ABSTRACT
Background
Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well‐studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population.
Methods
A retrospective, hospital‐based analysis was performed using records from Pauls Stradiņš Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD‐10 codes. Incidence and prevalence rates were calculated per 100,000 population and age‐standardized to the 2013 European Standard Population.
Results
A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult‐onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age‐standardized incidence of ALS was 1.22 per 100,000 person‐years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4 months for ALS, 43.8 months for PLS, 206.8 months for SBMA and 17.3 months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed.
Conclusion
This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under‐recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.
Keywords: amyotrophic lateral sclerosis, epidemiology, motor neuron disease, spinal muscular atrophy, X‐linked Bulbo‐spinal atrophy
This first nationwide study of motor neuron diseases (MNDs) in Latvia provides epidemiological and clinical data about 181 patients identified with motor neuron diseases during a 5‐year observational period revealing lower incidence and prevalence rates compared to other European countries. In this study amyotrophic lateral sclerosis was the most common type of MND, with a mean age at the moment of diagnosis being 66 years and a diagnostic delay of 14,2 months.
Abbreviations
- ALS
Amyotrophic Lateral Sclerosis
- ALSbi
Amyotrophic Lateral Sclerosis Behavioral impariment
- ALSci
Amyotrophic Lateral Sclerosis Cognitive impairment
- ALSFRS‐R
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale
- ALS‐FTD
Amyotrophic Lateral Sclerosis—Frontotemporal Dementia
- AR
Androgen receptor
- ASO
Antisense oligonucleotides
- CCUH
Children's Clinical University Hospital
- CI
Confidence interval
- CSB
Central Statistical Bureau
- CSF
Cerebrospinal fluid
- ESP
European Standard Population
- F
Females
- ICD
International Classification of Diseases
- M
Males
- MLPA
Multiplex ligation‐dependent probe amplification
- MMA
Monomelic Atrophy
- MND
Motor neuron disease
- Mo
Months
- MRI
Magnetic resonance imaging
- N/A
Not available
- NBS
Newborn screening
- NFL
Neurofilament
- NGS
Next‐generation sequencing
- NIV
Non‐invasive ventilation
- PCR
Polymerase chain reaction
- PET‐CT
Positron emission computed tomography
- PLS
Primary Lateral Sclerosis
- PMA
Progressive Muscular Atrophy
- PSCUH
Pauls Stradiņš Clinical University Hospital
- REUH
Riga East University Hospital
- SBMA
Spinal and Bulbar Muscular Atrophy
- SD
Standard deviation
- SMA
Spinal Muscular Atrophy
- SMN
Survival motor neuron
- SNIP
Sniff nasal inspiratory pressure
- SOD
Superoxide dismutase
1. Introduction
Motor neuron diseases (MNDs) are rare, progressive neurodegenerative disorders characterized by the selective loss of upper and/or lower motor neurons, resulting in muscle weakness, atrophy, and functional decline. Amyotrophic lateral sclerosis (ALS) is the most common and best‐studied subtype, whereas other forms, including primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), remain less well characterized in population‐based studies [1, 2].
Epidemiological data are crucial for quantifying disease burden, informing healthcare planning, and guiding early diagnostic and therapeutic strategies. In Europe, ALS incidence typically ranges from 1.5 to 3.1 per 100,000 person‐years, with prevalence between 4 and 8 per 100,000 [3]. However, these figures vary regionally due to genetic background, healthcare access, case ascertainment, and environmental exposures [4].
Despite Latvia's centralized healthcare system and specialized neurology centers, no comprehensive nationwide data on MNDs have been published. This gap not only limits healthcare planning but also hinders Latvia's contribution to European surveillance efforts. With the recent emergence of gene‐targeted therapies such as nusinersen and risdiplam for SMA, and tofersen for SOD1‐associated ALS, accurate national epidemiology has become critical to inform treatment policies and ensure clinical trial readiness [5].
Here, we present the first nationwide epidemiological analysis of MNDs in Latvia. We aimed to determine the incidence, prevalence, and clinical characteristics of ALS, SMA, and SBMA across adult and pediatric populations, with a focus on diagnostic delays and symptom patterns to align Latvia with regional and international disease surveillance initiatives.
2. Methods
This retrospective, population‐based study included all patients diagnosed with motor neuron diseases and admitted to the two national tertiary neurology centers in Latvia—Pauls Stradiņš Clinical University Hospital (PSCUH) and Riga East University Hospital (REUH)—between January 1, 2020, and December 31, 2024. Pediatric patients were identified separately through the Children's Clinical University Hospital (CCUH). Together, these institutions provide nationwide referral services, ensuring comprehensive case capture in a country with a centralized healthcare system.
Patients were identified through hospital registries using ICD‐10 diagnostic codes G12, G12.1, G12.2, G12.8, and G12.9. Eligible cases included adults aged ≥ 18 years and children under 18 years with a confirmed diagnosis of any MND subtype—such as amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, or related phenotypes during the study period.
ALS diagnoses were confirmed according to internationally accepted criteria. Patients fulfilling definite, probable, or possible ALS by the revised El Escorial/Airlie House criteria were included [6]. Patients with primary lateral sclerosis and progressive muscular atrophy were classified according to established consensus definitions [7, 8]. SMA diagnoses were confirmed through clinical evaluation supported by genetic testing of the SMN1 gene. Genetic testing included detection of homozygous SMN1 deletions or pathogenic variants using multiplex ligation‐dependent probe amplification (MLPA) and/or next‐generation sequencing (NGS) panels. SBMA was confirmed by PCR‐based fragment sizing, with repeat lengths > 36 considered pathogenic. Genetic testing was performed selectively in patients with early‐onset familial or atypical presentations, primarily targeting SOD1 mutations and, in selected cases, C9orf72 repeat expansions. Family history was reviewed from available records; however, variability in retrospective documentation precluded systematic classification of sporadic versus familial ALS across the entire cohort.
For all included patients, demographic and clinical data were extracted from electronic health records. These included age, sex, initial symptoms (subjectively reported and objectively documented), time from symptom onset to first neurological consultation and to confirmed diagnosis, final diagnosis with classification by MND subtype, and, where available, disease duration. Electrophysiological findings from electromyography and nerve conduction studies, as well as neuroimaging reports, were reviewed when available. Pulmonary function data, sniff nasal inspiratory pressure (SNIP) values, noninvasive ventilation (NIV) use, positron emission computed tomography (PET‐CT) findings, CSF results, and neurofilament measurements were not systematically available across the cohort and were therefore excluded from the analysis.
A separate pediatric cohort with confirmed or suspected MND, primarily SMA, was identified through the Children's Clinical University Hospital. Pediatric cases were analyzed independently because of distinct diagnostic procedures, care pathways, and therapeutic availability.
2.1. Statistics
Incidence and prevalence were calculated using official annual midyear population estimates from the Central Statistical Bureau of Latvia (CSB) for 2020–2024 expressed per 100,000 population, with 95% confidence intervals (CIs) estimated from a Poisson distribution. Age standardization was performed using the direct method with the 2013 European Standard Population (ESP) as the reference.
Descriptive statistics (means, standard deviations, medians, interquartile range) were used to summarize patient demographics and clinical characteristics. Categorical variables were compared using chi‐squared tests; gender‐specific differences in incidence and prevalence were evaluated using Poisson regression. Statistical significance was defined as p < 0.05. All analyses were conducted using IBM SPSS Statistics, version 29.0.
3. Results
A total of 160 adult patients with motor neuron diseases were identified from hospital records between January 1, 2020, and December 31, 2024, using ICD‐10 diagnostic codes. After applying the inclusion criteria and verifying the diagnosis, 148 patients were retained for analysis. Among these, 131 were classified as having amyotrophic lateral sclerosis (ALS) and related phenotypes, including 119 cases of classical ALS, 3 cases of ALS with frontotemporal dementia (ALS‐FTD), 5 cases of primary lateral sclerosis, 3 cases of progressive muscular atrophy, and 1 case of monomelic amyotrophy (MMA). In addition, 10 patients were diagnosed with adult‐onset spinal muscular atrophy, and 7 with spinal and bulbar muscular atrophy (SBMA). A separate pediatric cohort comprised 33 patients with genetically confirmed or clinically suspected SMA, who were analyzed independently because of differences in diagnostic procedures and treatment protocols.
An overview of the study design and cohort segmentation is shown in Figure 1.
FIGURE 1.
Study Flow Diagram of Patient Inclusion and Classification by MND Subtype. Showing the study design and cohort segmentation. ALS, Amyotrophic lateral sclerosis; ALS, Amyotrophic lateral sclerosis; ALS‐FTD, Amyotrophic lateral sclerosis with frontotemporal dementia; ICD‐10, International Classification of Diseases, 10th Revision; MMA, Monomelic amyotrophy; MRI, Magnetic resonance imaging; PLS, Primary lateral sclerosis; PMA, Progressive muscular atrophy; SBMA, Spinal and bulbar muscular atrophy (Kennedy's disease); SMA, Spinal muscular atrophy (adult and pediatric).
3.1. Demographics in the Adult ALS and Related Phenotypes Group
As of 1 January 2025, the population of Latvia was 1,856,932. The 131 patients with amyotrophic lateral sclerosis or related phenotypes were included in the prevalence analysis.
At the time of data collection, 64 patients (48.9%) were alive, 32 (24.4%) had died, and 35 (26.7%) had an unknown status due to loss to follow‐up. Considering all identified cases of ALS and related motor neuron disease phenotypes (living and deceased), the crude point prevalence was 7.05 per 100,000 population (95% CI: 5.85–8.26). After age‐standardization to the 2013 ESP, the prevalence was 4.69 per 100,000.
Among the 131 patients, 62 (47.3%) were male and 69 (52.7%) were female. The crude point prevalence was 7.68 per 100,000 in males (95% CI: 5.80–9.92) and 5.71 per 100,000 in females (95% CI: 4.33–7.09). When analysis was restricted to patients confirmed to be alive at the time of data collection (n = 64; 32 males and 32 females), the adjusted prevalence was 3.39 per 100,000 for males (95% CI: 2.55–4.23) and 3.21 per 100,000 for females (95% CI: 2.10–4.32). The age‐standardized prevalence among living patients was 3.15 per 100,000 (95% CI: 2.37–3.93), with rates of 3.80 per 100,000 in males (95% CI: 2.46–5.14) and 2.74 per 100,000 in females (95% CI: 1.78–3.70). No statistically significant difference in prevalence was observed between genders (p = 0.56).
The mean age of the ALS cohort was 66.0 years (SD ±12.5), with a range from 25 to 90 years. Males had a slightly younger mean age at diagnosis (64.2 years, SD ±12.4) compared to females (67.0 years, SD ±12.6). The most frequent age group at diagnosis was 65–69 years. A localized spike in prevalence was observed among males aged 90–94 years, attributable to the small denominator in this subgroup (2 cases among 2510 individuals). Figures 2 and 3 illustrate the overall age distribution and the age‐ and sex‐specific prevalence rates.
FIGURE 2.
Distribution of ALS Patients by Age Group in Latvia. Demonstrating the distribution of ALS patients in Latvia by age groups.
FIGURE 3.
Prevalence of ALS in Latvia per 100,000 individuals by age groups and gender. Demonstrates the prevalence of ALS per 100,000 individuals by gender and age group in Latvia. Blue line showing male prevalence and pink line showing female prevalence.
During the study period, Latvia's average population was 1,888,814. A total of 131 newly diagnosed cases of MND (excluding SMA and SBMA) were identified, corresponding to a crude annual incidence rate of 1.39 per 100,000 person‐years (95% CI: 1.15–1.63).
Sex‐specific crude incidence rates were 1.41 per 100,000 person‐years in males (95% CI: 1.10–1.82) and 1.35 per 100,000 person‐years in females (95% CI: 1.06–1.72). After age standardization using the 2013 ESP the overall incidence was 1.22 per 100,000 (95% CI: 0.98–1.46), with adjusted rates of 1.62 (95% CI: 1.20–2.05) for males and 1.13 (95% CI: 0.86–1.40) for females. No statistically significant difference in incidence was observed between sexes (p = 0.81).
The overall incidence trend rate is illustrated in Figure 4. Additional age‐ and sex‐specific incidence rates are seen in the Figure S1.
FIGURE 4.
Incidence rates of ALS by age groups. Demonstrates the incidence rates of ALS per 100,000 individuals by age groups in the Latvian population.
Paresis was the most frequently reported initial symptom, subjectively reported by 41.2% of patients and objectively confirmed on neurological examination in 48.1%. A detailed distribution of initial symptoms, stratified by sex and by subjective versus objective findings, is presented in Table 1.
TABLE 1.
Symptoms and clinical data in the ALS group.
| First symptom | Subjective | Objective | ||||
|---|---|---|---|---|---|---|
| Males n (%) | Females n (%) | Total n (%) | Males n (%) | Females n (%) | Total n (%) | |
| Bulbar | 18 (29.0) | 35 (50.7) | 53 (40.5) | 19 (30.6) | 32 (46.4) | 51 (38.9) |
| Paresis | 27 (43.5) | 27 (39.1) | 54 (41.2) | 32 (51.6) | 31 (44.9) | 63 (48.1) |
| Muscle atrophy/weight loss | 3 (4.8) | 2 (2.9) | 5 (3.8) | 5 (8.1) | 3 (4.3) | 8 (6.1) |
| Fasciculations | 3 (4.8) | 0 (0.0) | 3 (2.3) | 4 (6.5) | 0 (0.0) | 4 (3.1) |
| Gait disturbances | 2 (3.2) | 3 (4.3) | 5 (3.8) | 1 (1.6) | 2 (2.9) | 3 (2.3) |
| Unknown | 1 (1.6) | 0 (0.0) | 1 (0.8) | 1 (1.6) | 0 (0.0) | 1 (0.8) |
| Other | 8 (12.9) | 2 (2.9) | 10 (7.6) | 0 (0.0) | 1 (1.4) | 1 (0.8) |
Among the 131 patients in the ALS/MND subgroup, 119 (90.8%) were diagnosed with classical ALS, 3 (2.3%) with the ALS–frontotemporal dementia (ALS‐FTD) variant, 5 (3.8%) with primary lateral sclerosis (PLS), 3 (2.3%) with progressive muscular atrophy (PMA), and 1 (0.8%) with monomelic amyotrophy (MMA). ALS‐FTD was diagnosed based on documented clinical features, neuropsychological assessment, and, where available, neuroimaging findings. Because standardized ALS‐specific cognitive screening was not applied across the cohort, the Strong criteria could not be used systematically to classify ALSci or ALSbi. Selective genetic testing was performed in approximately 15–17 ALS or related phenotype cases, identifying two pathogenic SOD1 variants and one C9orf72 repeat expansion.
The mean diagnostic delay in the whole MND group, defined as the time from symptom onset to confirmed diagnosis, was 14.2 ± 16.1 months, with no statistically significant difference between sexes. Mean diagnostic delay in the PLS subgroup was 43.8 ± 24.5 months, PMA 18 ± 11.1, ALS subgroup 13.4 ± 14.3, and SBMA subgroup 206.8 ± 93.6 months. Among deceased patients (n = 32), mean disease duration from symptom onset to death was 26.5 ± 31.1 months (range: up to 144 months). For patients alive at the end of follow‐up (n = 64), mean disease duration was 30.9 ± 23.1 months. Sex‐specific breakdowns are provided in Table 2.
TABLE 2.
Description of timeframes for ALS group.
| Sex | Mean age ± SD (years) | Age range (years) | Time from symptom onset to first appointment (months) | Time from symptom onset to diagnosis (months) | Mean disease duration, deceased patients (months) | Mean disease duration, alive patients (months) |
|---|---|---|---|---|---|---|
| Male | 64.2 ± 12.4 | 28–90 | 10.4 ± 13.2 | 16.4 ± 19.5 | 33.1 ± 42.0 | 35.3 ± 24.8 |
| Female | 66.9 ± 12.6 | 25–88 | 8.8 ± 10.6 | 12.2 ± 12.0 | 21.3 ± 18.7 | 26.6 ± 20.8 |
| Total | 65.6 ± 12.5 | 25–90 | 9.6 ± 11.9 | 14.2 ± 16.1 | 26.5 ± 31.1 | 30.9 ± 23.1 |
Abbreviation: SD, Standard deviation.
Kaplan–Meier survival analysis was performed for all ALS patients, with survival defined as time from symptom onset to death or last follow‐up (censored on December 31, 2024). The median survival for the full cohort was 55.3 months (95% CI: 46.0–64.5). Median survival was 63.8 months in males (95% CI: 47.2–80.4) and 55.3 months in females (95% CI: 40.8–55.4), with no significant sex‐related difference (log‐rank p = 0.358). Kaplan–Meier curves are presented in Figure 5. Additional gender‐specific Kaplan–Meier curves may be seen in the Figure S2.
FIGURE 5.
Kaplan–Meier survival curve for ALS cohort. Illustrating an overall survival rate of ALS cohort.
3.2. Demographics in the SMA Group
A total of 43 patients were diagnosed with SMA during the study period, comprising 10 adults and 33 pediatric patients.
As of January 1, 2025, the overall point prevalence of SMA in Latvia was 2.48 per 100,000 population (95% CI: 1.76–3.19). Prevalence was significantly higher in children (9.91 per 100,000, 95% CI: 6.68–13.15) compared with adults (0.67 per 100,000, 95% CI: 0.25–1.08). The mean annual incidence during the study period was 0.49 per 100,000 person‐years, with markedly higher rates in children (1.92 per 100,000) than in adults (0.13 per 100,000).
Among pediatric patients, risdiplam was the most frequently prescribed therapy. Nine children received combined risdiplam and nusinersen; five received risdiplam alone, and one received nusinersen with onasemnogene abeparvovec.
The mean diagnostic delay in children (symptom onset to confirmed diagnosis) was 17.3 ± 30.8 months (range: < 1 to 108 months). SMA type II was the most common subtype, identified in 21 of 33 children (63.6%). Genetic testing was performed in all patients, confirming the diagnosis. Data completeness was limited, with five children being presymptomatic, seven children lacking full records on symptom onset or disease duration, and five missing information on treatment status. Detailed stratification by sex is presented in Table 3. Due to limited clinical documentation, direct comparison between adult and pediatric SMA patients was not feasible.
TABLE 3.
Demographic and Clinical Characteristics, SMA Type Distribution, and Treatment Modalities by Sex in the SMA Cohort.
| General characteristics | |||
|---|---|---|---|
| Parameter | Male (n = x) | Female (n = y) | Total (n = z) |
| Time from symptoms onset to appointment (mo) | 5.67 ± 6.76 | 9.77 ± 25.98 | 7.57 ± 18.11 |
| Time from symptoms onset to diagnosis (mo) | 16.60 ± 26.56 | 18.07 ± 35.83 | 17.31 ± 30.81 |
| Disease duration (mo) | 118.94 ± 69.44 | 103.69 ± 74.55 | 112.10 ± 70.88 |
| Distribution of SMA types by sex | |||
|---|---|---|---|
| SMA Type | Male n (%) | Female n (%) | Total n (%) |
| SMA 0 | 1 (5.3%) | 1 (6.3%) | 2 (5.7%) |
| SMA I | 1 (5.3%) | 1 (6.3%) | 2 (5.7%) |
| SMA II | 12 (63.2%) | 9 (56.3%) | 21 (60.0%) |
| SMA III | — | 2 (12.5%) | 2 (5.7%) |
| SMA IIIb | — | 1 (6.3%) | 1 (2.9%) |
| Therapies received | |||
|---|---|---|---|
| Therapy | Male n (%) | Female n (%) | Total n (%) |
| Risdiplam | 1 (5.3%) | 4 (25.0%) | 5 (14.3%) |
| Nusinersen | 4 (21.1%) | 2 (12.5%) | 6 (17.1%) |
| Nusinersen + Risdiplam | 4 (21.1%) | 5 (31.3%) | 9 (25.7%) |
| Nusinersen + Onasemnogene abeparvovec | 0 (0.0%) | 1 (6.3%) | 1 (2.9%) |
Abbreviations: Mo, months; SMA, spinal muscular atrophy.
3.3. Demographics in the SBMA Group
During the study period, seven male patients were diagnosed with spinal and bulbar muscular atrophy, also known as Kennedy's disease. As of January 1, 2025, the male population in Latvia was 860,422, resulting in a point prevalence of 0.81 per 100,000 males (95% CI: 0.213–1.413). The mean annual incidence rate was calculated at 0.16 per 100,000 person‐years (95% CI: 0.04–0.28).
The most frequently reported initial symptoms were generalized fatigue and muscle weakness. All seven patients underwent genetic testing, confirming the pathogenic CAG repeat expansion in the androgen receptor (AR) gene, with repeat lengths ranging from 47 to 54, exceeding the disease‐causing threshold (> 36 repeats).
The mean age at diagnosis was 46.4 ± 11.9 years. The clinical features of this cohort included a constellation of neuromuscular and endocrine symptoms, such as asymmetrical limb weakness, gynecomastia, facial muscle involvement, tongue atrophy, dysarthria, and fasciculations. Tendon reflexes were universally absent among the cohort.
A more detailed clinical characterization of five of these patients was previously published in a national study by Millere et al. [9]. Since that publication, two additional cases have been identified in Latvia. An updated summary of the clinical characteristics observed in this cohort is provided in Table S1.
4. Discussion
This is the first nationwide, population‐based study to assess the incidence, prevalence, and clinical characteristics of MNDs in Latvia across both pediatric and adult populations. Our findings provide crucial epidemiological insights from a previously underrepresented region of Northern Europe.
In our cohort, amyotrophic lateral sclerosis represented the overwhelming majority of MND diagnoses (88.5%), which aligns with global reports indicating ALS as the most common form of MND [10]. Other subtypes, including primary lateral sclerosis and progressive muscular atrophy, were rare in our population. Interestingly, spinal muscular atrophy and spinal and bulbar muscular atrophy were less frequently diagnosed, with 10 and 7 cases, respectively, underscoring their rarity in the adult population. For example, a European epidemiological study regarding SMA incidence, performed by Verhaart IEC and colleagues, reported an average of 11.9 cases per 100,000 individuals, which is nearly 10 times higher than our findings. This discrepancy may be attributable to underdiagnosis, especially in milder cases with later onset or atypical presentations. SMA prevalence in children shows variable rates across Europe, ranging from 0.00 to 4.11 per 100,000 people. In our study, the overall SMA prevalence was 2.48 per 100,000, with type II being the most common subtype (58.1%), which is slightly higher than reported proportions between 45% and 48% in other European cohorts [11].
A particularly important development during the study period was the implementation of Latvia's national newborn screening (NBS) program for SMA, which began in April 2023. This followed the identification of the first genetically confirmed case of SMA type 0 in Latvia, a neonate with prenatal indicators such as increased nuchal translucency and reduced fetal movements who died shortly after birth due to severe respiratory insufficiency. This tragic case emphasized the importance of early identification for prompt therapeutic intervention [12]. Since the NBS program's initiation, 15,000 neonates have been screened, resulting in one confirmed case of SMA, corresponding to an incidence of 1:5205 live births—a figure notably higher than in several other European cohorts [13]. The discrepancy between our reported pediatric SMA incidence (1.92 per 100,000 person‐years) and the higher birth incidence observed in Latvia's newborn screening program (~19.2 per 100,000 live births) can be attributed to several factors. First, these measures are based on different denominators—our incidence reflects cases diagnosed over time, while the NBS figure captures genetically confirmed cases at birth. Second, the clinical onset of SMA, especially for types II and III, can be delayed, and diagnosis may be missed or postponed, contributing to underestimation in cohort data. Finally, NBS offers comprehensive, unbiased screening of all neonates, whereas real‐world registries depend on clinical recognition and reporting. Together, these differences highlight the added value of systematic screening and the likelihood that earlier incidence estimates may have underrepresented the true burden of SMA in the population.
Unfortunately, there are no epidemiological studies performed in other Baltic countries to compare the incidence and prevalence rates of SBMA. In our study, both the prevalence and incidence rates were below 1 per 100,000, compared to Italy's 2.58 [14], again pointing toward probable underdiagnosis in outpatient settings and low clinical suspicion, compounded by the variable phenotype of the disease.
The crude incidence of MND in Latvia over the 5 years was 13.9 per million person‐years. This figure falls within the lower range reported in Europe, where ALS incidence rates typically vary between 1.5 and 2.5 per 100,000 person‐years (15–25 per million). Variability between countries can reflect differences in genetic background, environmental exposures, healthcare access, and case ascertainment methods. The slight male predominance in the incidence we observed is in line with some other reports showing higher ALS rates among males [15].
The observed ALS incidence and prevalence in Latvia fall within the lower range of European estimates. While this is broadly consistent with published data from neighboring countries, the lower figures may partly reflect incomplete case ascertainment rather than a true epidemiological difference. As our study was based on data from the tertiary referral centers located in the capital, patients managed exclusively in the regional hospitals or outpatient settings may not have been captured. Notably, prevalence appeared slightly lower than in Finland or Germany, possibly reflecting underdiagnosis of atypical or slowly progressive MND subtypes in Latvia. The comparison of incidence and prevalence of ALS between the neighboring countries is seen in Table S2 [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].
In analyzing research papers on epidemiology in other European countries, it is also worth mentioning that our cohort shares several similarities. For instance, the mean age at the time of diagnosis in Finland and Denmark was 65 years, and our cohort's mean age was 66 years [16, 17]. In the same paper by Hanhisuanto et al., it is mentioned that 28% of all the patients that were included in the study underwent genetic testing which resulted in detecting cases with SOD‐1 and C9orf72 mutations, whereas in our study there were only 2 patients with confirmed SOD‐1 mutation and the exact number of possible C9orf72 as well as other gene mutation carriers yet remains unknown due to the limited availability of genetic testing.
Diagnostic delays remain a significant challenge, with a mean time from symptom onset to confirmed diagnosis of over 14 months in our cohort, which is almost the same as in Estonia (14.2) [18]. Initial misdiagnosis was observed in a subset of patients, with alternative diagnoses including myasthenia gravis, immune‐mediated polyneuropathy, corticobasal degeneration, and spinal canal stenosis, most commonly in early or atypical presentations. Notably, bulbar symptoms were more frequently reported among women, while limb weakness and paresis were slightly more common in men. Despite advances in diagnostic techniques, a substantial proportion of imaging and neurophysiological studies in our cohort yielded nonspecific results, underscoring the need for reliable biomarkers. Neurofilament light chain (Nfl) remains the most discussed candidate; however, routine serum or CSF Nfl testing is not yet available in Latvia. Establishing a biobank would facilitate future research by enabling more detailed examinations and participation in analyzing potential disease markers, such as miRNA‐181, TDP‐43, neopterin, and p75 [19].
The emergence of disease‐modifying therapies, including antisense oligonucleotides (ASO) such as tofersen for SOD1‐mutant ALS, is transforming the therapeutic landscape; expanding genetic panel testing could improve diagnostic accuracy and identify trial‐eligible patients. In Latvia, riluzole is reimbursed and routinely prescribed; edaravone is unavailable to consenting patients. Assisted dying is not permitted, and no active ALS trials are currently running. Presymptomatic monitoring is offered to at‐risk relatives of genetically confirmed cases, although structured genetic counseling for adult neurological conditions is not systematically reimbursed.
Our study has limitations. Its retrospective design and restriction to three tertiary centers may underestimate true incidence. Survival data were incomplete for some patients, and standardized cognitive screening was not systematically applied, precluding ALSci/ALSbi classification. No post‐mortem examinations or brain banking were available. The apparent increase from ~16 new cases/year in 2020 to 33–34 in 2024–2025 likely reflects improved awareness and earlier referral rather than a true increase in incidence; prevalence, however, appears to be increasing, driven by wider availability of NIV and multidisciplinary care. Establishing a national MND registry remains a priority.
5. Conclusion
This first nationwide epidemiological study of MNDs in Latvia reveals lower incidence and prevalence than in European counterparts. ALS predominated, while adult SMA and SBMA remained under‐recognized. Diagnostic delays limited access to genetic testing, and disparities in access to care were identified as key challenges. Establishing a national registry and expanding genetic screening are priorities to improve early diagnosis, access to treatment, and Latvia's contribution to European rare disease surveillance.
Author Contributions
Diāna‐Patrīcija Grosa: investigation, resources. Gundega Ķauķe: investigation, resources. Renāte‐Ruta Kažmere: investigation, resources. Viktorija Ķēniņa: conceptualization, writing – review and editing, supervision, project administration, methodology. Vladimirs Krutovs: writing – review and editing, writing – original draft, investigation, formal analysis, resources, visualization. Arta Grosmane: investigation, resources. Marija Roddate: investigation, resources, methodology. Guntis Karelis: supervision, writing – review and editing. Signe Šetlere: investigation, resources. Mikus Dīriks: investigation, resources.
Funding
The authors have nothing to report.
Disclosure
There was no AI Technology use during the preparation and revision of the manuscript.
Ethics Statement
This study was approved by the Ethics Committee of Riga Stradiņš University (approval number: 2‐PĒK‐4/975/2025). All procedures were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. We confirm that we have read the Journal's position on issues involved in ethics publication and affirm that this report is consistent with those guidelines.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Incidence rates of ALS by age groups and gender. Demonstrates the incidence rates per 100 individuals by age group and gender in Latvia. Blue line showing male prevalence and pink line showing female prevalence.
Figure S2: Kaplan–Meier survival curve for ALS cohort by gender. illustrates the overall survival for ALS patients depicting survival rates for males (blue line) and females (pink line). Light blue crosses show censored male cases, and red crosses show censored female cases. M, Males. F, females.
Table S1: Clinical characteristics of SBMA patients. Demonstrates the clinical characteristics of SBMA patients reported in this cohort. N/A, not available; SBMA, Spinal and Bulbar Muscular Atrophy.
Table S2: Comparative Table: ALS Incidence and Prevalence in European Countries. Demonstrates the ALS incidence and prevalence rates in European countries reported from 1989 to 2025. ALS, Amyotrophic Lateral Sclerosis.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Incidence rates of ALS by age groups and gender. Demonstrates the incidence rates per 100 individuals by age group and gender in Latvia. Blue line showing male prevalence and pink line showing female prevalence.
Figure S2: Kaplan–Meier survival curve for ALS cohort by gender. illustrates the overall survival for ALS patients depicting survival rates for males (blue line) and females (pink line). Light blue crosses show censored male cases, and red crosses show censored female cases. M, Males. F, females.
Table S1: Clinical characteristics of SBMA patients. Demonstrates the clinical characteristics of SBMA patients reported in this cohort. N/A, not available; SBMA, Spinal and Bulbar Muscular Atrophy.
Table S2: Comparative Table: ALS Incidence and Prevalence in European Countries. Demonstrates the ALS incidence and prevalence rates in European countries reported from 1989 to 2025. ALS, Amyotrophic Lateral Sclerosis.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.