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KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.

ABSTRACT: Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin "motor." These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633-637.

SUBMITTER: Duis J

PROVIDER: S-EPMC5042851 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.

Duis Jessica J Dean Shannon S Applegate Carolyn C Harper Amy A Xiao Rui R He Weimin W Dollar James D JD Sun Lisa R LR Waberski Marta Biderman MB Crawford Thomas O TO Hamosh Ada A Stafstrom Carl E CE

Annals of neurology 20160824 4

Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnor ...[more]

PMID: 27463701

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Project description:OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

Project description:Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

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KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.

Publications

KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.

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