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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.

Background Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The approximately 50 known ALS-associated genes do not fully explain its heritability, which suggests the existence of yet unidentified causative genes. We report results of studies aimed at identification of the genetic cause of ALS in a pedigree (three patients) without mutations in the common ALS-causative genes. Methods Clinical investigations included thorough neurological and non-neurological examinations and testings. Genetic analysis was performed by exome sequencing. Functional studies included identification of altered splicing by PCR and sequencing, and mutated proteins by western blot analysis. Apoptosis in the presence and absence of tunicamycin was assessed in transfected HEK293T cells using an Annexin-PE-7AAD kit in conjunction with flow cytometry. Results Clinical features are described in detail. Disease progression in the patients of the pedigree was relatively slow and survival was relatively long. An RNF13 mutation was identified as the cause of the recessively inherited ALS in the pedigree. The gene is highly conserved, and its encoded protein (RING finger protein 13) can potentially affect various neurodegenerative-relevant functions, including protein homeostasis. The RNF13 splice site mutation caused expression of two mis-spliced forms of RNF13 mRNA and an aberrant RNF13 protein, and affected apoptosis. Conclusion RNF13 was identified as a novel causative gene of recessively inherited ALS. The gene affects protein homeostasis, which is one of most important components of the pathology of neurodegeneration. The contribution of RNF13 to the aetiology of another neurodegenerative disease is discussed. [ABSTRACT FROM AUTHOR]

Background and purpose: Spinal–bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. Methods: Clinical investigations included thorough neurological and non‐neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. Results: The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non‐Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin‐like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin–proteasome system. Interestingly, UBA1 mutations can also cause infantile‐onset X‐linked spinal muscular atrophy (XL‐SMA). The mutation identified here and the XL‐SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. Conclusion: UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL‐SMA is discussed. [ABSTRACT FROM AUTHOR]

Objective(s): Amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disorder, is the most common motor neuron disease in European populations. Approximately 10% of ALS cases are familial (FALS) and the other patients are considered as sporadic ALS (SALS). Among many ALS causing genes that have been identified, mutations in SOD1 and C9orf72 are the most common genetic causes of the disease. In Iranian patients, it has been shown that SOD1, as compared to C9orf72, plays a much more prominent role. To date, more than 170 mutations have been reported in SOD1. Genotype/phenotype correlation with respect to either different causative genes or different mutations of a specific gene has not been well established. Materials and Methods: Five exons of SOD1 and flanking intronic sequences of an Iranian FALS proband were screened for mutations by direct sequencing. Also, the clinical features of the proband were described. Results: Heterozygous p.Val48Phe causing mutation was identified in SOD1. Age at onset was 29 years and site of the first presentation was the lower extremity in the proband. Conclusion: The p.Val48Phe causing mutation appears to cause early onset of ALS. [ABSTRACT FROM AUTHOR]

Background: As a disease of motor nervous system (motor neuron disease), amyotrophic lateral sclerosis (ALS) has a great impact on several aspects of quality of life (QoL). Generic questionnaires of QoL do not address all the especial features of ALS and therefore translation and validation of disease specific questionnaires such as Amyotrophic Lateral Sclerosis Assessment Questionnaire 40-item (ALSAQ-40) is necessary for assessment of patients with different languages. The aim of this study was to review the validation of the Persian version of the ALSAQ-40. Methods: Meticulously translated ALSAQ-40 was completed by 21 ALS patients. Internal reliability was evaluated using Cronbach's alpha coefficient and itemtotal correlation was also used to evaluate the correlation of each question with total score. Validity was evaluated through comparison with Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-r) and the 36-Item Short Form Health Survey (SF-36). Results: Cronbach's alpha coeficient was 0.91-0.96 for different scales of the ALSAQ-40. All the 40 questions of the questionnaire had correlation greater than 0.5. Correlation coefficient of all the related scales of the Persian version of ALSAQ-40, SF-36 and ALSFRS-r was greater than 0.59 with P value < 0.001. Conclusion: Measures of the Cronbach's alpha coefficient and item-total correlation demonstrated reliability and consistency of the questionnaire, and correlation coefficients confirmed the validity of different items in the questionnaire. This study showed that the Persian version of the ALSAQ-40 is a reliable and valid questionnaire for the evaluation of QoL in ALS patients with Persian language. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boostani, Olfati, Shamshiri, Salimi, Fatehi, Hedjazi, Fakharian, Ghasemi, Okhovat, Basiri, Haghi Ashtiani, Ansari, Raissi, Khatoonabadi, Sarraf, Movahed, Panahi, Ziaadini, Yazdchi, Bakhtiyari and Nafissi.)

Background: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The approximately 50 known ALS-associated genes do not fully explain its heritability, which suggests the existence of yet unidentified causative genes. We report results of studies aimed at identification of the genetic cause of ALS in a pedigree (three patients) without mutations in the common ALS-causative genes., Methods: Clinical investigations included thorough neurological and non-neurological examinations and testings. Genetic analysis was performed by exome sequencing. Functional studies included identification of altered splicing by PCR and sequencing, and mutated proteins by western blot analysis. Apoptosis in the presence and absence of tunicamycin was assessed in transfected HEK293T cells using an Annexin-PE-7AAD kit in conjunction with flow cytometry., Results: Clinical features are described in detail. Disease progression in the patients of the pedigree was relatively slow and survival was relatively long. An RNF13 mutation was identified as the cause of the recessively inherited ALS in the pedigree. The gene is highly conserved, and its encoded protein (RING finger protein 13) can potentially affect various neurodegenerative-relevant functions, including protein homeostasis. The RNF13 splice site mutation caused expression of two mis-spliced forms of RNF13 mRNA and an aberrant RNF13 protein, and affected apoptosis., Conclusion: RNF13 was identified as a novel causative gene of recessively inherited ALS. The gene affects protein homeostasis, which is one of most important components of the pathology of neurodegeneration. The contribution of RNF13 to the aetiology of another neurodegenerative disease is discussed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)