Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

Long term follow-up of refractory/relapsed hairy cell leukaemia patients treated with low-dose vemurafenib between 2013 and 2022 at the Department of Internal Medicine and Oncology, Semmelweis University.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy. Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University. Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022. Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5 months while the overall survival was 82 months. Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time-months or even years-before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants.

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

[Beta-thalassemia and vitamin B12 deficiency and associated complement-mediated hemolysis]. / Béta-thalassaemia, B12-vitamin-hiány és társuló komplementmediált hemolízis.

We present the case of a 67-year-old male patient admitted to our clinic due to weakness and repeated dizziness. Due to his severe microcytic anemia in his laboratory tests, he needed a transfusion of 6 units of selected blood in the days following admission. Our patient was diagnosed with beta-thalassemia minor, which was accompanied by a severe deficiency of vitamin B12. Surprisingly, parallel to vitamin B12 deficiency, we detected laboratory abnormalities indicating complement-mediated autoimmune hemolysis. After correcting the vitamin B12 deficiency, the patient's blood count improved, and the observed immunological abnormalities disappeared. Genetic testing of the hemoglobin gene confirmed the c.118C>T (p.Gln40STOP) variant in heterozygous form. Beta-thalassemia is a relatively common hematological disease, although rarely encountered in Hungary. Genetic testing of patients is possible at the Laboratory Medicine Institute of the Clinical Center in Debrecen. Unfortunately, we do not have accurate information about published domestic epidemiological data. Furthermore, establishing a diagnosis can be difficult if the disease is combined with other hematological disorders, such as the lack of vitamin B12, which can clinically mimic hemolytic anemia in certain features. Our case is considered a rarity in the literature, so in the case of a positive family history, it is recommended to screen immediate family members, which may facilitate the accurate establishment of a later diagnosis. Orv Hetil. 2023; 164(24): 954-960.

Likely Pathogenic Variants of Cav1.3 and Nav1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways.

Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only is the clinical picture of ALS heterogenous, but also the pain sensation due to different types of pain involvement. ALS used to be considered a painless disease, but research has been emerging and depicting a more complex pain representation in ALS. Pain has been detected even a couple years before the symptomatic stage of ALS, referring to primary pain associated with muscle denervation, although secondary pain due to nociceptive causes is also a part of the clinical picture. A new non-contact dying-back injury mechanism theory of ALS recently postulated that the irreversible intrafusal proprioceptive Piezo2 microinjury could be the primary damage, with underlying genetic and environmental risk factors. Moreover, this Piezo2 primary damage is also proposed to dysregulate the primary pain pathways in the spinal dorsal horn in ALS due to the lost imbalanced subthreshold Ca2+ currents, NMDA activation and lost L-type Ca2+ currents, leading to the lost activation of wide dynamic range neurons. Our investigation is the first to show that the likely pathogenic variants of the Cav1.3 encoding CACNA1D gene may play a role in ALS pathology and the associated dysregulation or loss of the pain sensation. Furthermore, our reanalysis also shows that the SCN1A gene might also contribute to the dysregulated pain sensation in ALS. Finally, the absence of pathogenic variants of Piezo2 points toward the new non-contact dying-back injury mechanism theory of ALS. However, molecular and genetic investigations are needed to identify the functionally diverse features of this proposed novel critical pathway.

Re-analysis of the Hungarian amyotrophic lateral sclerosis population and evaluation of novel ALS genetic risk variants.

Amyotrophic lateral sclerosis (ALS) is a presently incurable neurodegenerative disease. Some genes have a causal relationship to ALS, others act as susceptibility and/or risk factors. We aimed to elucidate the role of 14 ALS-related genes in the Hungarian ALS population of 183 patients. Mutation screening of major ALS genes was performed. SMN1 and SMN2 genes were examined by multiplex ligation-dependent probe-amplification assay; intermediate repeat expansions in the ATXN1 and ATXN2 genes were analyzed by fragment analysis. Additional variants in putative ALS genes were screened from previously acquired next generation sequencing data. We confirmed the repeat expansion of the C9orf72, ATXN1 and ATXN2 genes as ALS risk factors in this Hungarian cohort. Additionally, we identified a pathogenic SOD1 mutation and suggested its founder effect. A likely pathogenic variant in the MFSD8 gene was detected, and variants of interest were uncovered in the ANXA11 and GLT8D1 genes. We provide valuable data as part of the growing body of work on population-specific aspects of the genetic background of ALS.