The neurodevelopmental spectrum of synaptic vesicle cycling disorders

John, Abinayah; Ng‐Cordell, Elise; Hanna, Nancy; Brkić, Diandra; Baker, Kate

doi:10.1111/jnc.15135

Cited by 43 publications

(36 citation statements)

References 135 publications

(140 reference statements)

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“…Irrespective of seizure burden and independent from the pathogenic gene variation, the overall development was described as normal in 95% of patients and affected relatives. Behavioral issues were not reported, which is in line with previous reports [ 30 ]. Behavioral comorbidities were not assessed systematically.…”

Section: Discussionsupporting

confidence: 92%

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

et al. 2020

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Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

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Section: Discussionsupporting

confidence: 92%

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

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 (reviewed in Boyle et al, 2020 ; Gabrych et al, 2019 ; Guo et al, 2020 ; John et al, 2020 ; Nicita et al, 2020 ; Van Beusichem et al, 2020 ). In KIF1A-associated neurological disorder (KAND), the mutations span the entirety of the KIF1A protein sequence ( Boyle et al, 2020 ).…”

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. 2021

Journal of Cell Biology

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The kinesin-3 motor KIF1A functions in neurons, where its fast and superprocessive motility facilitates long-distance transport, but little is known about its force-generating properties. Using optical tweezers, we demonstrate that KIF1A stalls at an opposing load of ~3 pN but more frequently detaches at lower forces. KIF1A rapidly reattaches to the microtubule to resume motion due to its class-specific K-loop, resulting in a unique clustering of force generation events. To test the importance of neck linker docking in KIF1A force generation, we introduced mutations linked to human neurodevelopmental disorders. Molecular dynamics simulations predict that V8M and Y89D mutations impair neck linker docking. Indeed, both mutations dramatically reduce the force generation of KIF1A but not the motor’s ability to rapidly reattach to the microtubule. Although both mutations relieve autoinhibition of the full-length motor, the mutant motors display decreased velocities, run lengths, and landing rates and delayed cargo transport in cells. These results advance our understanding of how mutations in KIF1A can manifest in disease.

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“…The orchestrated release of neuromodulators is essential for proper development and function of the nervous system. Variants in genes encoding for proteins involved in synaptic vesicular trafficking are increasingly recognized as a cause of neurodevelopmental disorders 8 . The importance of DCV trafficking in brain development is underlined by the fact that two protein members of the EARP complex, VPS‐51 and VPS‐53, have been associated with neurodevelopmental disorders 9‐12 .…”

Section: Introductionmentioning

confidence: 99%

A homozygous truncating variant in CCDC186 in an individual with epileptic encephalopathy

Brugger

Becker-Dettling

Brunet

et al. 2020

Ann Clin Transl Neurol

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Coiled‐Coil Domain Containing Protein 186 (CCDC186) is hypothesized to play an important role in the biogenesis of dense‐core vesicles in neurons and endocrine cells. Biallelic loss‐of‐function variants in the encoding gene CCDC186 have been suggested as a candidate gene for a neurodevelopmental phenotype, but only one patient has been described so far. We report a second patient with a CCDC186‐associated phenotype presenting with developmental delay, epileptic encephalopathy, and failure to thrive. Exome sequencing identified a homozygous loss‐of‐function variant in CCDC186 (NM_018017.2) c.767C> G; p.(Ser256Ter) thus providing further evidence to support CCDC186 as a new disease gene for an autosomal recessive neurodevelopmental disorder.

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The neurodevelopmental spectrum of synaptic vesicle cycling disorders

Cited by 43 publications

References 135 publications

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

Pathogenic mutations in the kinesin-3 motor KIF1A diminish force generation and movement through allosteric mechanisms

A homozygous truncating variant in CCDC186 in an individual with epileptic encephalopathy

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