Combination of familial transthyretin amyloidosis and hyperlipoproteinemia(a) in a patient with spinal canal stenosis: a case report

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INTRODUCTION

Transthyretin amyloidosis (ATTR amyloidosis) is a multisystem disorder caused by amyloid fibril deposition in various organs, with transthyretin as the precursor protein. In the presence of a gene mutation, transthyretin dissociates from its tetrameric form into monomers, which misfold and aggregate into amyloid fibrils. This condition is inherited in an autosomal dominant manner. It may present clinically as familial amyloid polyneuropathy, cardiomyopathy, or familial leptomeningeal amyloidosis, depending on the specific mutation. The availability of genetic, biochemical, and immunohistochemical diagnostic tests allows for identifying ATTR amyloidosis in patients in various countries. However, its verification often remains delayed and difficult. This is due to the heterogeneity of the clinical presentation, which is indistinguishable from that of polyneuropathy and cardiomyopathy of other etiologies [1–3] and the need for invasive diagnostic procedures, including myocardial biopsy, in certain types of amyloidosis. Improved diagnostic approaches, along with targeted therapy, may slow disease progression and improve patients’ quality of life.

Lipoprotein(a) (Lp(a)) is a subclass of human plasma lipoproteins. It resembles low-density lipoprotein (LDL) in structure and lipid composition. Similar to LDL, Lp(a) contains apolipoprotein B, but unlike LDL, it is covalently bound to apolipoprotein(a) via a disulfide bridge. Measurements of Lp(a) concentration require a separate laboratory test. Notably, Lp(a) is classified as an atherogenic lipoprotein; therefore, increased plasma Lp(a) levels are considered a significant risk factor for cardiovascular and cerebrovascular diseases, particularly myocardial infarction, ischemic stroke, aortic stenosis, and heart failure [4].

Westermark [5] believed that apolipoproteins, including apolipoprotein E, are key components of amyloid fibrils in tissues across all amyloid types. However, data on the association between ATTR amyloidosis and Lp(a) and its potential clinical significance remain limited.

This study presents a clinical case of a female patient with familial ATTR amyloidosis and hyperlipoproteinemia(a).

CASE DESCRIPTION

Anamnesis Morbi

A 50-year-old female had a 5-year history of hypertension, with increased blood pressure (BP) up to 150/90 mmHg. Her medical history indicated no acute myocardial infarction, cerebrovascular accident, obesity (height, 170 cm; body weight, 75 kg; stable over the past 5 years), and diabetes mellitus. She denied any harmful habits such as smoking and alcohol abuse. The patient had been under neurologic follow-up for essential tremor and gynecologic follow-up for fibrocystic breast disease, right breast fibroadenoma, perimenopausal ovarian dysfunction, internal endometriosis, and atrophic vulvovaginitis.

Following a COVID-19 infection between June 2, 2021, and June 25, 2021, the patient began experiencing increased BP up to 290/150 mmHg; stabbing left-sided chest pain lasting for 20–30 min unrelated to physical activity, which was relieved by Corvalol® (peppermint leaf oil + phenobarbital + ethylbromisovalerianate; Pharmstandard-Leksredstva JSC, Russia); and pain in the cervical and thoracic spine. In October 2021, the patient consulted a cardiologist.

Electrocardiography (ECG) findings were as follows:

• Sinus rhythm
• Heart rate (HR): 64 bpm
• Normal electrical axis
• Normal QRS voltage: >5 mm in limb leads and >10 mm in precordial leads
• Nonspecific repolarization changes in the inferior wall and lateral and apical regions of the left ventricle (Fig. 1).

Fig. 1. Twelve-lead electrocardiogram of a patient with familial transthyretin amyloidosis and hyperlipoproteinemia(a).

 

Holter (24hour) rhythm monitoring revealed a predominant sinus rhythm with a mean HR of 78 bpm during the day, 73 bpm at night, and 82 bpm during the entire monitoring period. The maximum HR was 117 bpm, and the minimum was 63 bpm. Four ventricular premature beats and one supraventricular couplet were recorded. No pauses nor diagnostically significant ST-segment deviations were observed during the monitoring period.

The results of the patient’s complete blood count and biochemical blood tests are summarized in Table 1.

 

Table 1. Results of complete blood count and blood chemistry

Parameters	Result	Reference range
Complete blood count
Hemoglobin, g/L	136	117–1601
Hematocrit	0.38	0.35–0.471
Red blood cells, ×1012/L	4.1	3.8–5.31
White blood cells, ×109/L	4.99	4.5–11.32
Platelets, ×109/L	177	180–320
Blood chemistry
Aspartate aminotransferase, U/L	17	5–34
Alanine aminotransferase, U/L	29	0–32
Total protein, g/L	73	65–85
Triglycerides, mmol/L	3.7	2.5–8.33
Creatinine, µmol/L	75	53–88
Sodium, mmol/L	143	130.5–156.6
Potassium, mmol/L	4.2	3.44–5.30
Glucose, mmol/L	5.4	3.3–5.5
Low-density lipoprotein cholesterol, mmol/L	4.53	≤3
Total bilirubin, µmol/L	19	1.7–20.5
Lipoprotein(a), g/L	1.46	≤0.5
Note. 1, reference value for red blood cell count in women aged 45–64 years; 2, reference value for white blood cell count in women aged 17–65 years.

 

The glomerular filtration rate, calculated using the CKD-EPI equation, was 80 mL/min/1.73 m². Urinalysis showed no abnormalities; however, the urinary microalbumin concentration was 4.1 mg/dL (reference value: ≤2 mg/dL).

Doppler ultrasound of vessels revealed atherosclerosis in the extracranial parts of the brachiocephalic arteries with carotid bifurcation, with up to 20% stenosis of the right internal carotid artery. Echocardiography showed concentric left ventricular wall hypertrophy, with interventricular septal and posterior wall thickness of 15.2 mm and 13.1 mm, respectively. The left ventricular ejection fraction was preserved (55%). Additional findings included the following:

• Diastolic dysfunction of the impaired relaxation (type I): early diastolic filling velocity of the left ventricle (E) = 46 cm/s; E/A ratio (ratio of early diastolic filling velocity to peak velocity flow in atrial contraction) = 0.6
• Thickening of the interatrial septum up to 7.4 mm and anterior mitral valve leaflet up to 7 mm, with prolapse into the left atrial cavity by 3.1 mm
• Grade I mitral and tricuspid regurgitation (Fig. 2).

 

Fig. 2. Echocardiography findings in the patient: a, thickening of the interventricular and interatrial septa (white arrows); b, thickening of the anterior mitral valve leaflet (white arrow).

 

Spinal magnetic resonance imaging (MRI) revealed cervical disk protrusions at the C4–5, C5–6, and C6–7 levels and spinal canal stenosis at the C5–6 level, which is considered a finding for amyloidosis. To exclude an amyloid etiology of the spinal canal stenosis, genetic testing was performed using dried blood spot samples from the patient and her relatives. Sanger sequencing identified a heterozygous variant in the transthyretin gene (Chr18: 29171879 G > A, p.Arg5His) in the patient, both parents, two sisters, and one brother (Fig. 3).

 

Fig. 3. Pedigree of the patient with familial transthyretin amyloidosis. Circles represent females; squares represent males. The family members with a confirmed mutation are marked in black, those without the mutation in white, and those not yet tested (testing planned) in gray. The year of birth is indicated in figures. AF, atrial fibrillation (in the patient’s father); Lp(a), increased lipoprotein(a) levels in the patient and her father (not assessed in other family members because of technical reasons).

 

In May 2022, the patient underwent myocardial scintigraphy using a technetium-labeled radiopharmaceutical (^99mTc-pyrophosphate); no tracer uptake characteristic of ATTR amyloidosis was noted (grade 0).

Clinical Diagnosis

Primary diagnosis: Familial ATTR amyloidosis; heterozygous nucleotide variant of uncertain clinical significance in the transthyretin gene.

Comorbidities: Hypertensive heart disease, stage 3; target BP not achieved; risk 4 (very high).

Dyslipidemia (hyperlipoproteinemia(a)). Cervical spinal canal stenosis at the C5–6 level. Dorsopathy of the cervical, thoracic, and lumbar spine with chronic cervicocranialgia (C5–6 disk herniation, spondyloarthrosis, and L3–4 disk herniation); prolonged exacerbation associated with myotonic syndrome. Essential tremor of the hands.

Treatment and Recommendations

The patient was prescribed triple antihypertensive therapy and high-intensity statin therapy combined with ezetimibe, resulting in achievement of target BP and LDL cholesterol levels. The patient was invited to participate in a randomized, double-blind, placebo-controlled multicenter clinical trial (TQJ230) to address hyperlipoproteinemia(a). However, the study drug pelacarsen¹ was discontinued because of an allergic reaction at the injection site. Inclisiran was prescribed.

Follow-up by a cardiologist and neurologist is recommended, with regular BP, lipid profile, and neurologic status monitoring and periodic reassessment of the indication for tafamidis therapy targeting transthyretin amyloidosis (Fig. 4).

 

Fig. 4. Timeline of disease progression in the patient with familial transthyretin amyloidosis and hyperlipoproteinemia(a). PCR, polymerase chain reaction; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); MRI, magnetic resonance imaging; EchoCG, echocardiography; ENMG, electroneuromyography; RPH, radiopharmaceutical; SSR, sympathetic skin response; C, cervical spine; pelacarsen is not authorized in the Russian Federation.

 

Follow-up and Outcomes

Despite the prescribed treatment, the patient was hospitalized twice between October and December 2023 for suspected non-ST-elevation acute coronary syndrome in the setting of increased BP up to 220/110 mmHg, accompanied by pressing retrosternal pain radiating to the neck and scapula. The blood troponin I level was <0.01 ng/mL, and electrocardiography showed no negative changes. Coronary angiography was not performed. Stress echocardiography, conducted after BP stabilization, achieved submaximal HR and exhibited no regional wall motion abnormalities.

Stimulation electroneuromyography performed in May 2024 revealed mildly expressed axonal changes in the right peroneal nerve at the preganglionic level and decreased amplitude of the sympathetic skin response in the left hand and right foot.

Family History

Notably, the patient’s father had a long-standing history of hypertension, with BP levels reaching 170/90 mmHg. He had been taking telmisartan 40 mg/day, but later noted a tendency of hypotension and independently reduced the frequency of intake. In November 2022, he was diagnosed with permanent atrial fibrillation. Electrocardiography revealed low-voltage QRS complexes in the limb leads (Fig. 5). Blood chemistry analysis showed an increased Lp(a) concentration of 0.67 g/L (up to 0.5²), creatinine level of 107 μmol/L (53–88), and LDL cholesterol of 3.68 mmol/L (up to 3²). The immunochromatograph of venous blood revealed an increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 1881 pg/mL (0–125²). Neurological evaluation identified essential tremor and local conduction disturbances in the median nerves of the wrist (bilateral carpal tunnel syndrome). Myocardial scintigraphy showed no uptake of the radiopharmaceutical (^99mTc-pyrophosphate) characteristic of ATTR amyloidosis (grade 0).

 

Fig. 5. Twelve-lead electrocardiogram of the patient’s father: a, standard and augmented limb leads recorded at 25 mm/s; b, precordial leads recorded at 50 mm/s. Standard calibration: 1 mV corresponds to a 10-mm deflection.

 

Furthermore, the patient’s mother had a long-standing history of arterial hypertension and chronic heart failure. Echocardiographic findings indicated the following abnormalities:

• Aortic dilatation (ascending aorta diameter up to 41 mm);
• Decreased left ventricular ejection fraction (52%);
• Thickening of the interventricular septum (16.6 mm), posterior wall of the left ventricle (13 mm), and right ventricular wall (7 mm);
• Moderately pronounced calcification of the aortic and mitral valve leaflets and their fibrous rings.

Left ventricular diastolic function was not assessed. In addition, blood chemistry analysis revealed the following changes:

• Increased creatinine level of 107.6 μmol/L (53–88² μmol/L) and increased LDL cholesterol of 5.36 mmol/L (up to 3¹ mmol/L);
• Increased activity of the cardiac isoenzyme of creatine phosphokinase to 29.9 U/L (0–241² U/L).

The patient’s brother had no cardiologic symptoms and was not taking any drugs. Both of her sisters were diagnosed with hypertension; one of them also had thyroid dysfunction.

DISCUSSION

In this clinical case, the patient was diagnosed with combined familial ATTR amyloidosis and hyperlipoproteinemia(a). The former initially presented with spinal canal stenosis and neurological symptoms, whereas increased Lp(a) levels were detected during a screening evaluation for dyslipidemia and hypertension. A search of the database PubMed did not identify any study describing the co-occurrence of familial ATTR amyloidosis and hyperlipoproteinemia(a).

Familial ATTR amyloidosis is a rare, autosomal dominant hereditary disorder that typically presents in adulthood with progressive polyneuropathy and/or cardiomyopathy. ATTR amyloidosis is endemic in Northern Portugal, Sweden, Brazil, and Japan, where the Val30Met mutation accounts for nearly 100% of cases [6, 7]. Although Russia is not considered an endemic region for ATTR amyloidosis, the rate of identified cases has been steadily increasing, and the spectrum of genetic mutations that cause this disease is diverse [6, 7].

ATTR amyloidosis in the patient was clinically suspected based on echocardiographic findings and the presence of spinal canal stenosis. Molecular genetic testing of the transthyretin gene (Chr18:29171879 G > A) confirmed the diagnosis (Fig. 3). In patients with ATTR amyloidosis, spinal canal stenosis has been associated with amyloid deposition in the ligamentum flavum, particularly in the lumbar spine. Many studies have recommended routine screening for amyloid cardiomyopathy in patients with spinal canal stenosis to identify those who may benefit from cardiologic follow-up. Amyloid deposition is frequently associated with spinal canal stenosis and may provide an opportunity for early diagnosis of systemic amyloidosis [8].

In nonendemic regions, the interval between the onset of clinical manifestations and diagnosis is typically 3–4 years. In the present case, the diagnosis was established within a few months owing to clinical vigilance and the presence of red flags. The Chr18:29171879 G > A (p.Arg5His) mutation is extremely rare, with an allele frequency of 1.26 per 10,000. This mutation has not been reported in the Transthyretin Amyloidosis Outcomes Survey registry of patients with ATTR amyloidosis [6, 14, 33].

It is crucial to suspect cardiac amyloidosis in patients with left ventricular wall thickness >12 mm and amyloid deposition in extracardiac tissues, even in the presence of hypertension or other potential causes of myocardial hypertrophy. In the present patient, cardiac assessment revealed marked thickening of the left ventricular wall (15.3 mm), interatrial septum (7.4 mm), and mitral valve leaflet. Additionally, occasional ventricular extrasystoles and a supraventricular couplet were documented. Cardiac scintigraphy showed no radiotracer uptake in the myocardium, indicating an early disease stage [3].

In the patient’s father, ECG revealed low-voltage QRS complexes in the limb leads. However, the absence of this finding in younger or middle-aged individuals does not exclude the diagnosis of amyloid cardiomyopathy. QRS voltage may reflect the extent of myocardial amyloid infiltration, which tends to increase with age. In patients presenting symptoms of amyloidosis, such as spinal canal stenosis, bilateral carpal tunnel syndrome, arrhythmias and conduction disturbances of unclear etiology, hand or foot tremor, and idiopathic polyneuropathy, screening for amyloidosis is warranted [9, 10]. Genetically confirmed ATTR amyloidosis in the patient’s father was also accompanied by hyperlipoproteinemia(a).

Signs of myocardial wall thickening and dyslipidemia, characterized by an increase in LDL cholesterol to 5.36 mmol/L, were identified in the patient’s mother. However, Lp(a) levels were not assessed. We plan to evaluate Lp(a) concentration in the patient and her other blood relatives, along with echocardiography, myocardial scintigraphy, and electroneuromyography.

Although cardiac MRI is informative in the diagnosis of amyloid cardiomyopathy, it was not performed. The assessment of late gadolinium enhancement involves evaluating the presence of circular and/or transmural enhancement in the basal, mid-, and apical segments of the left ventricle and in the right ventricular myocardium. This allows for differentiation between light chain amyloidosis and ATTR, with a reported sensitivity of 82% and specificity of 76% [11]. In cardiac amyloidosis, prolonged native T1 relaxation time may be observed even before the development of left ventricular wall thickening, myocardial contrast enhancement, or the detection of circulating biomarkers. MRI and evaluation of longitudinal (T1) relaxation time may be beneficial for monitoring the degree of cardiac amyloid infiltration and its progression over time [12].

The question is when to initiate treatment for ATTR amyloidosis if a mutation is detected by genetic testing or amyloid deposition is confirmed by biopsy. A logical answer would be as early as possible; however, the evidence-based medicine perspective should also be considered.

According to current treatment guidelines for ATTR amyloidosis, which reflect the results of clinical studies in patient cohorts with cardiomyopathy and polyneuropathy, scintigraphy with radiopharmaceuticals is required. At this stage, heart failure of functional class I–II according to the New York Heart Association classification is typically observed [13, 14]. It usually corresponds to stage 3 of infiltrative heart disease, which is considered irreversible [9]. Therefore, the therapeutic effect may be limited. The present patient and her relatives do not meet the current criteria for initiating anti-amyloid-specific therapy, despite evident cardiomyopathy and polyneuropathy progression. Additional clinical studies are warranted in such patients to reconsider the timing of initiation of preventive anti-amyloid therapy at earlier stages.

Hyperlipoproteinemia(a) is an independent risk factor for cardiovascular diseases such as myocardial infarction, stroke, aortic stenosis, and heart failure [4]; therefore, Lp(a) levels should be assessed in all patients at least once in a lifetime. Studies have shown that Lp(a) contributes to cardiovascular disease through proatherogenic, pro-inflammatory, and antifibrinolytic mechanisms. The increased risk associated with Lp(a) is attributed to the combined effects of the highly procoagulant apolipoprotein(a) and atherogenic and pro-inflammatory properties of apolipoprotein B-associated oxidized phospholipids [4]. In the present patient, further evaluation of cardiac symptoms revealed dyslipidemia, with increased LDL cholesterol concentration (4.53 mmol/L) and Lp(a) level (1.46 g/L). These findings were accompanied by atherosclerosis of the extracranial segments of the brachiocephalic arteries, with stenosis at the carotid bifurcation and ostium of the right internal carotid artery. Her father also had dyslipidemia, specifically hyperlipoproteinemia(a).

Lowering Lp(a) concentrations is critical to decrease the risk of cardiovascular events. Statins are ineffective for treating hyperlipoproteinemia(a) and may increase Lp(a) levels [15]. A prospective cohort study from the Copenhagen General Population Study demonstrated that, in secondary prevention with a mean follow-up of 5 years, an absolute decrease in Lp(a) concentration by 50 mg/dL and 99 mg/dL was required to achieve a 20% and 40% reduction in the risk of major cardiovascular events, respectively [16]. Currently, clinical trials are evaluating therapies for patients with hyperlipoproteinemia(a). Several agents have shown promising results, including pelacarsen¹ and inclisiran. Pelacarsen¹ is an antisense oligonucleotide that targets hepatocytes and the messenger RNA of the Lp(a) gene. In a phase 2 randomized controlled trial, weekly or monthly subcutaneous injection of pelacarsen¹ resulted in a dose-dependent decrease in Lp(a) levels by 35%–80% [4]. Inclisiran is a novel antisense small interfering RNA-based therapy. By binding to the precursor mRNA of proprotein convertase subtilisin/kexin type 9, inclisiran inhibits the expression of its gene, leading to enhanced hepatocyte recycling and membrane expression of LDL receptors and a decrease in LDL cholesterol and Lp(a) concentrations by up to 30% [15]. Considering the risk of cardiovascular complications, the patient was prescribed a lipid-lowering agent targeting Lp(a). Initially, pelacarsen¹ was administered, but was discontinued after the first injection because of an allergic reaction. Subsequently, inclisiran was prescribed. After the first injection in November 2023, Lp(a) concentration decreased from 3.58 to 2.21 g/L, and LDL cholesterol decreased from 2.21 to 1.03 mmol/L (Fig. 4). The effectiveness of this treatment requires further evaluation during ongoing therapy and in the context of clinical data from large-scale studies.

Apolipoproteins are considered crucial components of amyloid fibrils [5]. In amyloid deposits, apolipoprotein E, along with P component and glycosaminoglycans, may act as pathological molecular chaperones that induce a β-sheet conformation in amyloidogenic polypeptides [5]. In addition to apolipoprotein E, apolipoprotein B has been identified in amyloid fibrils in the brain of patients with Alzheimer’s disease [17]. In this amyloid-associated disorder, the apolipoprotein E-4 allele serves as a genetic risk factor [18]. Furthermore, variant forms of apolipoprotein A-I have been associated with hereditary amyloidosis [19], which is characterized by the deposition of N-terminal fragments of this protein.

Studies on familial amyloid polyneuropathy caused by the Val30Met mutation in the transthyretin gene have shown that transthyretin is associated with lipoproteins [20, 21]. Specifically, high-density lipoprotein (HDL) and LDL fractions were found to contain this protein [20]. Transthyretin was present in the HDL fraction in healthy individuals and those with the Val30Met mutation, whereas the LDL fraction contained higher transthyretin levels in patients with the Val30Met mutation [20]. However, the relationship between Lp(a) and ATTR amyloidosis remains unclear. Further research is required to explore this association and its potential clinical application for the prevention and treatment of these diseases.

The treatment of hypertension in the present patient also warrants discussion. The relationship between COVID-19 and hypertension is multifaceted:

• Similarities in pathogenesis, involving systemic inflammation and endothelial dysfunction;
• Activation of the renin–angiotensin–aldosterone system;
• Potential onset or progression of hypertension after infection;
• BP instability as a manifestation of post-COVID syndrome [22].

A study involving 200 patients in Croatia who had recovered from COVID-19 showed that 1 in 7 patients was at risk of developing new-onset hypertension or preexisting hypertension progression [22]. BP destabilization may be one of the manifestations of post-COVID syndrome in patients with hypertension. According to data from the registry of the Eurasian Association of Therapists, uncontrolled hypertension was recorded in 20.1% of patients 3 months after COVID-19 [22]. Periodic increases in BP were observed, with peak values 1 month post-infection, a decrease by month 3, and a second wave of increase by month 6 [22]. Approximately 52% of physicians reported switching from monotherapy to dual combination therapy in patients with hypertension who had recovered from COVID-19, 20% increased the dose of dual therapy, and 13% used triple therapy [22]. Managing hypertension following COVID-19 remains a clinical challenge. Despite optimal antihypertensive therapy, the patient was hospitalized multiple times with suspected non-ST-segment elevation acute coronary syndrome, associated with episodes of increased BP reaching 220/110 mmHg (Fig. 4).

CONCLUSION

This is a clinical case of familial ATTR amyloidosis associated with the rare p.Arg123His mutation combined with hyperlipoproteinemia(a). Timely diagnosis and appropriate treatment of these conditions require clinicians to maintain a high index of suspicion for amyloidosis and measure Lp(a) levels in all patients with cardiovascular disease, including those with amyloid cardiomyopathy. The implementation of modern approaches to the diagnosis and treatment of rare diseases may help improve quality of life and increase life expectancy in patients with isolated and coexisting disorders.

ADDITIONAL INFORMATION

Funding source. This article was not supported by any external sources of funding

Disclosure of interests. The authors declare that they have no relationships, activities or interests (personal, professional or financial) with third parties (commercial, non-commercial, private) whose interests may be affected by the content of the article, as well as no other relationships, activities or interests over the past three years that must be reported.

Authors' contribution. T.L. Nguyen: сollection and processing of materials, analysis of obtained data, writing the text of the manuscript; E.V. Reznik: analysis of obtained data, editing the manuscript. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication. Written consent was obtained from the patient for publication of relevant medical information and all of accompanying images within the manuscript in Digital Diagnostics journal.

¹ The drug is not authorized in the Russian Federation.

²Reference values refer to the range considered normal for physiological parameters in healthy individuals.

About the authors

Thanh L. Nguyen

108 Military Central Hospital

Author for correspondence.
Email: truongthianh0302@gmail.com
ORCID iD: 0000-0002-8856-4542
SPIN-code: 9408-1899

MD, Cand. Sci. (Medicine)

Viet Nam, Hanoi

Elena V. Reznik

City Clinical Hospital No 31 named after academician G.M. Savelieva; The Russian National Research Medical University named after N.I. Pirogov

Email: elenaresnik@gmail.com
ORCID iD: 0000-0001-7479-418X
SPIN-code: 3494-9080

MD, Dr. Sci. (Medicine), Assistant Professor

Russian Federation, Moscow; Moscow

References

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