Transthyretin familial amyloid polyneuropathy: clinical guidelines

List of Abbreviations

Terms and Definitions

Amyloidosis — a disorder of protein metabolism accompanied by the formation of a specific protein-polysaccharide complex (amyloid) of fibrillar structure in tissues, characterized by high ordering of fibrils 5–10 nm thick due to the abundance of β-pleated conformation in the secondary structure of the main amyloidogenic protein. Amyloidosis is subdivided into local (the source of amyloid production is located in the affected tissue itself) and systemic (amyloid formation in tissues is due to the delivery of the amyloid precursor protein via the bloodstream); primary (idiopathic and associated with multiple myeloma and other B-cell lymphoproliferative malignancies), secondary (developing against the background of an underlying disease, most often inflammatory), and hereditary (caused by a mutation in the gene encoding the corresponding protein).

Transthyretin — a tetrameric protein consisting of 4 identical subunits, each comprising 127 amino acid residues and containing a beta-structure, which functions as a transport protein for thyroxine and retinol.

Hereditary transthyretin amyloid polyneuropathy — the most common form of familial amyloidosis, a multisystem disorder associated with pathogenic variants of the transthyretin gene, characterized by a varying combination of symptom complexes affecting peripheral nerves, the central nervous system, the gastrointestinal tract, the heart, kidneys, and eyes.

Carpal tunnel syndrome — a compression-ischemic neuropathy in which the median nerve undergoes local compression at the wrist level within the carpal tunnel formed by the carpal bones and the flexor retinaculum. Carpal tunnel syndrome is a characteristic clinical manifestation of ATTR-PN, frequently developing bilaterally or accompanying polyneuropathy.

Amyloid cardiomyopathy — a form of systemic protein metabolism disorder with predominant deposition of beta-fibrillar protein (amyloid) in cardiac tissues (myocardium, endocardium, pericardium), the aorta, and coronary vessel walls.

Tafamidis — a drug used to treat ATTR-PN, which is a selective transthyretin stabilizer. Tafamidis binds with negative cooperativity to the two thyroxine-binding sites of TTR in its native (tetrameric) form, which prevents the dissociation of the complex into monomers and slows down amyloidogenesis.

Eplontersen — a drug from the class of TTR synthesis blockers (silencers) used for the treatment of adult patients with hereditary transthyretin-mediated amyloidosis-associated polyneuropathy (ATTR-PN). Eplontersen selectively binds to the transthyretin mRNA segment, leading to the degradation of both wild-type and mutant TTR fragments and a decrease in serum TTR concentration.

Liver transplantation — a treatment method for ATTR-PN in which a donor liver is transplanted in place of the recipient's removed liver. The efficacy of the method lies in replacing liver cells with a pathological genotype, which eliminates the main source of synthesis of the altered unstable protein from the pathological process.

OMIM — Online Mendelian Inheritance in Man, an online database of human genes and genetic phenotypes containing information on known inherited disorders and the genes responsible for them.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hereditary transthyretin amyloid polyneuropathy (ATTR-PN) — a progressive systemic hereditary disease based on the extracellular deposition of fibrillar protein (amyloid) predominantly in peripheral nerve fibers, as well as in cells of the heart, gastrointestinal tract, kidneys, and eyes, leading to varying degrees of functional impairment [1-5].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The development of ATTR-PN is caused by heterozygous pathogenic variants in the TTR gene (18q12.1), which encodes the structure of the transthyretin (TTR) protein synthesized predominantly by liver cells and, to a much lesser extent (< 5%), by the choroid plexus of the brain and the retinal pigment epithelium from the prealbumin fraction. To date, more than 130 pathogenic variants in the TTR gene resulting in a neurogenic phenotype have been described [1-5]. The TTR gene is localized on the long arm of chromosome 18; the presence of a pathogenic variant in a single copy of the gene (heterozygous state) is sufficient for the development of ATTR-PN. The disease is inherited in an autosomal dominant manner, and the risk of transmitting the disease to any of the patient's children is 50%. Males and females are affected with equal frequency [4, 6].

TTR is a tetrameric protein consisting of 4 identical subunits, each comprising 127 amino acid residues and containing a beta-structure. TTR functions as a transport protein for thyroxine and retinol [7]. Pathogenic variants lead to conformational changes in the protein, thermodynamic instability of the tetramer, and its dissociation into oligomers and monomers. Protein precipitation and subsequent polymerization result in the formation of amyloid fibrils, which exert a direct damaging effect on tissue structures via compression and also lead to vessel obliteration and, consequently, ischemia. On the other hand, studies show that it is not amyloid fibrils, but rather low-molecular-weight TTR oligomers that trigger the activation of voltage-gated calcium channels, leading to cell death. The specific distribution of amyloid in organs and tissues is associated with the type of amyloidogenic pathogenic variant [4, 8]. In ATTR-PN, amyloid deposits are predominantly deposited in the epineurium, perineurium, and endoneurium of various types of nerve fibers, leading to progressive axonal degeneration of large and small fibers of peripheral nerves. Amyloid deposition in ATTR-PN is also observed in cells of other target organs (heart, kidneys, eyes, central nervous system), which determines the phenotypic heterogeneity of the disease [4, 9-12].

ATTR-PN is characterized by a wide spectrum of causative variants [2, 4, 8, 9]. The most common is the substitution of methionine for valine at position 30 (Val30Met), found in approximately 50% of patients and identified in regions endemic for this disease in Portugal, Cyprus, and Mallorca. In non-endemic countries such as France, Italy, Germany, and Japan, a broader spectrum of causative variants is noted [13].

In certain genetic variants, cardiomyopathy predominates in the clinical picture of the disease (e.g., Val122Ile, Ile68Leu, Thr60Ala, Leu111Met), while others are primarily associated with PNP (e.g., Val30Met), but both manifestations of the disease can be observed in various ratios [4, 8, 9]. The clinical picture may change over time as amyloid continues to accumulate in other tissues; symptom variability within the same family may be observed. Disease penetrance varies across different regions and families. If penetrance is less than 100%, carriers of pathogenic variants in the TTR gene may live to old age without signs of the disease, yet their children may develop manifestations of the disease [9]. The phenomenon of anticipation (more severe disease course and earlier onset in successive generations) is observed in endemic regions.

In Russia, according to the DNA Diagnostics Laboratory of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, based on molecular genetic analysis results of 35 unrelated probands with ATTR-PNP from various regions of the Russian Federation, it was established that in 54.3% of cases the cause of the disease was the frequent pathogenic variant Val30Met (similar to most European countries); in 4 cases the Ile107Val variant was detected (11.4%); the Phe33Leu (5.7%) and Ala81Val (5.7%) variants were encountered twice. The variants Ser23Asn, Ala25Thr, Val32Ala, Thr40Asn, Gly47Ala, Glu54Gln, Tyr69Phe, and Glu92Lys were identified once each, accounting for 2.8% of cases each [4, 11].

1.3 Epidemiology of the Disease or Condition

The total frequency of all types of amyloidosis is estimated at 47/100,000. The incidence of hereditary forms of amyloidosis is estimated at approximately 1 per 1,000,000 per year, with the figure being significantly higher in endemic regions. The estimated worldwide prevalence of ATTR-PNP is 10,000 (1/1,000,000 individuals), and in Europe—at least 1 per 100,000 population [13].

The first cases of ATTR-PNP were described in 1952 by the Portuguese neurologist C. Andrade in Northern Portugal. In Sweden, the first case of the disease was described in 1965. By 1994, 1,233 cases had been diagnosed at the Amyloidosis Study Center in Porto (Portugal) [14, 15]. For a long time, ATTR-PNP was considered an endemic disease with high prevalence in Portugal and Sweden; however, progress in molecular genetic diagnostics and the accumulation of knowledge regarding ATTR-PNP have led to the disease currently being diagnosed worldwide [13].

Over the period 2010–2016, the average incidence rate of ATTR-PNP in Portugal was 0.87/100,000 (95% CI 0.68–1.10). The proportion of late-onset cases (age ≥ 50 years) among those affected was 28.7%. The estimated total prevalence in 2016 was 22.93 per 100,000 adult residents (95% CI 21.90–23.99) [14].

The prevalence of ATTR-PNP in Japan is estimated at 0.87–1.1 per 1,000,000 individuals. The highest prevalence was in Nagano Prefecture (11–15.5), followed by Kumamoto (10.1–10.3), and then Ishikawa (3.5–4.2) [16, 17]. In Spain (Balearic Islands), 144 cases of ATTR-PNP were diagnosed between 1976 and 2003 [18]. As of December 1, 2003, the prevalence of the disease in Cyprus was 3.72/100,000, and the incidence was estimated at 0.69/100,000 per year [19]. No epidemiological studies on the prevalence of ATTR-PNP have been conducted in the Russian Federation.

In endemic regions (Portugal, Sweden, Cyprus, Mallorca, Japan), the pathogenic variant Val30Met in the TTR gene is predominant with high penetrance. In other regions, cases of the disease are mostly sporadic, genetically heterogeneous, with relatively low penetrance (11% starting from 50 years of age) [4, 9, 11, 13].

1.4 Features of Coding the Disease or Condition

ICD-10: E85.1 – Neuropathic heredofamilial amyloidosis

1.5 Classification of the disease or condition

The modern classification of amyloidosis (WHO, 2003) is based on the principle of specificity of the major amyloid fibril protein (Table 1).

Table 1. Classification of amyloidosis [5, 11].

At least 10 hereditary forms of amyloidosis are distinguished (Table 2).

Table 2. Hereditary forms of amyloidosis [5, 11].

^{*The names of genetic variants of hereditary forms of amyloidosis and the protein products of the corresponding genes are given according to the OMIM database. **The most frequent genetic variant of hereditary amyloidosis is transthyretin. Note. AD – autosomal dominant.}

1.6 Clinical presentation of the disease or condition

ATTR-PN is characterized by multisystem clinical manifestations and phenotypic heterogeneity. To explain the observed phenotypic heterogeneity in carriers of the most frequent Val30Met variant, various hypotheses have been put forward: the influence of modifier genes, parental origin of variants, gender effect, contribution of non-coding regulatory variants, monoallelic gene expression, and external factors [2, 4, 5, 8, 11, 12]. However, the exact cause of this phenomenon has not yet been established.

ATTR-PN is characterized by a variable age of onset (ranging from 20 to 70 years) and incomplete penetrance. The age of disease onset varies widely even in ethnically identical populations with the same pathogenic variant in the TTR gene [2, 4, 8].

The main clinical manifestation of ATTR-PN is distal ascending progressive symmetric sensorimotor polyneuropathy, which affects both thick and thin nerve fibers to varying degrees.

Clinical symptoms of thin nerve fiber involvement include [2-5, 10-12, 20]:

• neuropathic pain syndrome; paresthesias and burning in the distal extremities;

• orthostatic hypotension, fixed tachycardia;

• gastrointestinal disorders: constipation alternating with diarrhea, episodes of nausea and vomiting, delayed gastric emptying, gastrointestinal motility disorders;

• pelvic disorders (urinary retention or incontinence, neurogenic bladder);

• erectile dysfunction, impotence;

• sweating disorders, anhidrosis.

  Clinically, manifestations of thick nerve fiber involvement include [2-5, 10-12, 20]:

• distal symmetric tetraparesis, more pronounced in the lower extremities;

• hypotrophy and hypotonia of the limb muscles, areflexia;

• impaired superficial pain and deep sensation of a polyneuritic type, sensory ataxia.

Amyloid deposition in the ligamentous apparatus causes the development of clinical features of carpal tunnel syndrome, tendon rupture, and spinal canal stenosis. In some cases, these disorders may be the first manifestation of ATTR-PN and are particularly pronounced in patients with such TTR gene variants as p.Leu78His, p.Leu78Arg, p.Lys90Asn, p.Ile104Ser, p.Ile127Val, and p.Tyr134His [4, 8, 10, 21].

ATTR-PN at any stage of the disease is characterized by varying degrees of involvement of other organs and systems:

1) the heart (restrictive and/or hypertrophic cardiomyopathy phenotype, left ventricular wall thickening, various types of cardiac conduction disorders, heart failure, aortic stenosis) [2, 4, 5, 10, 22];

2) the gastrointestinal tract (nausea and vomiting, early satiety, alternating postprandial diarrhea and constipation, irritable bowel syndrome, unintentional weight loss) [2, 4, 5, 10, 23];

3) the kidneys (proteinuria, nephropathy, renal failure) [2, 4, 5, 10];

4) the eyes (vitreous opacities, glaucoma, pupillary abnormalities, keratoconjunctivitis, corneal ulcers) [2, 4, 5, 10, 24-26];

5) the CNS (cognitive impairment, headache, ischemic or hemorrhagic stroke, epileptic seizures, hydrocephalus, ataxia) [2, 4, 5, 10].

There are 4 stages of ATTR-PN [1-5]:

0 − asymptomatic (subclinical);

I − lower flaccid paraparesis with minimal walking impairment, no additional support required;

II − flaccid tetraparesis, more pronounced in the lower extremities, the patient requires a cane or crutch for walking;

III − severe neurological deficit, the patient is unable to move independently, bedridden or wheelchair-bound.

PNP in ATTR-PN can progress over 10–20 years. In the late stage of the disease, cachexia develops. Causes of patient death include heart or renal failure, as well as infectious complications [1-5].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis and condition: the presence of clinical manifestations of polyneuropathy with signs of autonomic dysfunction/small fiber neuropathy/polyneuropathy and carpal tunnel syndrome, or a burdened family history of ATTR-PN combined with the identification of a pathogenic (likely pathogenic) variant in the TTR gene, serves as the basis for confirming the diagnosis.

2.1 Complaints and Anamnesis

Comment: patients complain of unintentional weight loss, weakness of the arm and predominantly leg muscles, gait changes; numbness, decreased sensation in the hands and feet, and instability when walking. Complaints of neuropathic pain, concomitant cardiovascular and gastrointestinal dysfunction are typical. When taking the history, attention should be paid to the rate of symptom progression, the presence of concomitant somatic diseases, and the toxicological and oncological history should be assessed. The disease most frequently debuts at the age of 30 years and older.

Comment: concomitant polyneuritic complaints, as well as complaints of cardiovascular and gastrointestinal dysfunction, may be present. Since carpal tunnel syndrome is a common condition in the population, it is advisable to suspect ATTR-PN in a patient with progressive, frequently bilateral carpal tunnel syndrome that is refractory to standard treatment regimens prescribed according to the severity of the lesion.

Comment: when taking the history, it should be clarified whether close relatives have progressive polyneuropathy, heart disease, or deaths under the age of 50 from cardiovascular failure.

2.2 Physical Examination

Comment: it is necessary to assess body mass index, pay attention to the condition of the skin and its appendages, and the presence of edema and osteoarticular deformities. Neurological status is assessed using standard methods. It is important to analyze autonomic nervous system functions. Analysis of autonomic nervous system function during the examination consists of determining the degree of sweating, measuring heart rate (HR), and performing hyperventilation and orthostatic tests [29].

2.3 Laboratory Diagnostics

Comment: the optimal molecular genetic analysis method for the TTR gene is direct Sanger sequencing of all coding regions and exon-intron junction areas of the gene. It is also possible to determine gene variants in a biological material sample, other or unspecified, unclassified in other categories, by Sanger sequencing, targeted high-throughput sequencing, whole-exome high-throughput sequencing, or high-throughput sequencing. The presence of a pathogenic variant in a single gene copy (heterozygous state) is sufficient for the development of ATTR-PN. The diagnosis is confirmed upon detection of a pathogenic or likely pathogenic variant in the TTR gene. To determine the tactics and scope of molecular genetic diagnostics and to interpret the results obtained, an initial and follow-up appointment (examination, consultation) with a geneticist is mandatory.

Comments: the differential diagnosis is presented in Appendix G1. Based on clinical and anamnestic indications, the list of additional laboratory diagnostic tests may be expanded. The tests are performed during diagnosis and subsequently monitored dynamically at least once every 6 months or more frequently if clinically indicated.

Comments: ATTR-PN can clinically mimic diabetic and other metabolically induced polyneuropathies. In clinical studies and diagnostic algorithms for ATTR-PN, diabetes mellitus and vitamin B12 deficiency are routinely ruled out, which justifies performing these laboratory tests in patients with suspected ATTR-PN [4, 84-90].

Comment: as renal impairment progresses, there may be an increase in blood levels of triglycerides, total cholesterol, and uric acid.

Comment: microalbuminuria is an early sign of renal involvement in ATTR-PN, representing stage 1 of amyloid nephropathy. In 32–36% of cases, microalbuminuria precedes the development of polyneuropathy in asymptomatic carriers of pathogenic mutations, whereas in patients with manifested polyneuropathy, microalbuminuria occurs in 78% of cases. As the disease progresses, proteinuria is detected in the routine urinalysis. Features of renal amyloidosis include the rare occurrence of hematuria and leukocyturia [30]. The tests are performed during diagnosis and subsequently monitored dynamically at least once every 6 months or more frequently if clinically indicated.

Comment: if monoclonal secretion and immunoglobulin light chains are detected, the patient requires an initial consultation (examination) with a hematologist.

Comment: dynamic monitoring of blood creatinine levels and microalbuminuria is an important prognostic factor for assessing the progression of amyloid nephropathy and ATTR-PN overall. Dynamic monitoring of blood cardiac troponins I and T and natriuretic peptide (NT-proBNP) concentrations serves as a laboratory marker for assessing the progression of amyloid cardiomyopathy in ATTR-PN. The tests are performed at initial diagnosis and subsequently monitored dynamically at least once every 6 months or more frequently if clinically indicated.

2.4 Instrumental Diagnostics

Comments: the study is performed at least for the following peripheral nerves: median nerve, ulnar nerve, tibial nerve, peroneal nerve, and sural nerve. Stimulation electromyography of both motor and sensory nerve fibers is mandatory; ENMG signs of carpal tunnel syndrome, typically bilateral, are frequently detected in ATTR-PN patients. ENMG results of peripheral nerves in most cases indicate an axonal type of lesion, characterized by low amplitudes of motor and sensory responses with normal latencies and conduction velocities. During ENMG, skin temperature must be maintained at least at 33 °C over the palm and at least at 30 °C over the lateral malleolus. It should be noted that ENMG does not assess the function of small nerve fibers. To evaluate autonomic nerve fiber function, heart rate variability and/or D. Ewing's comprehensive autonomic cardiovascular tests (hyperventilation test, orthostatic test, Valsalva maneuver, deep controlled breathing test, isometric stress test), autonomic evoked potentials (A05.24.002 recording of somatosensory evoked potentials of motor nerves), quantitative sensory testing (A01.24.004 examination of the sensory and motor spheres in peripheral nervous system pathology), tilt-table test, and corneal confocal microscopy are performed.

Comments: amyloid cardiomyopathy is characterized by the following changes:

- on ECG — mismatch between voltage (low voltage) and myocardial mass (hypertrophy); pseudoinfarct patterns; cardiac arrhythmias (atrial fibrillation is the most frequent manifestation); conduction disturbances;

- on echocardiography — marked unexplained biventricular wall thickening, left ventricular wall thickness > 12 mm (in the absence of a history of hypertension, hypertrophic cardiomyopathy, "athlete's heart", and other conditions); moderate pericardial effusion; biventricular hypertrophy and thickening of heart valves; apical sparing phenomenon (preserved longitudinal strain at the apex with a simultaneous significant reduction of this parameter in the basal segments); left atrial dilation; low gradient in low-flow aortic stenosis; left ventricular myocardial contractility can be either preserved or reduced.

Comments: osteotropic radiopharmaceuticals (technetium [99mTc] compounds group [ATC: V09BA]) are used to detect amyloid myocardial involvement in patients with heart failure with reduced ejection fraction [91-93, 99-102]. This is the gold standard for the non-invasive diagnosis of ATTR cardiomyopathy. Nuclear scintigraphy using technetium [99mTc] compounds [ATC: V09BA] demonstrates a characteristic myocardial uptake pattern in the presence of amyloid [4, 34-38, 73-79].

Comments: there are no specific criteria for amyloidosis-induced enteropathy: standard gastrointestinal examinations (abdominal X-ray/computed tomography, colonoscopy/esophagogastroduodenoscopy) reveal no pathognomonic changes. Therefore, a morphological examination is required (additional information below).

Comment: these studies are performed during initial diagnosis and subsequently during follow-up at least once every 6 months. Dynamic monitoring of cardiac function is an important prognostic factor for assessing the progression of amyloid cardiomyopathy in ATTR-PN. The appearance of signs of amyloid cardiomyopathy in ATTR-PN patients without previously identified cardiac changes provides grounds for revising the dose of tafamidis for specific therapy.

Comment: biopsy of the affected organ is the most informative. However, given the systemic nature of this disease, it is rational to use accessible tissues to detect amyloid deposits morphologically, such as the skin and subcutaneous adipose tissue of the anterior abdominal wall, the mucosa and submucosa of the duodenum and rectum, and the salivary glands. To detect amyloid during morphological examination, tissue specimens must be stained with Congo red followed by polarization microscopy. The definitive diagnosis is established upon detection of congophilic masses exhibiting apple-green or yellowish birefringence under polarized light. For the differential diagnosis of AA amyloidosis from AL and TTR amyloidosis, the most informative method is amyloid typing by immunohistochemical examination. Since some antisera may cross-react with different amyloid types, it is advisable to perform the study with a panel of antisera. For non-specialized inpatient facilities, it is advisable to use a panel of antisera against SAA, various types of immunoglobulin heavy chains, immunoglobulin light chains λ and κ, transthyretin, and fibrinogen.

2.5 Other Procedures

Comment: an appointment (examination, consultation) with a medical geneticist at the diagnostic stage is necessary to determine the tactics of DNA diagnostics and subsequent correct interpretation of molecular genetic test results, as well as to determine genetic risks within the family.

Comments: special attention should be paid to the timely detection of amyloid cardiomyopathy.

Comments: ATTR nephropathy is characterized by gradual progression starting from microalbuminuria and proteinuria, followed by impaired concentration function, elevated creatinine levels, and the development of end-stage renal disease. Timely detection of nephropathy is also important to ensure optimal pharmacotherapy adjustment taking into account renal excretory function [4]. If the disease is confirmed and symptoms are present, an appointment (examination, consultation) with a nephrologist is required at least once every 6 months [30].

Comments: differential diagnosis is specified in Appendix A3.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Disease-Modifying Pharmacotherapy

Pathogenetic therapy has been developed for ATTR-PN. Currently, three methods are available in the Russian Federation [1-5]:

• lifelong oral administration of Tafamidis;

• lifelong administration of Eplontersen as independent subcutaneous injections using an auto-injector pen;

• liver transplantation.

Comment: all patients with a confirmed diagnosis of ATTR-PN need to undergo an assessment of the severity of neuropathic impairments with follow-up evaluations every 6 months in order to adjust ongoing therapy [96]. An increase in the evaluation score by 7–16 points indicates deterioration of the patient's condition and the need to revise the current therapy [96].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: tafamidis is a pathogenetic drug for the treatment of ATTR-PN. Tafamidis slows disease progression by selectively binding to the thyroxine-binding site of the TTR protein and stabilizing the TTR tetramer of both wild and mutant types. Preparation for therapy and additional examinations before starting treatment are not required.

The presence of cardiomyopathy in a patient with ATTR-PN requires the prescription of Tafamidis at a dose of precisely 61 mg, given that the 20 mg dose has no significant effect on cardiac symptoms. At the same time, cardiac pathology is the main factor limiting the life expectancy of patients with ATTR-PN and wild-type transthyretin amyloidosis.

Comment: according to the clinical guidelines of the International Society of Amyloidosis, patients with ATTR-PN at stages 1 and 2 of the disease are prescribed silencers (ATX N07XX Other drugs for disorders of the nervous system) in accordance with the decision of the attending physician and local regulatory documents [73]. Eplontersen is a silencer class drug approved in the Russian Federation for the treatment of adult patients with ATTR-PN [76]. Eplontersen acts by blocking transthyretin synthesis at the RNA level, preventing the formation of both variant and wild-type amyloid.

Eplontersen is used in patients with various gene variants and at different stages of the disease, including patients previously treated with stabilizers. The drug provides a pronounced and sustained reduction in serum transthyretin concentration by ~80%. Therapy with eplontersen is associated with slowed progression of transthyretin amyloid polyneuropathy based on comprehensive neurological parameters, as well as improved quality of life scores. Patients show a significant slowing of polyneuropathy progression according to the composite mNIS+7 score and a significant improvement in quality of life according to the Norfolk QoL-DN scale. Eplontersen is also used in patients with a mixed disease phenotype (polyneuropathy and cardiomyopathy) at the same dose as in patients with transthyretin polyneuropathy. Data on the efficacy of a similar dose in patients with transthyretin amyloid cardiomyopathy regarding the reduction of cardiovascular event risk continue to accumulate.

3.2 Surgical Disease-Modifying Treatment

Comment: the efficacy of the method consists in replacing liver cells with a pathological genotype, i.e., eliminating the main source of synthesis of the altered unstable protein. It has been shown that overall 5-year survival is approximately 100% for patients with the Val30Met variant and 59% for patients with other genetic alterations. The main causes of postoperative mortality are cardiovascular events (29%) and septicemia (26%). However, liver transplantation does not prevent the progression of cardiac disorders (some patients with non-Val30Met variants and cardiomyopathy may be indicated for combined liver and heart transplantation). Eye and CNS involvement also frequently progresses and/or develops after liver transplantation due to the ongoing local synthesis of pathological TTR in the retinal epithelium and the choroid plexus of the brain. According to the International Transplant Registry (n = 2044), the 20-year survival rate of patients with ATTR-PN was 55.3%. Liver transplantation is effective, but has a wide range of limitations and varying survival rates across different genetic variants. The best results are achieved when the procedure is performed in young patients whose disease has not reached stage 3.

3.3 Symptomatic Therapy and Pain Management

Comments: when prescribing drugs, the risk of falls should be taken into account in patients with ATTR-PN who have orthostatic hypotension [66, 83].

Comments: these drugs are prescribed in accordance with EFNS recommendations as first-line therapy (monotherapy or combination). When prescribing drugs, the risk of falls should be taken into account in patients with ATTR-PN who have orthostatic hypotension [66, 83].

Comments: when prescribing drugs, the risk of falls should be taken into account in patients with ATTR-PN who have orthostatic hypotension [66, 83].

Comment: the efficacy of the drug in studies was evaluated using subjective scales (chronic pain diagnostic questionnaire, Hospital Anxiety and Depression Scale [HADS], with a follow-up period of 2 months).

Comments: symptomatic therapy is selected depending on the leading clinical manifestations and may be aimed at correcting gastrointestinal disorders, orthostatic hypotension and other manifestations of autonomic dysfunction, heart failure, as well as cardiac rhythm and conduction disorders. In patients with amyloid cardiomyopathy, the management of cardiovascular disorders requires an individualized approach due to the risk of orthostatic hypotension and limited tolerance to a number of standard heart failure therapy regimens. In the presence of signs of congestive heart failure, the priority is to control fluid retention and volume overload. The issue of surgical treatment of cardiac arrhythmias is decided individually, according to general cardiological indications, taking into account the clinical condition and in accordance with relevant clinical guidelines. Patients with amyloidosis are contraindicated for drugs of groups C01A (cardiac glycosides) and C08 (selective calcium channel blockers with direct cardiac effects [C08DA01 verapamil**, C08DB01 diltiazem]), which can accumulate in amyloid. Implantation of a single-chamber***/dual-chamber*** cardioverter-defibrillator prevents symptomatic bradycardia with a high degree of atrioventricular block development. Treatment of heart failure and cardiac arrhythmias is carried out according to the relevant clinical guidelines. Vitrectomy may be required for vitreous opacities in patients with ATTR amyloidosis. In the presence of uncontrolled glaucoma, trabeculectomy (sinustrabeculectomy) or vitrectomy is performed to treat the ophthalmological form of amyloidosis.

3.4 Non-pharmacological therapy

Comments: prevention of pressure ulcers, hypostatic pneumonia, contractures, secondary infectious complications, deep vein thrombosis, and pulmonary embolism is necessary.

3.5 Diet therapy

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Sanatorium-resort treatment methods for ATTR-PN have not been developed. The use of natural medicinal resources is not indicated for ATTR-PN [68]. If a sanatorium-resort organization has a license for medical rehabilitation, it is advisable to provide a range of medical rehabilitation services for patients with nervous system diseases and ATTR-PN to increase the rate of recovery and prevent complications of hypodynamia [69]. A comprehensive approach is required, combining therapeutic exercise for peripheral nervous system diseases, adaptation of the environment in accordance with the patient's functional deficits (macro-environment adaptation procedures), the use of assistive devices and technical aids (ankle-foot orthoses, additional support (cane), etc.), and psychological support. Patients may need an initial and follow-up examination (consultation) by a physical therapy doctor, an initial and follow-up consultation by a physical and rehabilitation medicine doctor, an initial and follow-up examination (consultation) by a physical therapy specialist, an initial and follow-up therapeutic and diagnostic consultation by a physical and rehabilitation medicine doctor, and an initial and follow-up examination (testing, consultation) by a medical psychologist.

5. Prevention and Dispensary Observation

Methods for the specific prevention of ATTR-PN development have not been developed [1-5].

A multidisciplinary approach is required for patient monitoring, as these diseases are characterized by multi-organ and multisystem involvement, which in turn necessitates the co-management of the patient by specialists in various fields. To ensure comprehensive monitoring, therapy, and its timely adjustment, initial and follow-up (as needed) examinations (consultations) and/or follow-up check-ups by a neurologist, ophthalmologist, cardiologist, nephrologist, gastroenterologist, general practitioner/family physician, and geneticist are indicated for patients with a confirmed diagnosis of ATTR-PN who have functional impairments of the corresponding organs and systems.

Comment: It is advisable to discuss cascade family screening and examination of the patient's close relatives for early disease detection and subsequent monitoring. Patients with a confirmed diagnosis of ATTR-PN require medical genetic counseling to discuss genetic risks, options for family screening for a previously identified causative genetic variant, and prenatal diagnosis possibilities. As with other autosomal dominant diseases, the risk of transmitting the disease to the proband's offspring is 50%, which falls into the high genetic risk category. The risk for siblings (proband's brothers and sisters) is also 50% if the parents have the disease. If the proband's parents are clinically healthy and confirmed to lack the pathogenic variant in the TTR gene, the risk for the proband's siblings is low, but higher than the population risk due to the inability to rule out gonadal mosaicism in the parents. Prenatal diagnosis of adult-onset diseases that respond to sufficiently effective therapy is possible, but may be ethically questionable. The decision to perform it should be made after a detailed discussion of all risks with the family.

6. Organization of Medical Care

Indications for hospitalization of an ATTR-PN patient in a medical organization:

1) Emergency hospitalization (round-the-clock inpatient facility) is indicated for all patients with a confirmed diagnosis of ATTR-PN presenting with acute cardiac dysfunction, as well as progressive dysmetabolic disorders associated with chronic diarrhea;

2) Planned hospitalization (round-the-clock multidisciplinary inpatient facility) is indicated for all patients with progressive polyneuropathy and suspected ATTR-PN for comprehensive evaluation and differential diagnosis, and for patients with a confirmed diagnosis of ATTR-PN to undergo rehabilitation and symptomatic therapy.

Indications for discharging a patient from a medical organization:

1) Discharge of a patient from a medical organization after emergency hospitalization is possible upon full completion of all necessary diagnostic, therapeutic, and rehabilitation measures, provided the patient's condition is stable and satisfactory, with preserved vital functions.

2) Discharge of a patient from a medical organization after planned hospitalization is possible upon full completion of planned therapy and rehabilitation measures; provided the patient's condition is stable and satisfactory, with preserved vital functions.

7. Additional Information

Early diagnosis and initiation of disease-modifying therapy slow down disease progression. Severe neurological deficits at the time of diagnosis verification, concomitant somatic disorders, and advanced age are unfavorable prognostic factors [1-5, 38, 46, 47].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Piradov, Mikhail Aleksandrovich — D.Sc. in Medicine, Academician of the RAS, Director of the Research Center of Neurology (Moscow);

2. Kutsev, Sergey Ivanovich — D.Sc. in Medicine, Academician of the RAS, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov;

3. Nikitin, Sergey Sergeevich — D.Sc. in Medicine, Professor, Head of the Department of Genetics of Neurological Diseases at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Chairman of the NGO "Society of Neuromuscular Disease Specialists" (Moscow);

4. Suponeva, Natalia Aleksandrovna — D.Sc. in Medicine, Corresponding Member of the RAS, Director of the Institute of Rehabilitation and Neurotechnologies at the Research Center of Neurology, Scientific Consultant of the Peripheral Nervous System Disorders Center at the Research Center of Neurology, Scientific Secretary of the NGO "Society of Neuromuscular Disease Specialists" (Moscow);

5. Grishina, Daria Aleksandrovna — Ph.D. in Medicine, Senior Researcher at the Laboratory of Clinical Neurophysiology, Head of the Peripheral Nervous System Disorders Center at the Research Center of Neurology (Moscow);

6. Zinov'eva, Olga Evgenyevna — D.Sc. in Medicine, Professor at the Department of Nervous System Diseases and Neurosurgery, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University) (Moscow);

7. Rameev, Vilen Vilevich — D.Sc. in Medicine, Professor at the Department of Internal, Occupational Diseases and Pulmonology, I.M. Sechenov First Moscow State Medical University, Leading Researcher at the Nephrology Scientific and Educational Clinical Center, I.M. Sechenov First Moscow State Medical University;

8. Lysenko (Kozlovskaya), Lidia Vladimirovna — D.Sc. in Medicine, Professor at the Department of Therapy, Occupational Diseases and Pulmonology, I.M. Sechenov First Moscow State Medical University;

9. Moiseev, Sergey Valentinovich — D.Sc. in Medicine, Professor, Head of the Department of Internal, Occupational Diseases and Rheumatology, Director of the Tareev Clinic;

10. Tereshchenko, Sergey Nikolaevich — D.Sc. in Medicine, Professor, Head of the Department of Myocardial Diseases and Heart Failure, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Russian Ministry of Health;

11. Rachin, Andrey Petrovich — D.Sc. in Medicine, Neurologist, Professor, Deputy Director for Research, Head of the Department of Neurorehabilitation and Clinical Psychology, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation (Moscow);

12. Zhirov, Igor Vitalievich — D.Sc. in Medicine, Leading Researcher at the Department of Myocardial Diseases and Heart Failure, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Russian Ministry of Health, Professor at the Department of Cardiology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health;

13. Nasonova, Svetlana Nikolaevna — Ph.D. in Medicine, Senior Researcher at the Department of Myocardial Diseases and Heart Failure, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Russian Ministry of Health;

14. Anisimova, Inga Vadimovna — Ph.D. in Medicine, Head of the Medical Care Organization Department, Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists;

15. Subbotin, Dmitry Mikhailovich — Geneticist, Researcher at the Neurogenetics Laboratory, Specialist at the Medical Care Organization Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists;

16. Melnik, Evgenia Aleksandrovna — Ph.D. in Medicine, Leading Researcher at the Scientific and Consultative Department, Neurologist, Associate Professor at the Department of Genetics of Neurological Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Conflict of interest: none declared by any members of the working group.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Neurologists;

2. Functional diagnostics physicians;

3. General practitioners;

4. Cardiologists;

5. Gastroenterologists;

6. Nephrologists;

7. Ophthalmologists;

8. General practitioners (family physicians).

Methods used for evidence collection/selection: the working group reviewed all publications on the definition, diagnosis, and treatment of ATTR-PN published between 1980 and 2022. All systematic reviews of randomized controlled trials on the treatment of ATTR-PN were selected, and the levels of evidence (LE) and grades of recommendation (GR) were evaluated. The evaluation of LE and GR was performed in accordance with the scales presented in Tables 1–3 of Appendix A2. Literature searches were conducted in the Medline database, the Cochrane Library, the eLIBRARY.ru scientific electronic database, Google Scholar, and PubMed. To minimize potential errors, each study was evaluated independently.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.  Scale for evaluating levels of evidence (LE) for methods of prevention, treatment, and rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for methods of prevention, diagnosis, treatment, and rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A 3.1 Differential Diagnosis of ATTR-PN with Polyneuropathies of Other Genesis

^{Note: ENMG – electroneuromyography; CIDP – chronic inflammatory demyelinating polyneuropathy; PNP – polyneuropathy; CMT – Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy).}

Appendix B. Physician Action Algorithms

Appendix B1. Physician action algorithm

Appendix B2. Algorithm of physician actions in the presence of a mutation in the TTR gene in a patient or their relative

Appendix C. Patient Information

Definition and Epidemiology

Transthyretin familial amyloid polyneuropathy (ATTR-PN) is a progressive hereditary systemic disease characterized by extracellular deposition of fibrillar protein (amyloid) predominantly in peripheral nerve fibers, as well as in the cells of the heart, gastrointestinal tract, kidneys, and eyes, leading to varying degrees of functional impairment. The estimated worldwide prevalence of ATTR-PN is 10,000 (1/1,000,000 individuals), and in Europe it is at least 1 per 100,000 population [1–5].

Etiology

The development of ATTR-PN is caused by mutations in the TTR gene, which encodes the synthesis of the transthyretin (TTR) protein, synthesized primarily by liver cells and, to a significantly lesser extent (< 5 %), by the choroid plexus of the brain and the retinal pigment epithelium from the prealbumin component fraction. To date, more than 130 pathogenic mutations have been described. ATTR-PN is inherited in an autosomal dominant manner. The risk of inheriting the disease is 50 %. Males and females are affected with equal frequency [1-5].

Clinical presentation

Symptoms are variable, develop slowly over several years, and typically begin in the feet, subsequently spreading in an ascending pattern to the thighs, trunk, and hands. Symptoms of ATTR-PN usually present as relatively symmetrical limb involvement and include:

• weakness in the legs and arms, decreased muscle tone;

• gait disturbance; instability and impaired motor coordination;

• decreased sensitivity, numbness, or tingling in the hands and feet.

Neuropathic pain syndrome and autonomic disorders are characteristic, including: orthostatic hypotension; constipation alternating with diarrhea, bouts of nausea and vomiting, gastrointestinal motility disorders; urinary retention or incontinence, neurogenic bladder, erectile dysfunction, impotence; sweating disorders, anhidrosis.

ATTR-PN may debut with bilateral carpal tunnel syndrome or spinal stenosis [1-5].

Diagnostics

To establish a diagnosis, the physician thoroughly studies the medical history, performs an examination, and prescribes additional diagnostic methods [1-5]:

• blood and urine tests;

• molecular genetic analysis aimed at detecting mutations in the TTR gene;

• ENMG—a highly informative instrumental method for studying peripheral nerve function;

• general somatic examination.

If the diagnosis cannot be established using the aforementioned methods, a morphological examination (biopsy) of accessible tissues (skin and subcutaneous adipose tissue of the anterior abdominal wall, duodenal and rectal mucosa and submucosa, salivary glands) or the affected organ is recommended to verify amyloid deposits.

The definitive diagnosis of "ATTR-PN" is established based on molecular genetic analysis or morphological examination [1-5].

Treatment

Pathogenetic therapy has been developed for ATTR-PN. Currently, three methods are available in the Russian Federation [1-5]:

• lifelong administration of eplontersen as independent subcutaneous injections using an auto-injector pen;

• lifelong oral administration of tafamidis;

• liver transplantation.

When choosing a treatment method, many factors are taken into account: age, duration and severity of the disease, severity of systemic disorders, etc. In some patients, despite timely and adequate treatment, the disease may progress and remain refractory. None of the drugs known to date cures ATTR-PN.

General Recommendations

1. Avoid excessive emotional and physical stress, maintain a proper work-rest balance;

2. Limit alcohol intake and any other neurotoxic medications;

3. Follow the neurologist's prescriptions;

4. Adhere to the principles of continuous rehabilitation.

Timely initiation of treatment, careful monitoring of the patient, and assessment of the therapeutic effect are critically important for the prognosis.

It is important to perform molecular genetic testing of the patient's relatives.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.