Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report

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Abstract

Background

Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms.

Case presentation

We report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.

Conclusions

We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.

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Most cited references 9

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Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha.

Clifford H. Shin, Jaewon Ko, Juli Valtschanoff … (2003)

Liprin-alpha/SYD-2 is a multimodular scaffolding protein important for presynaptic differentiation and postsynaptic targeting of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid glutamate receptors. However, the molecular mechanisms underlying these functions remain largely unknown. Here we report that liprin-alpha interacts with the neuron-specific kinesin motor KIF1A. KIF1A colocalizes with liprin-alpha in various subcellular regions of neurons. KIF1A coaccumulates with liprin-alpha in ligated sciatic nerves. KIF1A cofractionates and coimmunopreciptates with liprin-alpha and various liprin-alpha-associated membrane, signaling, and scaffolding proteins including alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors, GRIP/ABP, RIM, GIT1, and beta PIX. These results suggest that liprin-alpha functions as a KIF1A receptor, linking KIF1A to various liprin-alpha-associated proteins for their transport in neurons.

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Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.

Simon Edvardson, Talya Dor, Orly Elpeleg … (2011)

Whole exome sequencing has become a pivotal methodology for rapid and cost-effective detection of pathogenic variations in Mendelian disorders. A major challenge of this approach is determining the causative mutation from a substantial number of bystander variations that do not play any role in the disease etiology. Current strategies to analyze variations have mainly relied on genetic and functional arguments such as mode of inheritance, conservation, and loss of function prediction. Here, we demonstrate that disease-network analysis provides an additional layer of information to stratify variations even in the presence of incomplete sequencing coverage, a known limitation of exome sequencing. We studied a case of Hereditary Spastic Paraparesis (HSP) in a single inbred Palestinian family. HSP is a group of neuropathological disorders that are characterized by abnormal gait and spasticity of the lower limbs. Forty-five loci have been associated with HSP and lesions in 20 genes have been documented to induce the disorder. We used whole exome sequencing and homozygosity mapping to create a list of possible candidates. After exhausting the genetic and functional arguments, we stratified the remaining candidates according to their similarity to the previously known disease genes. Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation. Our strategy can be useful for a large class of disorders that are characterized by locus heterogeneity, particularly when studying disorders in single families.

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De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.

Chihiro Ohba, Kazuhiro Haginoya, Hitoshi Osaka … (2015)

Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.

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Author and article information

Contributors

Carlotta Spagnoli:

ORCID: http://orcid.org/0000-0002-1828-4035

+39-0522-296033 , carlotta.spagnoli@gmail.com

Susanna Rizzi: susanna.rizzi@ausl.re.it

Grazia Gabriella Salerno: graziagabriella.salerno@ausl.re.it

Daniele Frattini: daniele.frattini@ausl.re.it

Carlo Fusco: carlo.fusco@ausl.re.it

Journal

Journal ID (nlm-ta): Ital J Pediatr

Journal ID (iso-abbrev): Ital J Pediatr

Title: Italian Journal of Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1824-7288

Publication date (Electronic): 3 December 2019

Publication date PMC-release: 3 December 2019

Publication date Collection: 2019

Volume: 45

Electronic Location Identifier: 155

Affiliations

[1 ]Neuropsichiatria Infantile, Presidio Ospedaliero Provinciale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

[2 ]SC Neuropsichiatria Infantile Laboratorio di Neurofisiologia dell’Età Evolutiva. Presidio Ospedaliero Provinciale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

Author information

Carlotta Spagnoli http://orcid.org/0000-0002-1828-4035

Article

Publisher ID: 752

DOI: 10.1186/s13052-019-0752-5

PMC ID: 6892221

PubMed ID: 31796088

SO-VID: ba28c4cd-e70a-4dfb-99cc-75a00777323a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 August 2019

Date accepted : 21 November 2019

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ScienceOpen disciplines: Pediatrics

Keywords: cerebellar atrophy,hereditary spastic paraplegia,spg30,kif1a

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ScienceOpen disciplines: Pediatrics

Keywords: cerebellar atrophy, hereditary spastic paraplegia, spg30, kif1a

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Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report

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Abstract

Background

Case presentation

Conclusions

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Estudio del peso al nacer

Most cited references 9

Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha.

Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.

De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.

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Cited by 5

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