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The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD ¼ 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.

Despite the remarkable burden of dysphagia, appropriate multidisciplinary management is lacking in Iran and patients are often deprived of effective treatments. Obtaining a full understanding of knowledge, attitude and practice (KAP) of healthcare providers is necessary to determine the gaps in improvement of the quality of care for dysphagic patients. A questionnaire was designed covering demographic information and the parameters of KAP. Face and content validity were determined. Test-retest reliability confirmed that the questionnaire scores are stable over time (r = 0.77, p value < 0.01). Participants were healthcare providers employed in university-affiliated hospitals in three major cities of Iran; Tehran, Shiraz and Mashhad. In total, 312 healthcare professionals completed our survey. The majority (96.8%) were familiar with the term "dysphagia or swallowing disorders". Most of the participants believed their profession (88.5%), as well as other disciplines (92.3%) can play an important role in the management of dysphagia; and this problem should be recognized in a multidisciplinary manner (96.2%). Also, 60.9% had encountered a patient with dysphagia. 52.2% had used at least one assessment method, while 49.9% had applied at least one treatment method. However, very few participants were familiar with a standard test for screening and assessment of dysphagia (11.9%). 74.7% were willing to participate in a workshop on dysphagia. As the main pitfalls of care lie in diagnosis and treatment expertise, the policy of hospitals should prioritize educating and updating the skills of healthcare professionals, encourage multidisciplinary teamwork, establishing clear guidelines and facilitate access to advanced tools.

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