Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis
Introduction
Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative diseases characterized by slowly progressive spastic gait and lower limb hyperreflexia. Currently, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified [1]. HSPs are classified as pure or complicated forms, based on the absence or presence of additional clinical features, such as dementia, extrapyramidal impairment, cerebellar ataxia, sensory deficit and polyneuropathy. An epidemiological study on 129 subjects showed that most Japanese HSP cases are caused by mutations in SPAST (OMIM *604277) (SPG4 OMIM #182601) [2], in line with a previous review from Europe [1].
SPG10 (OMIM #604187) is a rare form of autosomal dominant HSP caused by mutations of the kinesin family member 5A (KIF5A) gene (OMIM *602821). KIF5A protein is a part of a multi-subunit complex that acts as a plus-end-directed microtubule motor involved in anterograde axonal transport of membranous organelles, including mitochondria. SPG10 is generally characterized by early-onset pure HSP [3]. Phenotypic variations have also been reported, including a broad range of age-at-onset (8–50s), amyotrophy of hand muscles, parkinsonism and axonal neuropathy [4], [5].
Fasciculation is one of features of active denervation and can be seen in various peripheral nerve disorders. Especially, it has been considered the hallmark of amyotrophic lateral sclerosis. Detection of fasciculation potentials by electromyography is emphasized in the Awaji Criteria [6]. It has been postulated that dysfunction of Na+-K+ pump by mitochondrial impairment would cause fasciculations in ALS [7], [8]. Dysarthria is sometimes observed in HSP when accompanied by ataxia [9], but it can also be seen as pseudobulbar paralysis (isolated dysarthria) in a small number of HSP patients [10], [11], [12], [13]. Investigation of HSP genes, especially, SPG11, demonstrated a broad involvement of upper and/or lower neurons, leading to clinical diagnosis of juvenile ALS [14] or HSP [15] or Charcot-Marie-Tooth disease [16]. Further accumulation of genotype-phenotype correlations in HSP would further contribute to better understanding of pathomechanism of motor neuron degeneration. This report describes the first known Asian family with a KIF5A mutation, in which both upper and lower motor neuron involvement and fasciculations are observed, thus mimicking ALS. The mutation of KIF5A might cause the generation of fasciculation through impaired axonal transport of mitochondria, which is relevant to the pathophysiology of ALS in general.
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Clinical background and investigation
A 3 generation family was identified (Fig. 1-A), in which 2 family members showed walking impairment in their 60s. The proband was a 66 year-old woman, who presented at Tokushima University Hospital, Japan, reporting a 6-year history of leg stiffness and dysarthria (III-4). She also reported dysuria-related symptoms in the past few years. She was born to the fourth degree consanguineous parents. At physical examination, she had slow laborious speech and normal jaw jerk reflex. Despite
Electrophysiological investigation
Nerve conduction studies revealed mild sensorimotor polyneuropathy in the 2 affected members (III-2 and III-3) in Table 2. Electromyography showed abundant fasciculations in the first dorsal interosseous and rectus abdominis muscles. Prominent chronic denervation changes were also observed in cranial, cervical and lumbar regions, including frequent appearance of polyphasic motor unit action potentials and reduced recruitment of motor units (Fig. 1C); however, the above findings did not fulfill
Genetic investigation
Whole exome sequencing was performed in the proband as described in the Supplementary data Table 1. Combination of filtering sequence variants and bioinformatic analysis demonstrated a variant in KIF5A (c.484C > T [p.Arg162Trp], NM_004984). No pathological nucleotide variation was observed in the other currently known HSP genes. The variant was validated via Sanger sequencing (Fig. 1-B). The PCR-RFLP analysis demonstrated a complete co-segregation of the variant with the disease and the presence
Discussion
This report describes the first known Asian SPG10 family characterized by late-onset, dysarthria and fasciculations. These distinctive features indicate that the lesion is not restricted to upper motor neurons, but extends to lower motor neurons. Notably, the presence of fasciculations has never been reported in SPG10. It may be difficult to differentiate sporadic SPG10 from slowly progressive ALS. The missense mutation c.484C > T (p.Arg162Trp), discovered in this study, has been reported in a
Conflict of interests
The authors declare no conflict of interest.
Acknowledgements
We thank the patient and family members for taking part in this study. We also thank Michela Renna (M.A.) for her language assistance, and Ms. Akemi Takahashi, Mariko Hasegawa and Akie Tanabe for their technical support. We are extremely grateful to the Support Center for Advanced Medical Sciences, Tokushima University School of Medicine, for the use of their facilities to prepare the manuscript, as well as the Genetic Bank of the Laboratorio di Neurogenetica, Centro Europeo del Cervello -
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Strategy for genetic analysis in hereditary neuropathy
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Dysarthria in hereditary spastic paraplegia type 4
2023, ClinicsCitation Excerpt :Studies with other neurogenetic conditions such as Huntington's disease and ataxias have shown abnormalities in the acoustic analysis of speech even in preclinical stages of these diseases, highlighting its potential as a disease biomarker.13–17 Although dysarthria has been described in the case series of SPG4 patients7,18–20 as a negligible complaint, these previous studies performed a subjective assessment of speech (through a questionnaire) by physicians, without a completed speech assessment (acoustic and auditory perceptual analysis). Therefore, the present study aimed to perform a detailed characterization of the main aspects of speech in subjects with SPG4, which can contribute to a better understanding of speech abnormalities in this disease, and generate relevant information that can assist in improving the care and quality of life of these individuals.
An emerging role for mitochondrial dynamics in schizophrenia
2017, Schizophrenia ResearchCitation Excerpt :Additionally, a germline mosaic mutation in KIF5C was identified in a family in which all members carrying the mutation presented with impaired cortical development and microcephaly (Poirier et al., 2013). The neuron-specific kinesin heavy chain KIF5A is also critical, since missense mutations in this gene cause autosomal dominant spastic paraplegia type 10, a disorder that can present with a variety of both central and peripheral neurological problems, including cognitive decline, peripheral neuropathy, distal upper limb amyotrophy, as well as ALS-like symptoms (Goizet et al., 2009; Fink, 2013; Jerath et al., 2015; Lopez et al., 2015; Kaji et al., 2016). Additionally, a de novo mutation in KIF5A was described in a patient presenting with progressive neonatal degeneration of myelin and myoclonic seizures (Rydzanicz et al., 2016).
Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis
2023, Human Molecular GeneticsInsights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview
2021, Frontiers in Molecular Biosciences
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These authors contributed equally.