At present, brain tumours remain one of the “hard-to-treat” malignancies with minimal improvement in patients’ survival. Recently, miRNAs have been shown to correlate with oncogenesis and metastasis ...and have been investigated as potential biomarkers for diagnosis, prognosis and therapy prediction in different brain malignancies. The aim of the current study was to select an accurate and affordable brain tumour detection and grading approach. In the present study, we analysed the applicability of a restricted miRNA signature that could differentiate among patients with primary as well as metastatic brain tumours. Fresh tumour tissues were collected from Bulgarian patients (
n
= 38), including high-grade gliomas (
n
= 23), low-grade gliomas (
n
= 10) and brain metastases (
n
= 5) from lung cancer. Total RNAs enriched with microRNAs were isolated and differentially expressed miRNAs were analyzed by RT-qPCR using TaqMan Advanced miRNA assay. We selected a signature of miR-21, miR-10b, miR-7, miR-491 that showed good diagnostic potential in high-grade gliomas, low-grade gliomas and brain metastases compared with normal brain tissues. Our results showed that miR-10b could reliably differentiate brain metastases from high-grade gliomas, while miR-491 could distinguish low-grade from high-grade gliomas and brain metastases from low-grade gliomas. We observed that miR-21 and miR-7 correlated with disease recurrence, survival status and the Karnofsky Performance Status. The selected signature of miR-7, miR-21, miR-10b and miR-491 could be used as a highly accurate diagnostic, grading and prognostic biomarker in differentiating various types of brain tumours. Our data suggest that the 4-miRNAs signature could be further analysed for predicting treatment response and for future miRs-based targeted therapy. The ongoing studies on miRs-based targeted therapy related to our selected miRNA signature are also reviewed.
Ten girls with sporadic central precocious puberty were screened for mutations in the maternally imprinted gene MKRN3 . We detected 1 novel frameshift mutation (p.Arg351Serfs*44) and a previously ...described mutation (p.Pro161Argfs*10). In the course of investigating the family, genetic analysis found 2 asymptomatic males with paternally inherited MKRN3 mutations, which has not been reported in previous studies.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of motor function, disability, and death. Variants in the
gene, encoding the Profilin-1 ...protein, are related to ALS18.
We present a pedigree consisting of 3 generations and 4 affected individuals, 3 of which carry a novel heterozygous variant: c.92T > G (p.Val31Gly) in the
gene. This variant was discovered through means of whole exome sequencing (WES) and targeted analysis of ALS-related genes.
The mean age of onset in our pedigree was 59.75 (±10.11 SD) years with a significant difference between the first two generations (females) and the third (male) of 22.33 (±3.4 SD) years. For this ALS form, we observed a longer disease progression of 4 (±1.87 SD) years (three of four affected are still alive). Clinical manifestations displayed predominant impairment of the lower motor neuron (LMN) in one limb, with gradual involvement of other limbs. A novel heterozygous missense variant c.92T > G, p. Val31Gly (NM_005022.4) in exon 1 in the
gene was discovered through means of whole exome sequencing (WES). Segregation analysis in the family showed that the detected variant was inherited from the affected mother, and the affected aunt also turned out to be a variant carrier.
ALS18 is a very rare form of the disease. We report here a relatively large pedigree with a novel variant, leading to late onset (after 50 years), initial involvement of the lower limbs and relatively slow progression.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal ...dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype–phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.
In the 2021 WHO classification of Tumors of the Central Nervous System, additional molecular characteristics have been included, defining the following adult-type diffuse glioma entities: Astrocytoma ...IDH-mutant, Oligodendroglioma IDH-mutant and 1p/19q-codeleted, and Glioblastoma IDH-wildtype. Despite advances in genetic analysis, precision oncology, and targeted therapy, malignant adult-type diffuse gliomas remain "hard-to-treat tumors", indicating an urgent need for better diagnostic and therapeutic strategies.
In the last decades, miRNA analysis has been a hotspot for researching and developing diagnostic, prognostic, and predictive biomarkers for various disorders, including brain cancer. Scientific interest has recently been directed towards therapeutic applications of miRNAs, with encouraging results.
Databases such as NCBI, PubMed, and Medline were searched for a selection of articles reporting the relationship between deregulated miRNAs and genetic aberrations used in the latest WHO CNS classification.
The current review discussed the recommended molecular biomarkers and genetic aberrations based on the 2021 WHO classification in adult-type diffuse gliomas, along with associated deregulated miRNAs. Additionally, the study highlights miRNA-based treatment advancements in adults with gliomas.
•Molecular markers enhance the WHO CNS classification, but the prognosis for adults with diffuse glioma remains poor.•miRNAs related to the genetic aberrations in adult-type diffuse gliomas might improve patient diagnostics and monitoring.•We emphasize the link between deregulated miRNAs and the genetic biomarkers used in the WHO CNS classification.•miRNA-based therapies have potential for reducing drug resistance and improving patient outcome.
Leber's hereditary optic neuropathy (LHON) is a rare maternally inherited disease caused by mutations in mitochondrial DNA (mtDNA) genes encoding subunits of complex I in the mitochondrial ...respiratory chain. The most common mutations causing LHON are G11778A, G3460A and T14484C, but there are also several less common mutations. LHON presents as acute or subacute bilateral visual loss, usually affecting young males. The aim of this study was to assess the clinical symptomatology and genetic analysis of Bulgarian patients with LHON. Twenty-two patients were diagnosed with LHON based on clinical evaluation and genetic examination (17 males and 5 females); 12 of them were previously reported, while 8 males and 2 females are newly diagnosed. A full neuroophthalmologic and genetic examination was performed. Eight patients had a family history of LHON, while 14 were isolated cases. The age at onset ranged from 3 to 43 years, and visual acuity ranged from counting fingers to 0.9. Genetic testing revealed various mutations, including a rare mutation G3635A in MT-ND1 in five affected members of one pedigree and digenic inheritance of G11778A and T14484C in three individuals from a different family. A variant m.15988A > G in the mitochondrial gene MT-TP with a high level of heteroplasmy was found in one patient. In addition to the most common mutations causing LHON, our patients also had rare mutations. These results suggest that genetic analysis of the entire mtDNA sequence is recommended in cases with strong clinical suspicion of LHON, since new rare mtDNA pathogenic variants are being identified.
Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, autosomal-dominant (AD) multisystem disorder resulting from the extracellular deposition of amyloid fibrils formed by a ...destabilized mutant form of transthyretin (TTR), a transport protein predominantly produced by the liver.
The aims of the current study are to demonstrate the Bulgarian experience with the screening programs among the high-risk patient population over the last 7 years, to present the results from the therapy with TTR stabilizer in our cohort, as well as to stress on the importance of a follow-up of asymptomatic carriers with TTR pathogenic variants by a multidisciplinary team of specialists.
In 2014, a screening program among the high-risk patient population for ATTRv was initiated in Bulgaria. On one hand, it was conducted to identify new patients and families among people with "red flag" clinical features, while on the other hand, the program aimed to identify TTR mutation carriers among the families with already genetically proven diagnoses. Sanger sequencing methodology was used to make fast target testing for mutations in the
gene in the suspected individuals. All of the identified carriers underwent subsequent evaluation for neurological, cardiac, gastroenterological, and neuro-ophthalmological involvement. Those considered affected were provided with multidisciplinary treatment and a follow-up.
As a result of a 7-year selective screening program among the high-risk patient population and relatives of genetically verified affected individuals, 340 carriers of TTR mutations were identified in Bulgaria with the following gene defects: 78.53% with Glu89Gln, 10.29% with Val30Met, 8.24% with Ser77Phe, 2.06% with Gly47Glu, and 0.59% with Ser52Pro. All of these affected displayed a mixed phenotype with variable ages at onset and rate of progression, according to their mutation. From the 150 patients treated with TTR stabilizer, 84 remained stable, while in other 66 patients the treatment was terminated either because of polyneuropathy progression or due to death. A program for a regular follow-up of asymptomatic carriers in the last 3 years enabled us to detect the transition of 39/65 to symptomatic patients and to initiate treatment in a timely manner.
Bulgarian ATTRv patients display a mixed phenotype with some clinical peculiarities for each mutation that should be considered when treating the affected and the follow-up of the asymptomatic carriers of a specific gene defect.
We report two unrelated Bulgarian families with hereditary transthyretin (ATTR) amyloidosis due to a rare p.Glu74Leu (Glu54Leu) pathogenic variant found in seven individuals—three of them ...symptomatic. Only one family with the same variant and with a Swedish origin has been clinically described so far. Our patients are characterized by predominant cardiac involvement, very much similar to the Swedish patients. Although the initial complaint was bilateral carpal tunnel syndrome, advanced amyloid cardiomyopathy was found in two symptomatic carriers at diagnosis with heart failure manifestations. The neurological involvement was considered as mild, with mainly sensory signs and symptoms being present. We followed a non-biopsy algorithm to confirm the diagnosis. Tafamidis 61 mg has been initiated as the only approved disease modifying treatment for ATTR cardiomyopathy. Clinical stability in the absence of adverse events has been observed at follow up.
Pontocerebellar hypoplasia (PCH) type 2 is a very rare autosomal recessive neurodegenerative disorder with prenatal onset that disrupts brain development. We present three patients (two siblings and ...one unrelated child) with PCH 2 linked to the most common mutation c.919G > T (p.Ala307Ser) in
gene. The disease started soon after birth with feeding difficulties, extrapyramidal symptoms, psychomotor retardation, progressive microcephaly. Two of the patients were diagnosed with dyskinetic cerebral palsy (CP) at first. Despite the neurodegenerative character of PCH 2, the absence of regression and even some developmental progress in few patients, might erroneously lead to the incorrect diagnosis of dyskinetic CP. Megacisterna magna on brain ultrasound makes the diagnosis of PCH 2 highly probable and should prompt further imaging with MRI. MRI findings of PCH are pivotal for the diagnosis. Genetic testing for the most common mutation in
gene should also be performed. Correct diagnosis of PCH 2 is essential not only for the prognosis of the patient, but also for prenatal diagnosis in future pregnancies. Knowledge of the clinical picture of PCH 2 will lead to correct and timely diagnosis. Advanced neuroimaging procedures and molecular genetic techniques provide valuable tools for prompt diagnosis of rare, but clinically important, neurogenetic imitators of CP.
Abstract We report on a 13-year-old girl with a negative family history who manifested drug-resistant, mostly fever-induced seizures in clusters from age 5 months. Seizure frequency was not ...substantially reduced by anticonvulsant treatment, but tended to decrease with age. Early behavioral changes, i.e., autistic and aggressive features, worsened with time. Molecular genetic testing for PCDH19 mutations was performed by sequencing all exons of the gene, and revealed duplication c.2705dupA (p.Asp902Lysfs*6) in exon 5, which was also present in the fully asymptomatic mother. This case is among the few reported with a pathogenic PCDH19 mutation inherited from an unaffected heterozygous female carrier. It indicates that PCDH19 mutation testing should be performed in sporadic cases with no family history that still demonstrate well-established features of peculiar X-linked epilepsy with mental retardation limited to females.
PDF
