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Case Reports
. 2023 Oct 15;62(20):3047-3051.
doi: 10.2169/internalmedicine.1184-22. Epub 2023 Mar 8.

Long-term Observation of a Japanese Patient with a Multiple-system Neurodegenerative Disorder with a Uniallelic de novo Missense Variant in KIF1A

Katsuya Nakamura  1   2 , Tsuneaki Yoshinaga  1   2 , Minori Kodaira  2 , Emiko Kise  1   3 , Tomoki Kosho  1   4 , Yoshiki Sekijima  2
Affiliations
Case Reports

Long-term Observation of a Japanese Patient with a Multiple-system Neurodegenerative Disorder with a Uniallelic de novo Missense Variant in KIF1A

Katsuya Nakamura et al. Intern Med. .

Abstract

We encountered a 37-year-old Japanese man with KIF1A-associated neurological disorder (KAND) who exhibited motor developmental delay, intellectual disability, and slowly progressive cerebellar ataxia, hypotonia, and optic neuropathy. Pyramidal tract signs were evident late in this case. At 30 years old, the patient developed a neurogenic bladder. A molecular diagnosis revealed a uniallelic missense de novo variant (p.L278P) of KIF1A. Serial neuroradiological studies revealed atrophy of the cerebellum at an early age, and cerebral hemisphere atrophy progressed slowly over a 22-year observation period. Our study suggests that the primary etiology of KAND may be acquired, long-standing neurodegeneration rather than congenital hypoplasia.

Keywords: KAND; KIF1A; ataxia; intellectual disability; multiple-system neurodegeneration.

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Conflict of interest statement

The authors state that they have no Conflict of Interest (COI).

Figures

Figure 1.
Figure 1.
(A) Pedigree of the family. ■/●=affected individuals; /=deceased; →=proband. (B) Direct nucleotide sequencing of the PCR-amplified DNA of the KIF1A gene. Patient II-2 was heterozygous for this variant, whereas his parents were wild types.
Figure 2.
Figure 2.
Serial brain computed tomography (CT) and magnetic resonance imaging of patient II-2. CT at seven years old showed cerebellar atrophy (A), which progressed sequentially (B-D). In contrast, the cerebral cortex was normal on brain CT at 12 years old (F, K), but atrophy slowly progressed from 18 years old (G-J, L-O).
Figure 3.
Figure 3.
Magnetic resonance imaging (MRI) of the brain and spinal cord at 34 years old. Atrophy of the optic nerve (A) and posterior part of the corpus callosum (B) was evident. Cervical and thoracic MRI showed spinal cord atrophy (C, D).
Figure 4.
Figure 4.
Ribbon-stick diagram showing the structure of the motor domain of KIF1A. Wild type (A) and the p.L278P variant (B) of the motor domain. L278 is located in the fourth alpha-helix (red) in the microtubule-binding properties of the motor domain of KIF1A. Three-dimensional structural prediction indicated that the p.L278P variant would alter the alpha-helix structure (B).
Figure 5.
Figure 5.
Homologs of the KIF1A gene at the L278 residues conserved across multiple species.
See this image and copyright information in PMC

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