A clinical case of hereditary transthyretin amyloidosis with predominant involvement of the peripheral nervous system

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Introduction

Amyloidosis is a protein metabolism disorder characterized by the formation in tissues of a specific fibrillar-structured protein-polysaccharide complex (amyloid), which is highly ordered with fibrils 5–10 nm thick due to an abundance of β-sheet conformation in the secondary structure of the main amyloid-forming protein [1]. Amyloidosis is classified into localized (where the source of amyloid production is located in the affected tissue itself) and systemic (where amyloid formation in tissues is due to the influx of amyloid precursor protein with the bloodstream) [1]; primary (idiopathic and associated with multiple myeloma and other B-lymphocytic hemoblastoses), secondary (associated with an underlying disease, most often inflammatory), and hereditary (caused by a mutation in the gene encoding the corresponding protein). The modern classification of amyloidosis is based on the specificity of the main fibrillar amyloid precursor protein.

To date, over 36 amyloid precursor proteins have been identified in various types of amyloidosis in humans [2], among which at least 10 hereditary types are distinguished [3]. In the name of an amyloid type, the first letter is a capital A, meaning amyloid, followed by the designation of the specific fibrillar amyloid protein: A (amyloid A protein), L (light chains of immunoglobulins), TTR (transthyretin), etc. [4]. The most common among the listed hereditary forms is transthyretin amyloidosis (ATTR) [5].

TTR is a transport protein for thyroxine (T4) and the retinol-binding protein–vitamin A complex. TTR is a tetramer composed of four identical subunits. Approximately 95% of TTR is produced in the liver, and less than 5% is synthesized in the choroid plexus of the brain and the retinal pigment epithelium. ATTR is a form of amyloidosis whose pathogenesis is based on destabilization (misfolding) of the TTR tetramer and deposition of misfolded TTR monomers in tissues [4, 6].

ATTR can be divided into two types: wild-type (previously called senile) and hereditary. Wild-type ATTR (ATTRwt, wt — wild type) develops with age due to destabilization of normal TTR¹ tetramers. These patients are usually over 60 years of age, Caucasian, and male. In accordance with ISA recommendations for amyloid diseases associated with mutant proteins, it is recommended to use the term hereditary rather than familial amyloidosis. Also, instead of the designations ATTRm (m — mutant) or hATTR (h — hereditary), the term hereditary ATTRv (v — variant) has been proposed [5].

ATTRv is a fatal systemic progressive disease caused by mutations in the TTR gene, inherited in an autosomal dominant pattern, primarily affecting the peripheral and autonomic nervous systems and the heart, as well as the kidneys, liver, eyes, and gastrointestinal tract [7]. The TTR gene is located on chromosome 18 and consists of 4 exons. According to the Human Gene Mutation Database, 162 mutation variants have been described in the TTR gene, most of which are pathogenic and associated with various disease phenotypes [8]. Most patients are heterozygotes, so they have not only the mutant TTR gene but also the normal non-mutant TTR gene in their body [4]. ATTRv is usually associated with the substitution of one amino acid in the protein, caused by a point mutation in the TTR gene. For example, in the dominant widespread Val30Met mutation (p.Val50Met, с.148G>A), described in 1980, valine is replaced by methionine at position 30 [9].

The endemic countries for this mutation are Portugal, Sweden, and Japan (in non-endemic regions, the mutation spectrum is more variable) [3]. H. Ohmori et al. suggested that the Val30Met mutation originally occurred in Europe and was introduced to Japan by Portuguese traders in the 16th century, who were actively trading in all regions of Kyushu until the early 17th century, when Japan became a closed country [2]. Subsequently, the mutant allele spread to Nagano and other regions of Japan [2, 3]. C. Zaros et al. also concluded that there were different founders for Portuguese and Swedish carriers of the Val30Met mutation and, moreover, demonstrated the Portuguese origin of the Brazilian Val30Met mutation [10]. Further evidence of independent multiple origins of the Val30Met mutation in Europe is provided by the work of A. Iorio et al., which shows the presence of a distinct founder for the Italian population, older in origin compared to the Portuguese one [11]. It has been established that in Italy, Val30Met arose approximately 850–900 years ago, in Portugal — 750 years ago, in Brazil — 650 years ago, and in Sweden — 375 years ago. The presence of several founders for Val30Met, indicating independent origins of this mutation in different countries, partly explains the phenotypic heterogeneity of ATTR: varying age of disease onset, variable penetrance, and different degrees and spectra of clinical manifestations in various populations [3].

In ATTR-Val30Met, a variety of symptoms have been described; most often, the typical clinical picture includes:

• peripheral polyneuropathy and autonomic dysfunction, carpal tunnel syndrome;
• amyloid cardiomyopathy, arrhythmias, heart failure with preserved ejection fraction;
• ocular involvement manifested as vitreous opacities leading to gradual vision loss, lacrimal duct obstruction (which may cause chronic open-angle glaucoma), conjunctival vessel anomalies, and pupillary abnormalities;
• gastrointestinal tract involvement — nausea, vomiting, early satiety, diarrhea, constipation, alternating diarrhea and constipation;
• unintentional weight loss due to secondary malabsorption and nutritional factors.

The article presents a clinical case of ATTRv caused by the most common mutation in the TTR gene — Val30Met.

Clinical case report

Patient P., 61 years old male, noticed weakness, numbness, and pain in the legs in 2019. The symptoms gradually progressed. He first sought neurological care at Kirov Regional Clinical Hospital in 2022. Neurological examination at that time revealed weakness in the feet (MRC score of 4), with predominant sensory disturbances in the legs consistent with polyneuropathic pattern.

Lumbar MRI (2022) showed osteochondrosis, protrusions at L3–L4, L4–L5, L5–S1, spondylosis, left-sided scoliosis, and spondyloarthrosis.

Nerve conduction study (NCS) of lower limbs (2022) demonstrated neural-level lesion — severely expressed axonal sensorimotor neuropathy of peripheral nerves in lower extremities. Upper extremity nerves were not examined.

The patient was assigned disability group 3 with a diagnosis of toxic polyneuropathy due to documented alcohol use history. He did not seek medical care until 2024.

Leg weakness progressively worsened, with subsequent involvement of the arms. Since January 2024, he reported marked deterioration: crutch-dependent ambulation due to leg weakness, severe pain and cramps in lower limbs, and limb muscle wasting.

He consulted a neurologist again in 2024. He was hospitalized in the neurology department of Kirov Regional Clinical Hospital for further examination and treatment. Upon more detailed questioning, it was revealed that the patient had lost weight due to decreased appetite and early satiety. He periodically reported episodes of diarrhea alternating with constipation. On standing, he experienced dizziness and unsteadiness, sometimes leading to falls with syncope. Over the past 6 months, the patient developed leg edema. The patient ambulates with two crutches, lives alone, does not leave the house independently, and has not abused alcohol for several years.

When collecting family history, it was found that the patient’s grandmother had severe leg weakness progressing to paralysis without a diagnosis being established. The patient has a 38-year-old daughter who is currently clinically healthy and lives in another city.

On admission to the hospital, the neurological status was notable for decreased muscle tone in the arms and legs, and marked muscle atrophy in the extremities. Muscle strength in the upper extremities: proximally — score of 4 points, distally — score of 2.5; in the lower extremities: proximally — score of 3, in the feet — score of 0-1. Tendon and periosteal reflexes in the arms and legs were absent. Abnormal reflexes were absent. Tactile, pain, and vibration sensation were reduced in the arms and legs in a polyneuropathic pattern. He was unsteady in the Romberg position and prone to falling. Sensory ataxia was observed. The patient’s gait was characterized by foot drop and slapping (steppage gait), with bilateral support.

According to laboratory tests, complete blood count was normal, urinalysis revealed mild hematuria. Blood chemistry showed that glucose, liver enzymes, C-reactive protein, and electrolytes were within normal limits. Notable was a slight decrease in total blood protein (58.1 g/L) and creatinine levels, likely due to malabsorption and reduced dietary protein intake. Glomerular filtration rate was normal. Creatine phosphokinase was slightly elevated to 275 U/L (normal up to 171 U/L), lactate dehydrogenase was 214 U/L (normal). The patient underwent lumbar puncture: CSF showed significantly elevated protein level of 1.45 g/L, with normal cell count.

Figure 1 shows that NCS of the upper and lower extremities confirmed a previously identified severe axonal and demyelinating sensorimotor peripheral neuropathy. Distal responses from the lower extremities were not recorded. In the upper extremities, the amplitude was reduced and the distal latency of the M-response (motor response) was increased.

 

Fig. 1. Nerve conduction study of the lower and upper extremities of patient P.

Tibial nerve: M-response is not recorded. Median nerve: amplitude reduced to 1 mV (normal above 3.5 mV), distal latency of M-response increased to 5.5 msec (normal up to 3.5 msec), motor conduction velocity in the forearm slowed to 26 m/sec.

 

Needle electromyography (EMG) revealed denervation and reinnervation changes of varying severity in the muscles of the arms and legs: an active ongoing denervation process, reorganization of motor unit potentials in a neurogenic pattern.

Initially, the patient was diagnosed with dysimmune polyneuropathy — chronic inflammatory demyelinating polyneuropathy (CIDP). Pulse therapy with glucocorticosteroids was administered, totaling 5 g by intravenous infusion, without effect.

Given the leg edema in the patient, an additional blood test for B-type natriuretic peptide was performed. A significant elevation to 1711 pg/mL (normal range up to 125 pg/mL) was detected, indicating heart failure.

Considering progressive sensorimotor polyneuropathy, no response to immunosuppressive therapy for the established diagnosis of CIDP (refractory form), and systemic manifestations including autonomic disturbances with orthostatic issues and gastrointestinal dysfunction, unintentional weight loss, and chronic heart failure (lower limb edema, elevated NT-proBNP), ATTR was suspected. Molecular genetic testing was performed, which revealed a Val30Met mutation in exon 2 of the TTR gene.

Thus, the cause of the patient’s neurological disorders was identified, and the diagnosis required revision.

Subsequently, a comprehensive cardiac examination was performed.

Holter ECG monitoring revealed transient first-degree atrioventricular block.

Echocardiography revealed thickening of the interventricular septum and posterior wall of the left ventricle up to 13 mm (normal ≤ 10 mm), concentric left ventricular hypertrophy, and global longitudinal strain of the left ventricle at 18%. A positive echocardiographic sign was identified: reduced longitudinal strain in the basal anteroseptal and inferoseptal segments, while preserved in adjacent apical segments. Despite heart failure, the patient maintained preserved ejection fraction (62% by Simpson’s method) and non-enlarged cardiac chamber dimensions, which is also characteristic of amyloid restrictive cardiomyopathy.

The patient underwent cardiac contrast-enhanced MRI (gadovist). MRI findings demonstrated diffuse infiltrative involvement of all cardiac chambers, predominantly affecting the right atrium and left ventricle, with left ventricular myocardial thickening and a contrast enhancement pattern typical of amyloidosis.

Whole-body scintigraphy showed increased myocardial uptake of the radiopharmaceutical agent compared to rib bone tissue, corresponding to Grade 3, as clearly illustrated in Fig. 2.

 

Fig. 2. Whole-body scintigraphy.

Whole-body, planar, and single-photon emission computed tomography (SPECT) imaging revealed increased uptake of the radiopharmaceutical in the cardiac region. The differential uptake ratio in the cardiac region relative to the symmetric area was 2.06. Myocardial uptake of the radiopharmaceutical was higher than in bone tissue (ribs).

 

According to the 2019 consensus algorithm for noninvasive diagnosis of cardiac amyloidosis, in patients with characteristic amyloidosis features on EchoCG/MRI, Grade II/III on scintigraphy, and without clonal abnormalities, ATTR can be diagnosed without endomyocardial biopsy [12].

Since the eyes can be a target for amyloid deposition, the patient underwent an ophthalmologic examination. Yellowish deposits (likely amyloid) were visualized under the conjunctiva in the outer sectors of both eyes; the cornea was clear. There were inclusions contaminating the precorneal tear film, initial lens opacities, and filamentous destructive changes in the vitreous body.

The patient underwent optical coherence tomography (OCT) of the retina: reduced corneal thickness was found (OD [right eye] 521 μm, OS [left eye] 515 μm [thinner than average]); examination of the optic nerves revealed a slightly reduced retinal nerve fiber layer thickness, a normal neuroretinal rim, and a slightly increased cup volume on the right; in the macular area, the retinal layers were well-differentiated, the foveal profile was normal, and there was a posterior hyaloid membrane detachment in the right eye (OD). Perimetry revealed nasal visual field constriction to 45° from the fixation point and temporal constriction to 70° from the fixation point. Based on the examination results, the ophthalmologist at Kirov Regional Clinical Hospital concluded: given moderate elevation of intraocular pressure (IOP = 22 mm Hg) in both eyes (OU) with relatively thin corneas, glaucomatous changes in the optic nerves, and perimetry data, the diagnosis was open-angle stage IIa-b glaucoma OU. Additionally, initial cataracts OU, conjunctival deposits in both eyes, dry eye syndrome OU, and vitreous destruction in both eyes were noted.

The ocular abnormalities identified in the patient is also highly characteristic of ATTR [13].

Thus, the patient was diagnosed with systemic ATTR with predominant involvement of the peripheral nervous system (progressive symmetric sensorimotor axonal and demyelinating polyneuropathy), autonomic dysfunction (diarrhea, orthostatic hypotension), cardiac involvement (amyloid cardiomyopathy), and a heterozygous TTR gene mutation in exon 2 (Val30Met).

Discussion

In this clinical case, the patient was found to have the most common TTR gene mutation, Val30Met. It is known that phenotypic manifestations, even within this single mutation, vary depending on the time of onset of the first symptoms of the disease, as indicated in the table. This fact is associated with the characteristics of the deposited amyloid fibrils. Early-onset ATTRv polyneuropathy is characterized by full-length fibrils and the classic form of the disease with significant involvement of the autonomic nervous system. At the same time, patients retain mobility independence longer and have a longer life expectancy (up to 10–20 years from the onset of the disease). In late-onset cases, fibrils of varying lengths and mixed TTR protein fragments are more commonly detected; patients have significant cardiac involvement and a shorter life expectancy (up to 7 years from the onset of the disease) [5, 14].

 

Table. Main characteristics of ATTRv caused by the Val30Met mutation depending on the time of onset of the first symptoms [5, 15]

Parameter	Val30Met mutation
	Early onset (before 50 years of age)	Late onset (after 50 years of age)
Country (endemic region)	Brazil, Sweden, Portugal, Japan	UK, Italy, USA, France, Sweden, Japan
Family history, %	94	48
Peripheral polyneuropathy, %	57	81
Autonomic neuropathy, %	48	10
Unintentional weight loss, %	5	0
Average time until the need for support while walking, years	>5.6	3
Average time until the need for wheelchair, years	10	6
Cardiac status	Progressive conduction disturbances	Restrictive cardiomyopathy, heart failure, progressive conduction disturbances
Average survival from first symptoms, years	11	7.3
Cause of death	Cachexia, infections	Heart failure, sudden death, cachexia or secondary infections

 

Patient P. had a late disease onset — after 50 years of age. This explains the pronounced peripheral polyneuropathy and restrictive cardiomyopathy with heart failure and cardiac arrhythmias. There is evidence that ATTR cardiomyopathy occurs predominantly in men (70–90%) [16, 17], while ATTR nephropathy is more common in women (F:M = 15:3). This is confirmed by our clinical case: absence of nephropathy (glomerular filtration rate unchanged, no proteinuria) despite the advanced stage of the disease [18].

In addition, our patient exhibits autonomic neuropathy, manifested as orthostatic hypotension, alternating postprandial diarrhea and constipation, and unintentional weight loss. According to the studies by E. Barroso et al., in patients with the Val30Met mutation, the average time from the onset of the first signs of the disease to the first autonomic symptoms is 2.7 years [19]. In general, autonomic disorders are not the most common symptom in late-onset Val30Met ATTR polyneuropathy, which is a distinctive feature of the presented clinical case.

Ocular lesions occupy a significant place in the ATTR clinical presentation in our case, largely due to ATTR production by the retinal pigment epithelium. It is known that plasma ATTR cannot penetrate the blood-retinal barrier. The literature describes cases of amyloid lesions in the ocular adnexa and structures: extraocular muscles, lacrimal gland, conjunctiva, cornea, iris, posterior lens capsule, pupillary area, vessels, and retina [9, 11, 20–23]. There are isolated publications describing amyloid lesions in the vitreous body [2, 8, 13, 24, 25]. In our patient, at the advanced disease stage, amyloid was detected in the corneal endothelium, lens capsule, vitreous body, lacrimal glands, and open-angle glaucoma was verified. Notably, the patient himself did not actively complain of visual impairment, attributing the vision deterioration to age-related changes that he considered insignificant against the background of pronounced movement limitations.

The world literature emphasizes the importance of early diagnosis of ATTRv. For this purpose, the expert community has developed a screening algorithm and a system of red flags for non-endemic regions (which include Russia) to suspect a patient with progressive sensorimotor ATTRv polyneuropathy and refer them for molecular genetic testing. These include confirmed progressive symmetrical sensorimotor polyneuropathy and refractory CIDP associated with one or more of the following features (according to [26], revised):

• family history of ATTR;
• autonomic neuropathy (orthostatic hypotension, erectile dysfunction, urinary incontinence, nocturia);
• gastrointestinal tract involvement (alternating diarrhea and constipation, nausea, vomiting, early satiety);
• unexplained weight loss;
• left ventricular myocardial hypertrophy, arrhythmias, conduction disorders, restrictive cardiomyopathy; apical sparing phenomenon is particularly characteristic; heart failure with preserved ejection fraction, low gradient in low-flow aortic stenosis, significantly elevated levels of natriuretic peptide;
• intolerance to angiotensin-converting enzyme inhibitors and beta-blockers in newly diagnosed chronic heart failure;
• bilateral carpal tunnel syndrome;
• kidney involvement;
• vitreous opacity, glaucoma;
• distal biceps tendon rupture (Popeye sign);
• lumbar spinal stenosis.

A gender-related red flag that increases the likelihood of ATTR in progressive sensorimotor polyneuropathy is males [5].

In our clinical case, a male patient with progressive symmetric sensorimotor polyneuropathy exhibited five additional red flag criteria: autonomic neuropathy, gastrointestinal dysfunction, unexplained weight loss, vitreous opacity, and specific cardiovascular involvement. Additionally, EMG-confirmed carpal tunnel syndrome and hereditary predisposition were present. This combination raised suspicion for ATTR, prompting molecular genetic testing that confirmed this rare disease.

In December 2024, the Annals of Clinical and Experimental Neurology journal published the results of the PRIMER study, outlining the main demographic, clinical, and electrophysiological characteristics of patients with ATTRv-polyneuropathy and chronic idiopathic axonal polyneuropathy in the Russian population [26]. A statistical analysis of these characteristics was performed, and a calculator was developed that accounts for factors contributing to the likelihood of ATTRv-polyneuropathy in a patient. Our patient was not included in this study because his ATTR diagnosis was established after the investigators had completed data collection. We decided to compare his features with those identified in the PRIMER study. Among demographic data, our patient shares the following characteristics with ATTRv-polyneuropathy patients identified in the PRIMER study: male sex, age at disease onset of 57 years (late onset), low body mass index of 19.7, and progressive polyneuropathy in close relatives (mother). Among clinical manifestations, our patient shares predominance of sensory disturbances (paresthesias and hypalgesia) at the initial stage and, particularly characteristic and proven in the PRIMER study, pronounced neuropathic pain syndrome in the limbs; imbalance, muscle weakness, gait disturbance; autonomic manifestations including alternating constipation and diarrhea, orthostatic hypotension, unintentional weight loss; cardiac disorders manifesting as heart failure and conduction block; ocular manifestations including vitreous opacity and glaucoma. According to electrophysiological examination in summer 2024, polyneuropathy manifestations were so severe that distal responses during lower limb nerve studies were no longer recordable, while upper limb nerve studies revealed signs of severe conduction impairment.

Thus, the prognostic predictors for hATTR polyneuropathy identified in the PRIMER study were fully confirmed in our patient. This once again demonstrates that screening data (demographic, clinical, and electrophysiological indicators) can predict hATTR-PN presence in patients with axonal polyneuropathy with good accuracy, sensitivity, and specificity, thereby justifying referral for genetic testing [27].

By the time of article preparation, molecular genetic testing results for the entire coding sequence and exon-intron junction regions of the TTR gene (responsible for ATTRv) in the patient’s daughter became available: no pathogenic or likely pathogenic variants were detected.

Conclusion

ATTR is a systemic progressive disease leading to disability and fatal outcome. Criteria have been developed to suspect and detect this disease at the earliest possible stage, enabling preservation and maximal improvement of patient function and quality of life through timely pathogenetic therapy initiation. To achieve this, increasing physician awareness about disease characteristics and early detection methods is essential, requiring heightened vigilance not only among neurologists and cardiologists but also ophthalmologists, nephrologists, and gastroenterologists. ATTR patient management necessitates multidisciplinary team involvement due to systemic clinical manifestations. Comprehensive care includes pathogenetic treatment (available in Russia) and symptom-targeted therapy to improve quality of life.

 

¹ Coelho T., Ericzon B.G., Falk R. et al. A guide to transthyretin amyloidosis. 2018. Amyloidosis Foundation. URL: http://amyloidosis.org/wp-content/uploads/2019/05/2018-ATTR-guide.pdf (accessed on October 27, 2022).

About the authors

Elizaveta A. Guseva

Kirov Regional Clinical Hospital

Author for correspondence.
Email: annaly-nevrologii@neurology.ru
ORCID iD: 0009-0006-2233-2040

neurologist

Russian Federation, Kirov

Natalia A. Suponeva

Russian Center of Neurology and Neurosciences

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0000-0003-3956-6362

Dr. Sci. (Med.), Corr. member of RAS, Director, Institute of Neurorehabilitation

Russian Federation, Moscow

Marianna V. Mukhacheva

Kirov Regional Clinical Hospital

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0009-0009-8303-9130

Cand. Sci. (Med.), Head, Department of neurology

Russian Federation, Kirov

References

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