Skip to main content
Journal cover image

De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.

Publication ,  Journal Article
Esmaeeli Nieh, S; Madou, MRZ; Sirajuddin, M; Fregeau, B; McKnight, D; Lexa, K; Strober, J; Spaeth, C; Hallinan, BE; Smaoui, N; Pappas, JG ...
Published in: Ann Clin Transl Neurol
June 2015

OBJECTIVE: To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children. METHODS: Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function. RESULTS: All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay. INTERPRETATION: De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Ann Clin Transl Neurol

DOI

ISSN

2328-9503

Publication Date

June 2015

Volume

2

Issue

6

Start / End Page

623 / 635

Location

United States

Related Subject Headings

  • 5203 Clinical and health psychology
  • 3209 Neurosciences
  • 1109 Neurosciences
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., … Sherr, E. H. (2015). De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann Clin Transl Neurol, 2(6), 623–635. https://doi.org/10.1002/acn3.198
Esmaeeli Nieh, Sahar, Maura R. Z. Madou, Minhajuddin Sirajuddin, Brieana Fregeau, Dianalee McKnight, Katrina Lexa, Jonathan Strober, et al. “De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.Ann Clin Transl Neurol 2, no. 6 (June 2015): 623–35. https://doi.org/10.1002/acn3.198.
Esmaeeli Nieh S, Madou MRZ, Sirajuddin M, Fregeau B, McKnight D, Lexa K, et al. De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann Clin Transl Neurol. 2015 Jun;2(6):623–35.
Esmaeeli Nieh, Sahar, et al. “De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.Ann Clin Transl Neurol, vol. 2, no. 6, June 2015, pp. 623–35. Pubmed, doi:10.1002/acn3.198.
Esmaeeli Nieh S, Madou MRZ, Sirajuddin M, Fregeau B, McKnight D, Lexa K, Strober J, Spaeth C, Hallinan BE, Smaoui N, Pappas JG, Burrow TA, McDonald MT, Latibashvili M, Leshinsky-Silver E, Lev D, Blumkin L, Vale RD, Barkovich AJ, Sherr EH. De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann Clin Transl Neurol. 2015 Jun;2(6):623–635.
Journal cover image

Published In

Ann Clin Transl Neurol

DOI

ISSN

2328-9503

Publication Date

June 2015

Volume

2

Issue

6

Start / End Page

623 / 635

Location

United States

Related Subject Headings

  • 5203 Clinical and health psychology
  • 3209 Neurosciences
  • 1109 Neurosciences
  • 1103 Clinical Sciences