Young-Onset Amyotrophic Lateral Sclerosis: Genetic Structure and Phenotypic Features

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Introduction

Amyotrophic lateral sclerosis (ALS) is the main form of both sporadic and hereditary neurodegenerative diseases in adults, collectively known as “motor neuron disease” [1]. ALS is more common in men, with a sex ratio in most populations ranging from 1.2 : 1.0 to 1.7 : 1.0 [2]. Most cases are classified as sporadic ALS, while 10% of patients have a family history of the disease, with two-thirds of them having mutations in ALS-associated genes [3]. Although ALS most commonly manifests between the ages of 50 and 70, in 10% of cases, the disease begins at a younger age, with symptoms appearing before the age of 45, and is classified as “young-onset ALS” (yALS) [4]. This subgroup of the disease is rare, and consequently, studies focusing on this age group are extremely limited [5, 6]. However, yALS is considered a variant of “classic” ALS with combined upper and lower motor neuron involvement and is typically represented by sporadic cases. yALS is characterized by several clinical features, including a less common bulbar onset, a predominance of upper motor neuron involvement, and a longer survival [7, 8]. Clinical cohort studies show that the young-onset phenotype is an independent prognostic factor for longer survival [7].

An extremely rare subgroup, usually included in the cohort of patients with yALS, consists of cases of juvenile ALS (jALS), which is defined as a form with the clinical onset before the age of 25 [7]. The global prevalence and incidence of jALS remain largely unknown. In one of the few multicenter studies, conducted in Europe and evaluating data from 46 specialized ALS centers, the annual prevalence of jALS was estimated to be 0.008 cases per 100,000 population for symptom onset before the age of 18, which accounts for less than 0.1% of all ALS cases [9]. In a Portuguese cohort of patients with yALS, jALS accounted for 14.3% of cases [6]. Since the clinical implementation of massive parallel sequencing, knowledge of the pathophysiological mechanisms of jALS has increased significantly, and the natural history and clinical manifestations of the different monogenic forms of jALS are better understood.

There are several important differences between jALS and adult-onset ALS. First, jALS has a greater genetic contribution: approximately 40% of cases are caused by specific mutations in ALS-specific genes [10, 11] compared to approximately 10% in adult-onset ALS [11]. Mutations in FUS, SETX, and ALS2 genes are most commonly associated with jALS. Associations with mutations in SPG11, SOD1, SPTLC1, UBQNL2, SIGMAR1 and other genes have also been reported. Mutations in the C9orf72 gene, which are the most common in adult-onset ALS, have not been reported in jALS. Second, jALS is characterized by a polysyndromic pattern. In addition to the upper and lower motor neurons, other parts of the central or peripheral nervous system are involved in the pathological process.

In yALS and jALS, the pathological process may involve various neuronal pathways and, less commonly, brain regions responsible for cognition and emotion, and rarely sensory cortical areas. Some genetic subtypes associated with various dysfunctions of neurons and glial cells have been identified [6]. The loss of motor neurons in yALS and jALS is due to multiple pathophysiological mechanisms similar to those in typical forms of sporadic and familial ALS [1]. There is considerable pathophysiological and genetic overlap between jALS and other hereditary neurological disorders, including hereditary spastic paraplegias, axonal forms of hereditary motor and sensory neuropathies, spinal muscular atrophies not associated with the 5q locus, autosomal recessive cerebellar ataxias, and hereditary neurometabolic diseases [12–14].

It is important to systematize the available data and update the current understanding of yALS in light of advances in diagnostic techniques and new therapeutic strategies based on antisense oligonucleotides and viral vectors in gene therapy. This study presents the most important clinical and genetic aspects of patients with yALS and potential directions for developing therapies to treat this severe disease.

The aim of this study was to analyze cases of yALS in the Russian Center of Neurology and Neurosciences.

Materials and methods

The study was conducted at Neurology department No. 6 and the Molecular genetic laboratory of Neurology department No. 5 of the Russian Center of Neurology and Neurosciences from 2022 to 2025. A total of 365 ALS cases were analyzed, of which 47 (12.8%) patients met the criteria for yALS based on the age of onset (i.e., before the age of 45) and were included in the study.

Each patient underwent the necessary set of diagnostic procedures to exclude or establish ALS according to the revised El Escorial [15] and Gold Coast 2019 [16] criteria. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) [17] was used to diagnose cognitive disorders. In addition to the standard clinical, neurophysiological, and neuroimaging examinations, all patients underwent molecular genetic testing, including analysis of the coding sequence of the SOD1 gene by direct capillary Sanger sequencing and amplified fragment length analysis of the tandem hexanucleotide repeat (GGGGCC)_n in the C9orf72 gene by polymerase chain reaction with an additional primer for the repeat region. In some cases, patients with yALS and jALS underwent massive parallel sequencing. The whole exome sequencing panel was obtained from patients at other clinics.

Identified pathogenic variants, probable pathogenic variants, and variants of uncertain clinical significance were validated by capillary sequencing on a Nanophore 05 genetic analyzer (NPF Syntol) in the Molecular genetics laboratory of Neurology department No. 5 of the Russian Center of Neurology and Neurosciences.

Written informed consent was obtained from patients for participation in the study and for the processing and presentation of the data obtained. The study was approved by the Local Ethics Committee of the Russian Center of Neurology and Neurosciences (Protocol No. 2-5/23 dated 15 February 2023).

Results

The study included 365 patients with confirmed ALS according to the current criteria. Of these, 47 (12.8%) patients met the age criteria for yALS, including 15 (32%) patients identified as carriers of mutations in ALS-associated genes (Table 1).

 

Table 1. Clinical and genetic profile of patients

No.	Age of onset / sex	Gene / locus	Exon / intron	Genetic variant	Amino acid substitution	Type of inheritance	Form of disease onset
1	38 / male	c9orf72/ 9p21.2	1	rs143561967	—	Sporadic	Cervicothoracic
2	36 / female	c9orf72/ 9p21.2	1	rs143561967	—	Autosomal dominant	Bulbar
3	44 / male	c9orf72/ 9p21.2	1	rs143561967	—	Sporadic	Cervicothoracic
4	33 / female	c9orf72/ 9p21.2	1	rs143561967	—	Sporadic	Bulbar
5	43 / male	SOD1/ 21q22.11	3’UTR	rs2516661924	—	Sporadic	Lumbosacral
6	35 / female	SOD1/ 21q22.11	5	rs1568811471	NP_000445.1: p.Asn140Asp	Autosomal dominant	Lumbosacral
7	37 / female	SOD1/ 21q22.11	5	rs1568811471	NP_000445.1: p.Asn140Asp	Autosomal dominant	Lumbosacral
8	41 / male	SOD1/ 21q22.11	4	rs80265967	NP_000445.1: p.Asp91Ala	Autosomal dominant	Lumbosacral
9	37 / female	SOD1/ 21q22.11	4	rs80265967	NP_000445.1: p.Asp91Ala	Sporadic	Lumbosacral
10	41 / female	SOD1/ 21q22.11	4	rs80265967	NP_000445.1: p.Asp91Ala	Autosomal dominant	Lumbosacral
11	37 / male	FIG4/ 6q21	5	rs1455052760	NP_055660.1: p.Val157Met	Autosomal dominant / incomplete penetrance	Cervicothoracic
12	24 / female	SOD1/ 21q22.11	5	de novo	NP_000445.1: p.Glu134Gly	Autosomal recessive	Lumbosacral
13	5 / male	UBQLN2/ Xp11.21	1	rs764837088	NP_038472.2: p.Thr134Ile	Sporadic	Associated with cognitive disorders
14	20 / male	FUS/ 16p11.2	14	rs387906627	NP_004951.1: p.Arg495Ter	Autosomal dominant	Bulbar
15	18 / male	FUS/ 16p11.2	14	rs387906627	NP_004951.1: p.Arg495Ter	Sporadic	Bulbar

 

Seven (14.8%) SOD1gene mutations, including 6 in the coding region and one in the 3’ untranslated region (3’UTR), were identified by coding sequence analysis. In addition, 5 (11%) cases were familial forms of SOD1-associated ALS, predominantly with an autosomal dominant inheritance, whereas the others were classified as sporadic (4%). The most common mutations in the SOD1 gene, typical of yALS, included the p.Asp91Ala and p.Asn140Asp mutations previously described in other populations.

Based on the number of hexanucleotide repeats (GGGGCC)_n in the C9orf72 gene, an expansion was identified in 4 (8.5%) cases, with the number of repeats exceeding the threshold of 50 copies in all cases. Most studies define a pathological repeat threshold of > 35 [18, 19].

As for jALS, massive parallel sequencing was recommended for all 4 patients because this form of ALS is extremely rare. The results were obtained from the patients for genotype-phenotype correlation analysis and validation of the identified variants. In 2 cases of jALS, a p.Arg495Ter mutation in the FUS gene was identified. In one case, the disease was hereditary, in the other it was sporadic with a de novo mutation not found in the proband’s parents. Variants in the SOD1 gene (p.Glu134Gly) for a familial form and UBQLN2 (p.Thr134Ile) for a de novo mutation were also identified as the cause of the ASL.

 

Fig. 1. Distribution of mutations in the causal genes of ALS among 47 patients with rNALS observed in the 6th neurological department of the Russian Center for Neurological Sciences.

 

In the structure of yALS phenotypes with identified mutations, the lumbosacral onset (47%) was predominant, which is typical for SOD1-associated cases. In 4 (27%) cases, a bulbar onset of symptoms was observed, which is typical of mutations in the C9orf72 and FUS genes. In 3 (20%) patients, a cervicothoracic yASL was associated with mutations in the C9orf72 and FIG4 genes. An extremely rare jALS phenotype with a predominance of upper motor neuron involvement and multimodal cognitive impairment was associated with a mutation in the UBQLN2 gene.

One patient with a confirmed yALS provided a result of whole exome sequencing that identified a heterozygous p.Val157Met mutation in the FIG4 gene of uncertain clinical significance. Validation of the identified variant revealed that the p.Val157Met mutation was heterozygous in the clinically healthy mother of the proband. A genetic structure of the identified mutations is presented in Figure 1.

Discussion

This study provides the only detailed description of the genetic structure and phenotypic features of a cohort of patients with yALS in Russia. The predominant form of disease onset in patients with yALS was found to be spinal (67% of patients with identified mutations), affecting the lower limbs (lumbosacral form) and/or upper limbs (cervicothoracic form). Most cases showed a lumbosacral onset of symptoms. The bulbar form was found in 27% of patients with confirmed mutations in causative ALS genes. Large European population studies showed that the percentage of bulbar forms increases with the age of symptom onset, reaching 10–51% in men and 6–72% in women [20, 21]. A low incidence of bulba-onsetr forms in patients with onset before age 41 (mean: 16%) contrasts with a higher incidence in older patients (mean: 43% for onset after age 70) [7]. Our data are consistent with these studies and confirm a higher percentage of spinal-onset forms in the structure of yALS.

Four key causative genes are known to explain approximately 48% of familial ALS cases and approximately 5% of sporadic ALS cases in populations of European origin [11]. These genes are C9orf72, SOD1, TARDBP, and FUS. In this study, 15% of yALS cases were associated with mutations in the SOD1 gene, and the most common mutations were p.Asp91Ala and p.Asn140Asp previously described in the European population. Lumbosacral ALS was the predominant clinical form. The data obtained are consistent with known studies [22], which report a higher percentage of spinal manifestations, especially with weakness in the lower limbs (lumbosacral form). However, a well-defined phenotype is only known for some mutations in the SOD1 gene, such as the D90A mutation (one of the most common in Europe), which is characterized by a slow progression and lumbosacral onset.

The hexanucleotide (GGGGCC)_n expansion in the non-coding region of the C9orf72 gene is the most common cause of familial ALS [19]. According to studies conducted [23], the percentage of C9orf72 mutations responsible for the development of ALS ranges from 7.84% to 41% in patients with a positive family history and is approximately 5% in sporadic cases, depending on the study population. Our study showed that mutations in the C9orf72 gene were causative in 8.7% of cases, and only one patient had a significant family history, whereas in the other cases were sporadic. Bulbar ALS and cervicothoracic ALS were the most common forms associated with mutations in the C9orf72 gene. Our data are consistent with one of the large cohort studies on the clinical and genetic features of C9orf72-associated ALS, which showed that the first symptoms often affect the bulbar level of the cerebrospinal axis, and the mean age of onset is 58 years, characterizing the hexanucleotide expansion in the C9orf72 gene as an extremely rare cause of yALS [19].

In 2009, a rare autosomal dominant form of ALS associated with heterozygous pathogenic variants in the FIG4 gene was first described in patients from North America [24]. FIG4 encodes a phosphoinositide 5-phosphatase involved in the regulation of phosphatidylinositol-3,5-bisphosphate, which is an intracellular signaling lipid that plays a key role in the transport of endosomal vesicles. Loss of function leads to neurodegenerative processes in the central nervous system, including spinal cord motor neurons, as well as peripheral neuropathy, which has been demonstrated in animal models [25]. To date, at least 14 rare non-synonymous variants in the FIG4 gene have been identified, and the contribution of these variants to the pathogenesis of ALS remains controversial, because pathogenic FIG4 variants were not detected in small patient cohorts, and some carriers of such variants showed incomplete penetrance (absence of clinical manifestations despite the presence of a mutation) [26, 27]. Incomplete penetrance probably explains the absence of clinical manifestations in the proband’s mother, who was also a carrier of the heterozygous p.Val157Met mutation in the FIG4 gene. The clinical phenotype in the proband was represented by signs of predominant upper motor neuron involvement, which is also a typical feature of FIG4-associated ALS [28], as well as by a cervicothoracic onset. The contribution of environmental factors as ALS risk modifiers is being investigated because even causative mutations may have incomplete penetrance. Potential exogenous factors associated with ALS include toxic factors (such as radiation, pesticides, organic solvents, β-methylamino-L-alanine, methylphenyl tetrahydropyridine, heavy metals, vaccination), infectious factors (such as retroviruses, herpesviruses), and environmental and lifestyle factors (such as dietary habits, low intake of polyunsaturated fatty acids, intense physical activity, sports, repeated traumatic brain injury, occupational exposure to electromagnetic fields, etc.) [1]. These factors can act as potential triggers for yALS in the presence of a genetic predisposition [1, 29].

The most common genetic basis associated with jALS includes mutations in the FUS, ALS2, SETX, and SPG11 [29]. Autosomal recessive inheritance is more common in consanguineous families and has been described in patients with variants in ALS2, SPG11, SIGMAR1, ERLIN1, VRK1, GNE, DDHD1, and SYNE1 genes. Autosomal dominant inheritance and sporadic cases with de novo mutations are more commonly associated with variants in the FUS [30], SETX, SOD1, SPTLC1 [31], SPTLC2, TRMT2B, BICD2, and TARDBP genes. X-linked inheritance is typical of rare pathogenic variants in the UBQLN2 gene [32], although it has been described in extremely rare cases for mutations in the TRMT2B gene [33]. Pathogenic variants in the FUS and SOD1 genes represent the most common monogenic forms of familial jALS with a global prevalence, despite the fact that most cases of jALS are sporadic and are caused by de novo mutations [34].

The current literature shows that SOD1 mutations are associated with three cases of jALS [35–37]. These cases are characterized by disease onset in the late second or early third decade of life, accompanied by a combination of symptoms of both upper and lower motor neuron involvement. All patients progressed rapidly and developed respiratory failure. Two patients died less than two years after the onset of symptoms. These mutations were considered to be de novo, because no clear family history could be identified. Patients with SOD1-associated jALS had no signs of sensory or cognitive impairment. Electromyography showed active denervation and chronic neurogenic changes. Sensory conduction parameters remained normal. Neuropathologic examination revealed severe degeneration of the anterior horns of the spinal cord, Bunina bodies, and gliosis in the spinal cord and brain in one patient [37]. Ubiquitin-immunoreactive inclusions and the SOD1 protein were found in the neurons of the anterior horns. An important feature of SOD1 mutations in jALS is that they are located near zinc-binding sites [35, 37] or in the β-structural domains of the protein [36] and in most cases differ from mutations detected in adult-onset ALS.

In our case of SOD1-associated jALS, the onset of symptoms was reported at the age of 24. The clinical presentation was characterized by predominant lower motor neuron involvement and a rapid progression of neurological deficit, leading to almost complete immobilization of the patient within 6 months of progression and death from severe respiratory failure 10 months after the onset of symptoms. The patient was a homozygous carrier of the p.E134G variant, whereas the proband’s mother (a heterozygous carrier) showed no signs of the disease, which may indicate autosomal recessive inheritance. This clinical case is interesting because SOD1 mutations most often have an autosomal dominant inheritance type and full penetrance [22], but some studies have shown that SOD1-associated ALS can also have a recessive inheritance type [38], and it is also known that incomplete penetrance of SOD1 mutations is extremely rare [39]. This variant was previously described in one study [40] as a cause of sporadic ALS with a lumbosacral onset at the age of 34 and a slow progression rate.

UBQLN2 is a transport protein involved in the function of the ubiquitin-proteasome system. Disruption of the ubiquitin-proteasome system caused by UBQLN2 mutations is one of the most actively studied mechanisms of the pathogenesis associated with UBQLN2. However, the role of the UBQLN2 protein in disrupting the cytoplasm localization of TDP-43 protein and its aggregation into insoluble inclusions, which is typical of ALS, is well established. Recent studies show that UBQLN2 mutations associated with ALS also lead to abnormal autophagy, neuroinflammation, and abnormal formation of stress granules [41]. Taken together, these data underscore the key role of UBQLN2 in the pathogenesis of ALS and frontotemporal dementia associated with abnormal metabolism of toxic proteins and failure of their clearance mechanisms.

In one study that included five families with rare cases of jALS, UBQLN2 mutations were characterized by an X-linked dominant inheritance pattern and also manifested in disease forms combined with dementia [32]. The age of clinical manifestation in UBQLN2-associated ALS ranged from 16 years to 71 years. The mean age of onset was 33.9 ± 14.0 years in men and 47.3 ± 10.8 years in women. The mean duration of the disease was about four decades, indicating its slow progression. Frontotemporal dementia is most often associated with UBQLN2 mutations. Of 40 patients with UBQLN2 mutations, three had disease onset before the age of 24. One patient had the classic presentation of ALS, another patient had a combination of ALS and frontotemporal dementia, and the third patient had a combination of upper motor neuron signs and dementia. Spinal cord pathomorphology in two patients showed degeneration of anterior horn neurons, atrophy of corticospinal tracts, and severe astrocytosis.

Our case presented a pediatric onset of ALS at the age of 5–6 years with delayed psychomotor development, hand tremor (probably due to muscle weakness) and calf muscle spasms with gradual addition of leg weakness over 10 years. The rate of disease progression in this clinical case can certainly be considered slow, which is consistent with the literature data, and the prognosis can be considered favorable, also due to the absence of respiratory dysfunction. A characteristic feature of our case is the combination of multimodal cognitive impairment, lower motor neuron involvement, which is clinically manifested as mild tongue tremor and marginal hypotrophy, cramps and spontaneous fasciculations in the arms, legs and abdominal muscles, and neurophysiologically manifested as a long-term (for several years) slowly progressive, generalized peripheral motor neuron involvement with a strong predominance of the reinnervation process over denervation, and upper motor neuron involvement manifested as increased deep tendon and periosteal reflexes and mild spastic hypertonia in the legs.

The FUS gene is considered one of the most frequent causes of jALS [34]. However, FUS-associated cases show considerable phenotypic variability, ranging from classic adult onset to aggressive forms with onset in childhood. Both in juvenile and pediatric populations, the disease with mutations in the FUS gene is generally more malignant and rapidly progressive. The pediatric group shows an extremely limited number of genes associated with classic ALS, and this disease is rare and often underestimated in the differential diagnosis of motor neuron diseases in children. However, cases associated with FUS mutations are disproportionately represented in this age category.

The reasons why the same gene can cause both an aggressive, early (pediatric) form of ALS and a classic adult-onset form remain unclear. The FUS gene is located on chromosome 16 and encodes a protein involved in some important processes related to the regulation of DNA and RNA functions. The literature suggests that the variability of clinical phenotypes may be related to the location of mutations within different functional domains of the FUS gene.

Analysis of 38 published cases of FUS-associated jALS showed that most of them are caused by de novo mutations [42]. The FUS mutations associated with jALS differ from FUS mutations typical of later-onset ALS, although both are often located in the C-terminal fragment of the protein [43]. The age of disease onset is usually 21 years. The clinical presentation of FUS-associated jALS includes signs of both lower and upper motor neuron involvement such as muscle weakness, hypotrophy combined with spasticity and hyperreflexia. FUS-associated jALS is characterized by rapid progression with a fatal outcome due to respiratory failure within 1–2 years from the onset of symptoms. Although bulbar onset is usually associated with faster progression, no significant differences in survival between spinal and bulbar forms of ALS have been identified in young age [43]. In some cases of FUS-associated ALS, movement disorders are described, such as myoclonic jerks [44], tremors, and in even rarer cases, oculomotor disorders manifested as diplopia [45].

In two of our cases, a previously described pathogenic p.Arg495Ter mutation in the FUS gene was found, which leads to the premature appearance of a stop codon, resulting in the truncation of the C-terminal fragment of the FUS protein. The literature shows that this nucleotide variant is associated with an aggressive disease phenotype [46], although the molecular mechanisms of such a malignant clinical presentation currently remain unclear. In the first clinical case, the identified mutation appeared to be inherited from the father, who developed signs of bulbar and respiratory dysfunction at the age of 29, progressing steadily to a fatal outcome at the age of 35. In another clinical case, the identified mutation was not inherited from the parents and, according to the trio analysis, it was a de novo variant, which is also consistent with the literature, because most published cases of FUS-associated jALS are de novo mutations [42].

The main phenotypic difference in our cases of FUS-associated jALS is that in the case of the hereditary disease, the onset of symptoms was represented by classic progressive bulbar palsy, which was later accompanied by facial muscle weakness and progressive neurogenic respiratory disorders, whereas in the sporadic FUS-associated jALS, the first symptom was facial asymmetry (facial diplegia) with later development of bulbar disorders.

The prognosis for ALS remains largely unpredictable. Although for most patients the course of the disease is similar to classical ALS, with a life expectancy from symptom onset to fatal outcome of 20–48 months [47], more than 10% of patients survive for more than 10 years [48]. Data on the natural history of the various genetic subtypes of jALS are extremely limited, and case series are the most valuable. In general, most young-onset and juvenile forms are characterized by a longer surviva;. However, even with relatively slow progression, patients experience a significant decrease in quality of life, significant loss of functional independence, and often require nutritional support, gastrostomy, and continuous respiratory support and mechanical ventilation [49]. Childhood onset, bulbar onset, and jALS with more complex neurological manifestations usually have a severe course and an unfavorable prognosis [29]. A rapid clinical progression is especially typical of jALS subtypes associated with FUS and SOD1 mutations [29, 50].

Conclusions

Young-onset ALS is a rare neurodegenerative disease with many unmet diagnostic and therapeutic challenges. The diagnosis is based primarily on clinical manifestations, neurophysiological findings, and molecular genetic analysis. However, a definitive diagnosis is not necessarily based on a monogenic cause. Early identification of both sporadic and familial forms of yALS and determination of their molecular genetic patterns is critical for timely genetic counseling and identification of potentially treatable etiologies. Clinical trials are underway for some genetic causes associated with ALS. At the time of this publication, antisense oligonucleotide-based agents for the treatment of SOD1- and FUS-associated ALS are in phase III clinical trials and are showing promising results.

About the authors

Denis V. Shevchuk

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: shevchuk.d.v@neurology.ru
ORCID iD: 0009-0002-1334-9730

neurologist, 6^th Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

Natalya Yu. Abramycheva

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0000-0001-9419-1159

Dr. Sci. (Biol.), senior researcher, Head, Molecular genetics laboratory, 5^th Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

Arina R. Protsenko

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0009-0000-5290-5045

junior researcher, Molecular genetics laboratory, 5^th Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

Darya A. Grishinа

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0000-0002-7924-3405

Dr. Sci. (Med.), Head, Center for Peripheral Nervous System Disorders, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

Angelina G. Makarova

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0000-0001-8862-654X

Cand. Sci. (Med.), neurologist, 3^rd Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

Maria N. Zakharova

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0000-0002-1072-9968

Dr. Sci. (Med.), Professor, leading researcher, Head, 6^th Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, 80 Volokolamskoye shosse, Moscow, 125367

References

Supplementary files