<i>KIF1A</i>‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

Nemani, Tarishi; Steel, Dora; Kaliakatsos, Marios; DeVile, Catherine; Ververi, Athina; Scott, Richard; Getov, Spas; Sudhakar, Sniya; Male, Alison; Mankad, Kshitij; Muntoni, Francesco; Reilly, Mary M.; Kurian, Manju A.; Carr, Lucinda; Munot, Pinki

doi:10.1111/jns.12368

Cited by 48 publications

(48 citation statements)

References 18 publications

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“…We noticed that all novel mutations acquired de novo, while described mutations were mostly found in the subgroup of 'pure' familial cases, thus the сase 30-3 is the only one with the 'pure' phenotype and a well-known mutation de novo. This mutation p.Ser69Leu was found also in the family 30-4 and was reported before in several families of different ethnicity with pure phenotypes [10,13,16,19,20], notably, only one patient with this mutation had non-severe additional feature: learning difficulties [20]. Evidently, the mutation may be world-wide spread.…”

Section: Discussionsupporting

confidence: 66%

“…All mutations were in exons 2-11 encoding KIF1A motor domain. Five mutations were reported earlier, where the mutation с.206C > T (p.Ser69Leu) that was found in a Russian (30-1) and in a Dargin families has been already reported in several families of a different origin [10,13,16,19,20].…”

Section: Molecular Characteristicsmentioning

confidence: 86%

“…In addition, one of the first cohorts with de novo mutations in KIF1A was a representative international group (Canada, USA, Netherlands and Finland): 14 patients (monozygotic twin pair among them) age 2.5-24 years, all had de novo mutations in KIF1A [8]. Recently, another international group was described, where 9 out of 10 patients (one of them also was monozygotic twin pair) had KIF1A mutations acquired de novo and only one was AD familial case [20]. Altogether sporadic SPG30 cases contribute significantly into AD SPG30 world pool.…”

Section: Discussionmentioning

confidence: 99%

“…Other KIF1A-related phenotypes with AD inheritance exist. Thus, several cases with phenotype of PEHO syndrome (Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy) and with mutated KIF1A were reported [20,34,35] (where 'classic' PEHO is severe AR disorder produced by ZNHIT3 mutations). Another case with a novel KIF1A mutation acquired de novo is describing a girl with typical Rett syndrome that was previously negatively tested for mutations in 'Rett genes' MeCP2, CDKL5, and FOXG1 [36].…”

Section: Discussionmentioning

confidence: 99%

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KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

et al. 2020

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Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel 'spastic paraplegias' with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole-exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others. Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

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Section: Discussionsupporting

confidence: 66%

Section: Molecular Characteristicsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

et al. 2020

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“…A number of inherited variants and de novo mutations have been identified in human KIF1A from clinical studies. These mutations have been linked to neurodevelopmental and neurodegenerative disorders including spastic paraplegias, encephalopathies, intellectual disability, autism, and sensory neuropathies (3,(10)(11)(12)(13)(14)(15). For KIF1A-associated neurological disorder (KAND), the mutations span the entirety of the KIF1A protein sequence; the majority are located within the kinesin motor domain (aa 1-369) and…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms

Budaitis

Jariwala

Rao

et al. 2020

Preprint

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The kinesin-3 motor KIF1A functions in neurons where its fast and superprocessive motility is thought to be critical for long-distance transport. However, little is known about the force-generating properties of kinesin-3 motors. Using optical tweezers, we demonstrate that KIF1A and its C. elegans homolog UNC-104 undergo force-dependent detachments at ~3 pN and then rapidly reattach to the microtubule to resume motion, resulting in a sawtooth pattern of clustered force generation events that is unique among the kinesin superfamily. Whereas UNC-104 motors stall before detaching, KIF1A motors do not. To examine the mechanism of KIF1A force generation, we introduced mutations linked to human neurodevelopmental disorders, V8M and Y89D, based on their location in structural elements required for force generation in kinesin-1. Molecular dynamics simulations predict that the V8M and Y89D mutations impair docking of the N-terminal (β9) or C-terminal (β10) portions of the neck linker, respectively, to the KIF1A motor domain. Indeed, both mutations dramatically impair force generation of KIF1A but not the motor's ability to rapidly reattach to the microtubule track. Homodimeric and heterodimeric mutant motors also display decreased velocities, run lengths, and landing rates and homodimeric Y89D motors exhibit a higher frequency of non-productive, diffusive events along the microtubule. In cells, cargo transport by the mutant motors is delayed. Our work demonstrates the importance of the neck linker in the force generation of kinesin-3 motors and advances our understanding of how mutations in the kinesin motor domain can manifest in disease.

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Long‐term clinical observation of patients with heterozygous KIF1A variants

Kawashima,

Kodama,

Okubo

et al. 2024

American J of Med Genetics Pt A

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KIF1A‐related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long‐term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long‐term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow‐up period was 30 years (4–44 years). This long‐term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age‐related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age‐related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long‐term follow‐up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype–genotype correlation.

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KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

Cited by 48 publications

References 18 publications

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms

Long‐term clinical observation of patients with heterozygous KIF1A variants

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