Mutation analysis of the paraplegin gene (
            <i>SPG7</i>
            ) in patients with hereditary spastic paraplegia

Elleuch, N.; Depienne, Christel; Benomar, Ali; Hernandez, Angel; Ferrer, Xavier; Fontaine, Bertrand; Grid, Djamel; Tallaksen, Chantal; Zemmouri, R; Stevanin, Giovanni; Dürr, Alexandra; Brice, Alexis

doi:10.1212/01.wnl.0000201185.91110.15

Cited by 96 publications

(121 citation statements)

References 18 publications

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“…This was the case for SPG7 (paraplegin) and SPG5 (CYB7B1). 16,17,22,23 In terms of disease progression, SPG30 differs from other ARHSPs, such as SPG11, 24 in having a less severe evolution, as all affected members were still able to walk after disease durations of between 9 and 22 years even if maximal walking distance was reduced in all patients.…”

Section: Spg30 Phenotypementioning

confidence: 95%

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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Section: Spg30 Phenotypementioning

confidence: 95%

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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“…4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. [5][6][7][8][9][10][11][12][13][14] SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases.…”

Section: Introductionmentioning

confidence: 99%

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

et al. 2015

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Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed wholeexome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients. INTRODUCTIONHereditary cerebellar ataxias and hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous and often overlapping neurological disorders. HSPs are characterized by a predominant progressive spasticity and weakness in the lower limbs due to degeneration of the corticospinal tracts, 1 whereas the main feature of cerebellar ataxias is progressive cerebellar degeneration leading to impaired balance, gait and speech. 2 Both HSP and hereditary ataxias can be associated with other neurological and non-neurological features, resulting in complex phenotypes with frequent intra-and inter-familial variability. Significantly, cerebellar ataxias are very often associated with pyramidal involvement leading to 450% of recessive ataxias manifesting as spastic ataxias. 3 Because of the individual rarity and genetic heterogeneity of these conditions, their molecular diagnosis remains challenging and time-consuming.Mutations in the gene SPG7 were the first identified genetic cause of autosomal recessive HSP in 1998 (MIM602783). 4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. 5-14 SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases. 6,7,9,12,15 In a study of a large Dutch cohort, cerebellar ataxia was found in 57% of cases and it was even the

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“…The p.His448Profs * 12 mutation is predicted to result in a premature stop codon. Previous reports (7,(9)(10)(11)(12)(13)(14)(15) have revealed that missense and nonsense mutations located closer to the C-terminal of paraplegin than the p.His448Profs * 12 mutation can cause disease ( Figure D). Recently, genotype-phenotype correlations were identified for SPG7: an association between cerebellar ataxia and SPG7 null alleles leading to an absence of protein products or severely truncated protein products and an association between optic nerve atrophy and a missense mutation in exon 10 (pArg470Gln) (9).…”

Section: Discussionmentioning

confidence: 85%

Identification of a Novel Homozygous <i>SPG7</i> Mutation in a Japanese Patient with Spastic Ataxia: Making an Efficient Diagnosis Using Exome Sequencing for Autosomal Recessive Cerebellar Ataxia and Spastic Paraplegia

et al. 2013

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Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SPG7, encoding paraplegin, in this patient. This is the first report of an SPG7 mutation in the Japanese population. For disorders previously undetected in a particular population, or unrecognized/atypical phenotypes, exome sequencing may facilitate molecular diagnosis.

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Mutation analysis of the paraplegin gene ( SPG7 ) in patients with hereditary spastic paraplegia

Cited by 96 publications

References 18 publications

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

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

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Identification of a Novel Homozygous <i>SPG7</i> Mutation in a Japanese Patient with Spastic Ataxia: Making an Efficient Diagnosis Using Exome Sequencing for Autosomal Recessive Cerebellar Ataxia and Spastic Paraplegia

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