Background: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder associated with a substantial clinical burden, high supportive-care needs, and a major economic impact. The introduction of disease-modifying therapies (DMTs) has transformed the management of SMA, but questions remain regarding their real-world effectiveness and economic value. Objective: To conduct a systematic literature review of published studies on the real-world effectiveness and economic evaluations of orphan medicines for spinal muscular atrophy approved within the European Union. Materials and methods: A systematic literature review was conducted according to a prespecified protocol registered in the Open Science Framework and reported in line with PRISMA 2020 and Joanna Briggs Institute methodologies. PubMed, Embase, Web of Science, and Google Scholar were searched between 16 and 30 May 2025 without date restrictions. Two review components were assessed under one protocol: (1) real-world clinical evidence for approved SMA therapies and (2) economic evaluations of these therapies. After screening and full-text review, 114 real-world evidence (RWE) studies and 19 economic studies met the eligibility criteria; an additional 16 RWE studies and 10 economic studies were identified from gray literature. Results: A total of 159 studies were included. Across real-world studies, nusinersen, risdiplam, and onasemnogene abeparvovec were generally associated with improved or stabilized outcomes, particularly for motor and respiratory function. The greatest benefits were observed with presymptomatic or very early treatment initiation, whereas in later-treated children and adults, stabilization and slowing of decline were often the most clinically meaningful outcomes. Bulbar and feeding outcomes remained less consistently improved and were reported heterogeneously. Survival outcomes were generally favorable in short- to medium-term follow-up. Economic evaluations consistently showed that treatment cost was the main driver of cost-effectiveness. Most analyses reported incremental cost-effectiveness ratios above conventional willingness-to-pay thresholds, although onasemnogene abeparvovec and presymptomatic treatment scenarios often appeared more favorable. Considerable uncertainty remains regarding the long-term durability of benefit and model assumptions. Conclusion: In routine practice, DMTs for SMA improve or stabilize important clinical outcomes, with the strongest effects seen when treatment is started early. However, high acquisition costs and limited long-term data continue to challenge cost-effectiveness. More standardized, long-term real-world evidence is needed to strengthen clinical guidance, improve economic models, and support sustainable access decisions.

Hereditary transthyretin-mediated (ATTRV; v, variant) amyloidosis is a genetic disorder that causes abnormal accumulation of amyloid deposits in organs and tissues. The most common neurological manifestation is polyneuropathy (PN) of the autonomic nervous system, cardiac involvement and average survival of 6–12 years since onset of symptoms. Recent years have been marked by advancements in diagnosis and management of ATTRv amyloidosis with PN. In Balkan countries, endemic regions for some TTR gene mutations exist, with particularities in patient’s access to care given the different health infrastructure set-up. A panel of multidisciplinary experts from Bulgaria, Croatia, Serbia and Slovenia have gathered to discuss country-specific insights and approaches on the current ATTRv amyloidosis with PN diagnosis and management, sharing challenges and best practices. Each country has instituted various strategies for screening, genetic testing, treatment and follow-up of patients. As an endemic country with an older center of excellence in place, Bulgaria has currently a high rate (95%) of patients with ATTRv amyloidosis with PN diagnosed in the early stages of the disease. Across the other countries, delays in referral to a specialist for diagnosis and initiation of treatment have been noted due to insufficient awareness of the disease among other healthcare professionals, low availability of therapies or issues with reimbursement. Enhancement of interdisciplinary collaboration, clinical awareness and screening programs are the key areas of improvement in the Balkan region.

BACKGROUND:The study compared access to disease-modifying treatments (DMTs), care, and services for multiple sclerosis (MS) patients across six Central and Eastern European Countries (CEECs). RESEARCH DESIGN AND METHODS:A 2-part questionnaire-based survey was conducted among experts from Bulgaria, Estonia, Poland, Romania, Serbia, and Slovakia over 4 months (1 December 2022 - 1 April 2023). RESULTS:The study reveals notable variations in the legal requirements for pricing and reimbursement of MS medications, as well as criteria for health technology assessment (HTA) across countries. Despite these differences, DMTs were fully reimbursed in all countries. Poland exhibited the highest MS expenditures in 2021, totaling 171 million euros. Administrative procedures for prescribing and dispensing MS drugs were similar across countries, but the range of services and support offered to MS patients varied. Assessment of treatment accessibility, based on the number of authorized DMTs listed in Positive Drug Lists (PDLs), shows Bulgaria leading with 84.21% access, followed closely by Poland and Slovakia with comparable rates of 78.95%. CONCLUSIONS:The study revealed disparities in health care and services for MS patients across the countries surveyed. Addressing these disparities and the need for targeted interventions to ensure equitable access is critical. Further research is needed to find effective solutions.

We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function - Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late- infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/ 101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of Gtube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon-intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein.

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a severe progressive disease, more common than previously expected. The main objectives were to evaluate hereditary and wild type ATTR-CM frequency and clinical manifestations. Material and methods: One hundred seventy-eight patients at mean age 68 ± 13 years (129 males), referred by cardiologists with suspected cardiac amyloidosis (left ventricular wall thickness ≥ 12 mm and red flags) were evaluated. Pyrophosphate scintigraphy (99mTc-PYP) grade 2-3 myocardial uptake in the absence of monoclonal protein confirmed the diagnosis. Genetic test differentiated variant from wild type ATTR-CM. Endomyocardial biopsy with amyloid typing was performed in two patients. Results: Cardiac amyloidosis was diagnosed in 69 patients: light chain in 24 (13%) and ATTR-CM in 45 patients (25%). Wild type (ATTRwt) was found in 21 (12%) male patients at mean age 81 ± 6 years and variant type (ATTRv) in 24 patients (13%) at mean age 58 ± 7 years (15 males). In all ATTRv-CM patients some degree of peripheral polyneuropathy was found. The most common clinical red flags at diagnosis in both ATTRv and ATTRwt were heart failure in all patients, atrial fibrillation (16; 36%), pacemaker (5; 11%), and carpal tunnel syndrome (8; 18%). Severe aortic stenosis (4; 19%), spinal stenosis (2;10%), biceps tendon rupture (1; 5%) were characteristic for the wild type. At follow up, four patients needed a pacemaker for high degree AV block, six patients developed new onset atrial fibrillation, seventeen patients needed either initiation or an increase of the dose of loop diuretic, another 7 patients were hospitalized for heart failure exacerbation. Eight patients (18%) died, 7 (33%) with ATTRwt-CM and 1 (4%) with ATTRv-CM, all with advanced heart failure, 4 with concomitant severe aortic stenosis. Conclusions: This study provides the first nationwide estimates of the frequency and the clinical manifestations of ATTR-CM. Confirming the severity of the disease and poor prognosis, a low threshold for screening is needed for early diagnosis and timely treatment.

BACKGROUND:Autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterizedby early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lowerlimb spasticity. We present clinical andgenetic data of the first Bulgarian patients diagnosed with ARSACS by wholeexome sequencing (WES). METHODS:Variant filtering was performed usinglocally established pipeline and the selected variants were analysed by Sangersequencing. All patients underwent clinical examination and testingincluding the standard rating scales for spastic paraplegia and ataxia. RESULTS:Five different SACS gene variants, three of which novel, have been identified inpatients from three different ethnic groups. In addition to the classicalclinical triad, brain MRI revealed cerebellar atrophy, linear pontineT2-hypointensities, and hyperintense rim lateral tothalamus combined with retinal nerve fiber layer thickening on opticcoherence tomography (OCT). CONCLUSION:We expand the mutation, geographic, and phenotypic spectrum of ARSACS, adding Bulgaria to the world map of the disease, and drawing attention to the fact that it is still misdiagnosed. We demonstrated that brain MRI and OCT are necessary clinical tests for ARSACS diagnosis, even if one of the cardinal clinical features is lacking.

Background: Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. Objective: This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Methods: Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. Results: We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Conclusion: Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.

The current research project is being conducted in IMDL Genome Center Bulgaria / GMDL Genica (part of the Expert Centers for ATTR in Bulgaria1). It aims at advancing the accurate prognosis and monitoring of the onset and progression of hereditary transthyretin amyloidosis (vATTR) in Bulgarian Glu89Gln positive asymptomatic and symptomatic polyneuropathy stage I patients on Tafamidis by investigating the biomarker potential of NfL. Furthermore, our goal is to evaluate other better-known biomarkers for cardiac affection such as hs-cTnT, NT-ProBNP and eGFR. In so doing, our multidisciplinary team aims to improve the processes of timely diagnosis and therapy of the Bulgarian vATTR patient community.

This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan–Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ2 = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan–Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.

MELAS e митохондриално заболяване, съчетаващо енцефало-миопатия, лактатна ацидоза и инсулто-подобни епизоди. Началото му е в първите две десетилетия от живота, с вариабилни клинични симптоми, най-често от страна на нервната система. Клиничната и образната находка при MELAS е топична и не отговаря на даден съдов басейн, по-често е в задната краниална ямка, лезиите могат да са обратими, но често са рецидивиращи и постепенно нарастват в съседство с вече наличните в рамките на седмици до месеци, често придружени от епилептични пристъпи, неврологична дисфункция и корова атрофия. За поставянето на диагнозата е необходимо и установяването на хетероплазмия на мутацията и мултисистемно засягане. В настоящата публикация представяме пациентка (МПС) на 33-годишна възраст с доказана A3243G мутация в митохондриал ния геном с 31,6% хетероплазмия в кръвта и 74% хетероплазмия в епителни клетки от уринен седимент, отговаряща на MELAS синдром. Началните оплаквания са на 22-годишна възраст, като поради погрешна интерпретация на образната находка от МРТ като туморна формация, при нея е проведена резекция вляво темпорално две години след началните оплаквания. От неврологичния статус са налице квадрипирамиден, панцеребеларен, епилептичен и когнитивен синдроми, и двустранно невро сензорно намаление на слуха. Проведена е симптоматична терапия с Levetiracetam, витаминни препарати и нутрицевтици.

Introduction: The purpose was to assess the level of medication adherence (MA) and related factors among individuals with multiple sclerosis (MS) in Bulgaria. Materials and methods: A prospective one-year study was conducted among 54 patients with MS diagnosed, treated, and monitored in Clinic of Neurology, University Hospital “Alexandrovska”, Sofia in 2022/2023. Clinical data, patients reported outcomes, patients’ characteristics such as age, gender and reduced work capacity, and other data were collected to define the predictors of non-adherence to medicines. MA level was assessed through a free Morisky–Green 4-item questionnaire. Results: Мost of the observed patients were rated with high and moderate adherence to MS therapy (n = 44; 81.48%). The remaining 18.52% of the patients with poor adherence to therapy were women. There was no statistical basis for asserting differences in adherence levels among the various factors considered. Conclusion: The current study demonstrates the importance of MA assessment and provides insights into MA among patients with MS in Bulgaria. Still, there are low-adherent patients, and the responsible factors should be further investigated.

Mitochondrial diseases are rare and heterogeneous conditions frequently affecting the heart. They are caused by mutations in nuclear or mitochondrial DNA with maternal inheritance or de novo occurrence. We present a case of 13-year-old girl with malignant mitochondrial cardiomyopathy. First presentation of the disease is with tamponade and atrial fibrillation. Cardiac imaging shows non-specific changes of the left ventricle that cannot be explained by any cardiomyopathy: hypertrophy, dilation, hypertrabeculation. These findings raised the suspicion for mitochondrial cardiomyopathy.&nbsp;The patient is examined by neurologist due to multisystem character of the disease. Electromyography reveals myopathy. Serum lactate and creatine phosphokinase are elevated. Acute inflammation is excluded with endomyocardial biopsy which also discovers complex III deficiency. Genetic testing identified likely pathogenic mutation in mitochondrial DNA with maternal inheritance. Two years after initial presentation patient was referred for cardiac transplantation due to fast progression of the disease. Mitochondrial cardiomyopathies have variable clinical manifestation which impedes the diagnosis and makes impossible the creation of unified criteria. The disease often affects various organs with high oxygen demand. Multiparametric approach and multidisciplinary team are recommended to increase diagnostic accuracy.

Sarcoglycanopathies are among the most frequent and severe forms of autosomal recessive forms of limb-girdle muscular dystrophies (LGMDs) with childhood onset. Four subtypes are known: LGMDR3, LGMDR4, LGMDR5 and LGMDR6, which are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. We present the clinical variability of LGMD 2C/R5 among a genetically homogeneous group of 57 patients, belonging to 35 pedigrees. Molecular genetic analysis showed that all 57 patients were homozygous for the C283Y variant. The muscles of the pelvic girdle and the trunk were affected early and were more severely affected, followed by the shoulder girdle. Macroglossia, hypertrophy of the calves, scapular winging and lumbar hyperlordosis were common in the ambulatory phase. A great intra and interfamilial variability in the clinical presentation of LGMD 2C/R5 was observed, despite having the same underlying molecular defect. Females demonstrated a relatively milder clinical course compared to males. Mean creatine phosphokinase (CK) CK levels were 20 times above normal values. Muscle computer tomography (CT) CT or MRIs showed earlier and more severe involvement of the flexor proximal limb muscles in comparison to extensor muscles.

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.

Charcot–Marie–Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.