A Novel &lt;i&gt;de novo KIF1A&lt;/i&gt; Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia

Kurihara, Masanori; Ishiura, Hiroyuki; Bannai, Taro; Mitsui, Jun; Yoshimura, Junichi; Morishita, Shinichi; Hayashi, Toshihiro; Shimizu, Jun; Toda, Tatsushi; Tsuji, Shoji

doi:10.2169/internalmedicine.3661-19

Cited by 16 publications

(14 citation statements)

References 22 publications

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“…Recently reported novel KIF1A ‐associated phenotypes include behavioral traits such as autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD) (Kurihara et al, 2020; Tomaselli et al, 2017). One local case (BG4) harboring the same variant as reported by Tomaselli et al (p.Arg13His) also presented with ADHD.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

et al. 2020

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KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic inframe deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of

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Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

et al. 2020

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“…A novel feature of KAND is the large number of disease-causing variants, predominantly missense variants within the motor domain of the protein. In the existing literature, 71 variants have been described to date, and here we describe 48 additional variants 2-34,37-39,41,43-45 . More than 30% of individuals with KAND have private variants, and there are likely many more variants that remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

“…More than 30% of individuals with KAND have private variants, and there are likely many more variants that remain to be identified. KAND has a broad phenotypic spectrum, which can include spasticity, neurodevelopmental delay, intellectual disability, autism, microcephaly, progressive spastic paraplegia, autonomic and peripheral neuropathy, optic nerve atrophy, cerebral and cerebellar atrophy, and seizures 2-34,37-39,41,43-45 .…”

Section: Introductionmentioning

confidence: 99%

Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A Associated Neurological Disorder

Boyle

Rao

Kaur

et al. 2020

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KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified group of rare neurodegenerative conditions caused by variants in KIF1A, a member of the kinesin-3 family of microtubule (MT) motor proteins. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in regions involved with ATP and MT-binding: the P-loop, switch I, and switch II. For a subset of identified variants, we generated recombinant mutant proteins which we used to assess transport in vivo by assessing neurite tip accumulation, and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all patient variants result in defects in transport, and describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The molecular rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a new way to describe KAND subtypes to better capture the breadth of disease severity.

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“…Our 4 sporadic cases may add to this variability. mutations acquired de novo [6,9,11,24,[26][27][28][29][30][31][32][33] several groups of sporadic cases were reported: 4 Dutch patients [25], 6 patients age 1.5-16 years from USA [7], 5 cases among 62 unrelated patients with cerebral atrophy of unestablished nature [9]. 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].…”

Section: Discussionmentioning

confidence: 99%

“…In the Finnish family ADHD with learning difficulties in an affected boy was considered to be independent of clinical phenotype since his father had ‘pure’ SPG30 [ 13 ]. However newly reported cases of ASD and/or ADHD in SPG30 [ 25 – 27 ] permit to regard them as possible parts of SPG30 phenotypes. Our case 30–9 may be in line with the idea though special examination of the patient could not be performed.…”

Section: Discussionmentioning

confidence: 99%

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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A Novel <i>de novo KIF1A</i> Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia

Cited by 16 publications

References 22 publications

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A Associated Neurological Disorder

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

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