Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review

Vecchia, Stefania Della; Tessa, Alessandra; Dosi, Claudia; Baldacci, Jacopo; Pasquariello, Rosa; Antenora, Antonella; Astrea, Guja; Bassi, Maria Teresa; Battini, Roberta; Casali, Carlo; Cioffi, Ettore; Conti, Greta; Michele, G. De; Ferrari, Anna Rita; Filla, Alessandro; Fusco, Carlo; Gallone, Salvatore; Germiniasi, Chiara; Guerrini, Renzo; Haggiag, Shalom; Lopergolo, Diego; Martinuzzi, Andrea; Melani, Federico; Mignarri, Andrea; Panzeri, Elena; Pini, Antonella; Pinto, Anna Maria; Pochiero, Francesca; Primiano, Guido; Procopio, Elena; Renieri, Alessandra; Romaniello, Romina; Sancricca, Cristina; Servidei, Serenella; Spagnoli, Carlotta; Ticci, Chiara; Rubegni, Anna; Santorelli, Filippo M.

doi:10.1007/s00415-021-10792-3

Cited by 14 publications

(13 citation statements)

References 67 publications

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“…Comparisons of our patients with the available literature data are shown in Tables 3-5. KIF1A-related disorders probably remain underdiagnosed because of the dominant relation with HSP and less known coincidence with a multisystem and progressive course with upper motor neuron dysfunction and extrapyramidal signs with neuropathy [24][25][26][27][28][29][30][31].…”

Section: Molecular Characteristics and Clinical Correlation Of Polish...mentioning

confidence: 99%

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

Paprocka

Jezela‐Stanek²,

Śmigiel

et al. 2023

Genes

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Background: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. Materials and Methods: The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. Results: Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. Conclusions: The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.

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Section: Molecular Characteristics and Clinical Correlation Of Polish...mentioning

confidence: 99%

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

Paprocka

Jezela‐Stanek²,

Śmigiel

et al. 2023

Genes

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“…Interestingly the first Asian (Japanese) case with a KIF5A mutation was identified only recently and broadened the clinical and electrophysiological phenotypic spectrum of KIF5A (Kaji et al, 2016). Remarkable examples also include the AR HSP forms that were first identified in highly consanguineous populations such as the KIF1A variants which were first identified in African and Palestinian families, and subsequently reported in a multitude of families from all over the world (Vecchia et al, 2021). On many occasions, genes which were the solely identified in some ethnic groups turned out later to be quite frequent causes of AR HSP; for example SPG11 and SPG15 (Boukhris et al, 2009).…”

Section: Genetic Diagnosis: Approaches Yield and Gap In Genetic Etiologymentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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“…Considering the shared clinical manifestations between these diseases and ALS, the ALS patients with variants in KIF1A were carefully examined to rule out a misdiagnosis. Furthermore, the variants identified in our ALS cohort have not been reported in SPG30, HSAN2, or MRD9, except for the variant p.R370C, which has been reported in a patient with complex SPG [ 42 ]. The phenomenon of different phenotypes caused by the same variant in the KIF1A gene has also been described previously [ 27 ].…”

Section: Resultsmentioning

confidence: 87%

“…We noted several interesting genotype–phenotype correlation phenomena. For example, a same variant, R370C [ 42 ] or P1587L, is associated with different clinical manifestations. We speculate that the different phenotypes in these patients with P1587L might be caused by the difference in disease duration.…”

Section: Discussionmentioning

confidence: 99%

Association of variants in the KIF1A gene with amyotrophic lateral sclerosis

Liao

Yuan

Liu

et al. 2022

Transl Neurodegener

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Background Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30. Methods Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS. Results We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor. Conclusions Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.

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Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review

Cited by 14 publications

References 67 publications

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Association of variants in the KIF1A gene with amyotrophic lateral sclerosis

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