial neuropathy and cutis laxa,9 although disease onset can occur later16 17 as the case of our patients. Less frequently, patients present with neurological manifestations, with asymptomatic corneal involvement,9 17 like patient 1. The personal history of patient 2 supports that facial dropping and corneal erosions and inflammation, sometimes leading to surgical procedures, are frequent complications.17 18 However, in both cases, corneal lattice dystrophy was diagnosed only after facial palsy thanks to an ad hoc ophthalmological evaluation.
Progressive bilateral facial weakness is the main symptom of our patients and it is the most frequent neurological manifestation of FAF.9 16 According to the literature,9 11 17 facial neuropathy in FAF is typically bilateral and progressive, usually symptomatic around 50 years, with initial involvement of the upper facial nerve branches and later spread to the lower ones. However, in our families, it was not possible to identify this pattern due to advanced stage. Late onset and slow progression of bilateral facial weakness can turn its early recognition more struggling. FAF may be more common than expected and should be considered in differential diagnosis of progressive bilateral facial neuropathy, which includes sarcoidosis, Lyme disease, vasculitic peripheral neuropathy, among others.
Dysphagia and dysarthria due to bulbar palsy may occur, as in our patients. It is interesting to note that bulbar dysfunction in carriers of a c.G640A gelsolin mutation has been less severe and of later onset compared with the ones with c.G640T gelsolin mutation.9
Peripheral nerve involvement is usually minor and mainly sensory, and only a few cases of loss of balance has been reported associated to this rare type of amyloidosis.17 19 The peripheral neuropathy is clinically characterised by distal numbness and paresthesia, predominant loss of vibration sense, and absent or decreased tendon reflexes. At advanced stage, gait ataxia and manual clumsiness suggesting large-fibres loss were described, while muscle weakness and atrophy in the extremities is less frequently reported.9 16 19
There is only limited data about neurophysiological findings in FAF.9 16 19 20 Facial muscles are typically denervated. Peripheral neuropathy is usually described as mild and primarily axonal, a but conduction blocks, slowed nerve conduction, repetitive high-frequency bursts and increased motor latencies also occur, implying demyelination.19 20 Electrophysiological findings compatible with CTS were frequent even though clinical symptoms and signs were scant in most patients, and CTS did not correlate with polyneuropathy.20 The exact mechanism of nerve fibre injury has not yet been established, and the relationship between amyloid deposits and nerve fibre degeneration is still incompletely understood. We found marked denervation of the facial muscles and CTS findings, but no signs of sensory or motor polyneuropathy.
Regarding EMG and SEP studies in FAF, proximal nerve involvement may explain why clinical nerve affection often seems out of proportion to distal nerve involvement. Ataxia reflects lesions in the sensory peripheral nerve and its spinal projections. Besides, amyloid deposition in large myelinated nerves vasculature, distinct from classic amyloid neuropathies, have been reported.19 21 22 In our patients, sensory ataxic symptoms were confirmed by SEP studies, suggesting possible posterior column involvement. This was also observed in the previously described Portuguese c.G640A gelsolin carrier.16
FAF is an inherited and lifelong chronic condition with systemic symptoms. There are no specific treatments but the diagnosis allows patients to understand their disease and symptomatic treatments often improve their quality of life. Ophthalmological follow-up is essential to prevent and/or treat corneal complications18 as observed in patient 2. Surgical treatment can include carpal tunnel surgery in symptomatic patients and plastic surgery to improve facial asymmetry and function, for instance, when skin lagging affects vision or mouth closure.
Due to its late onset, slow progression, and varying neurological and other systemic clinical features, FAF may still be underdiagnosed. It is important to recognise that this condition can occur in any population even in the absence of Finland ancestor, and should be considered in the differential diagnosis of progressive bilateral facial neuropathy. An early diagnosis helps to provide appropriate management, genetic counselling and to avoid future complications.
Learning points
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Familial amyloidosis of the Finnish type (FAP) can occur in populations other than Finnish and even with no known Finnish ancestor.
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FAF should be considered in the differential diagnosis of progressive bilateral facial neuropathy, specialty if it is associated with ocular symptoms.
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Despite the lack of specific treatment, the diagnosis allows patients to understand their disease and the physician to enhance appropriate management of this chronic condition.
Ethics statements
Patient consent for publication
Footnotes
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Contributors IAC drafted the manuscript and had an important role in acquisition, analysis and interpretation of data. AB drafted the manuscript, analysed and revised data critically for important intellectual content. FS revised data critically for important intellectual content. AM had an important role in acquisition, analysis and revised data critically for important intellectual content. All authors read and approved the final version of the manuscript. Supervised by AM.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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