Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10

Goizet, Cyril; Boukhris, A.; Mundwiller, Emeline; Tallaksen, Chantal; Forlani, Sylvie; Toutain, Annick; Carrière, Nathalie; Paquis, V.; Depienne, Christel; Dürr, Alexandra; Stevanin, Giovanni; Brice, Alexis

doi:10.1002/humu.20920

Cited by 117 publications

(124 citation statements)

References 30 publications

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“…Mutations in KIF5A have been associated with both HSP (SPG10) and CMT2 8. Previous reports of autosomal dominant HSP caused by KIF5A mutations have shown a clinical variability within and between families, but complicated cases are more frequent, especially in some populations 9. In addition to spasticity, some patients have peripheral neuropathy manifesting with muscle atrophy and weakness, and sensory loss in extremities 8.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss

Guinto

Diarra

Diallo

et al. 2017

Ann Clin Transl Neurol

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Hereditary spastic paraplegias (HSPs) are well‐characterized disorders but rarely reported in Africa. We evaluated a Malian family in which three individuals had HSP and distal muscle atrophy and sensory loss. HSP panel testing identified a novel heterozygous missense mutation in KIF5A (c.1086G>C, p.Lys362Asn) that segregated with the disease (SPG10). Lys362 is highly conserved across species and Lys362Asn is predicted to be damaging. This study shows that HSPs are present in sub‐Saharan Africa, although likely underdiagnosed. Increasing efficiency and decreasing costs of DNA sequencing will make it more feasible to diagnose HSPs in developing countries.

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Section: Discussionmentioning

confidence: 99%

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss

Guinto

Diarra

Diallo

et al. 2017

Ann Clin Transl Neurol

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“…Mutations in the ATL1 and REEP1 gene had previously been excluded by direct sequencing and multiplex ligationdependent probe amplification (MLPA) at the following frequencies: SPG3A sequencing in 55% of cases, SPG3A MLPA in 85% and SPG31 (sequencing and MLPA) in 84% of cases. 7,9,[12][13][14] The HSP phenotype was pure in 125 (57%) and complicated in 95 (43%) patients. Informed consent was obtained in all cases.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

et al. 2010

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The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutationnegative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by multiplex ligation-dependent probe amplification assay. We could not identify potentially disease-causing mutations in our patients either by mutation scanning or by gene dosage analysis, as for the latter specific positive controls are not available to date. As our sample represents ADHSP patients for whom SPAST mutations and almost in all cases ATL1 and REEP1 mutations had been excluded, we consider SLC33A1 gene mutations as being very rare in a European ADHSP cohort, if present at all. To date, as SPG42 has still not been identified in a second, unrelated family, systematic genetic testing for SLC33A1 mutations is not recommended.

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“…11 The phenotype of KIF1A knockout mice includes motor and sensory disturbances, a reduction in the density of synaptic vesicles in nerve terminals, and the accumulation of clear vesicles in nerve cell bodies. 12 In addition, mutations in other kinesinencoding genes, such as KIF5A 13,14 and KIF1b (MIM 605995), have been implicated in motor neuron diseases, and intracellular trafficking is a well known mechanism causing the degeneration of the long axonal tracts in such diseases. 15 In particular, mutations in the KIF5A gene leading to autosomal dominant SPG10 13,14 have been shown to reduce the microtubule affinity and/or gliding velocity of kinesin.…”

Section: Rearrangement Detectionmentioning

confidence: 99%

“…Age at onset varied from 2 to 39 years old (mean, 13.6 ± 11.4 years) but very early ages at onset were exclusively observed in the family published by Erlich et al 4 The coexistence of pure and complicated profiles within one form of HSP is well known in SPG4, SPG5, SPG7, SPG10, SPG27 and SPG31 patients. 13,[16][17][18][19][20][21] Several recently discovered ARHSP forms were initially thought to be pure ARHSP without any cerebellar signs or cerebellar atrophy on brain imaging, a view that was subsequently revised after more families were identified. This was the case for SPG7 (paraplegin) and SPG5 (CYB7B1).…”

Section: Spg30 Phenotypementioning

confidence: 99%

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

et al. 2012

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The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotypegenotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. INTRODUCTIONThe hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. 1 The mode of inheritance may be autosomal dominant, autosomal recessive (ARHSP) or X-linked. More than 48 different loci (SPGn) have been mapped so far, and 23 responsible genes identified. The corresponding proteins are often involved in intracellular trafficking or mitochondrial functions. 2,3 Clinically, one can distinguish between pure and complicated forms of HSP. 1,2 Pure forms consist of isolated pyramidal signs, such as spasticity, abnormal reflexes (brisk reflexes and Babinski sign) and motor deficit, often associated with sphincter disturbances and deep sensory loss. In the complicated forms of HSP the disease is variably associated with numerous combinations of neurological and extraneurological signs, such as cerebellar ataxia, dysarthria, mental retardation, peripheral neuropathy, optic atrophy, retinitis pigmentosa and/or hearing loss, which may be accompanied by abnormal brain MRI (atrophy of the cortex, cerebellum or corpus callosum, white matter abnormalities, etc).Mutations in the KIF1A gene (MIM 601255) were very recently described in two different clinically and genetically heterogeneous groups of neurodegenerative diseases. 4,5 In hereditary sensory and autonomic neuropathy (HSAN), all patients from four families with different origins shared a common hom...

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Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10

Cited by 117 publications

References 30 publications

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

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