Clinical heterogeneity and genotype‐phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11)

Background: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum is a distinct and usually severe form of complex hereditary spastic paraplegia classified as SPG11. Recently mutations on SPG11 gene (KIAA1840), which is localized to chromosome 15q13‐q15, were shown to cause the majority of SPG11 cases. Methods: We analysed the 40 coding exons of this gene in the probands from eight families with complex ARHSP, four of these families had a thin corpus callosum and two has mild thinning. Results: Three families were identified with novel mutations in the SPG11 gene. One family was of Asian origin with a homozygous nonsense mutation and had a very severe phenotype but only very mild thinning of the corpus callosum. In the other two English families the parents were unrelated and the mutations were compound heterozygotes. In these two families the phenotype was mild and both probands had a thin corpus callosum. Conclusion: Given the probable mechanism of action of the mutations in the Spatacsin gene, we discuss the probable genotype phenotype correlations in these families. This study confirms the frequent occurrence of Spatacsin mutations in complex ARHSP with genotype phenotype effects and exposes the spectrum of clinical heterogeneity in SPG11.     

SPG11 spastic paraplegia

Autosomal recessive hereditary spastic paraplegia (AR HSP) with thin corpus callosum (TCC) is a rare neurodegenerative disorder often caused by mutations in the gene encoding for spatacsin at the SPG11 locus on chromosome 15q. The disease is characterized by progressive spastic paraparesis and mental retardation which occur during the first two decades of life and frequently with peripheral neuropathy. Brain magnetic resonance imaging (MRI) reveals typical TCC with periventricular white matter changes. We describe two patients, of Turkish descent, from the same consanguineous family and affected with SPG11 in association with unusual early-onset parkinsonism. Parkinsonism occurred during the very early stages of SPG11 in both patients, being in one the inaugural symptom of the disease presented as a resting tremor with akinesia, rigidity and expressing an initial moderate levodopa-response that progressively weakened. The second patient presented a resting tremor with mild akinesia and no levodopa-response. Both patients were affected with progressive spastic paraparesis which had initially occurred at 15 and 12 years of age, respectively, in association with mild mental retardation and an axonal polyneuropathy. TCC with periventricular white matter changes (PWMC) was evident by MRI and ¹²³I-ioflupane SPECT was abnormal. Genetic analysis detected for both patients a new c.704_705delAT, p.H235RfsX12 homozygous mutation in SPG11. This report provides evidence that parkinsonism may initiate SPG11-linked HSP TCC and that SPG11 may cause juvenile parkinsonism.     

Thinning of the Corpus Callosum and Cerebellar Atrophy is Correlated with Phenotypic Severity in a Family with Spastic Paraplegia Type 11

Background

Mutations in the spatacsin gene are associated with spastic paraplegia type 11 (SPG11), which is the most-common cause of autosomal recessive hereditary spastic paraplegia. Although SPG11 has diverse phenotypes, thinning of the corpus callosum is an important feature.

Case Report

Clinical, genetic, and radiological evaluations were undertaken in a large family from Gujarat in North India with hereditary spastic paraplegia, whose affected members presented with varying degrees of spasticity, ataxia, and cognitive impairment. The clinical severity and the degree of corpus callosum and cerebellar atrophy varied among the four affected individuals in the family. Genetic testing of the affected members revealed recessive mutations in the spatacsin gene, consistent with a diagnosis of SPG11.

Conclusions

We believe that the extent of corpus callosum thinning and cerebellar atrophy is correlated with disease severity in affected patients. The addition of extrapyramidal features in the most-affected members suggests that SPG11 exhibits considerable phenotypic heterogeneity.     

Novel SPG11 mutations in Chinese families with hereditary spastic paraplegia with thin corpus callosum

BackgroundHereditary spastic paraplegia is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Mutations in SPG11 gene have been recently identified as a major cause of hereditary spastic paraplegia with thin corpus callosum.MethodsTwo unrelated Chinese families were examined by clinical evaluation, mutation analysis of SPG11, detailed neuropsychological assessment and diffusion tensor imaging.ResultsBoth patients presented with spastic paraparesis and learning disability. Two novel and one known mutations in SPG11 were detected through genetic analysis. Cognitive impairment was found with severe deficits in domains such as executive functions and memory. Magnetic resonance imaging showed thin corpus callosum while diffusion tensor imaging revealed increased mean diffusion and decreased fractional anisotropy in the corpus callosum and subcortical white matter in frontal, temporal lobe compared with the healthy controls.ConclusionsThis study widens the spectrum of mutations in SPG11. The application of detailed neuropsychological tests and diffusion tensor imaging could detect cerebral subtle involvement even in early stage of the disease.     

Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47)

We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis, intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.     

Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization

Mutations in the spatacsin gene have recently been identified as the genetic cause of autosomal–recessive spastic paraplegia (SPG) with thin corpus callosum, mapping to chromosome 15p13–21. While several nonsense and frameshift mutations as well as splice mutations have been identified, large genomic deletions have not yet been found, potentially due to the absence of an efficient analysis tool. After complete sequencing of 12 autosomal recessive hereditary spastic paraplegia patients with suggestive clinical signs, we were able to define nine SPG11 cases but were left with three patients in which only one SPG11 mutation could be identified by direct sequencing. In these patients, we performed high-resolution comparative genomic hybridization using a predesigned human chromosome 15 tiling array with an average spacing of 100 bp. Data analysis suggested heterozygous genomic deletion within the spatacsin gene in all three patients. In one patient, a relatively small genomic deletion (8.2 kb) could be validated by quantitative polymerase chain reaction (PCR) and long-range PCR, allowing the diagnosis of the deletion of exons 31 through 34. For two patients, quantitative PCR validation could not confirm a genomic deletion. As high density tiling arrays are available for the entire human genome, we suggest this approach for the screening of heterozygous genomic deletions in candidate genes down to a few kilobases.     

Hereditary spastic paraplegia with hypoplastic corpus callosum in a Turkish family

Hereditary spastic paraplegia is composed of a heterogeneous group of neurodegenerative disorders and is classified as pure or complicated due to its clinical variability. Autosomal recessive hereditary spastic paraplegia with hypoplastic corpus callosum is a rare form of complicated hereditary spastic paraplegia. In complicated hereditary spastic paraplegia, autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been noted. The diagnostic criteria of autosomal recessive hereditary spastic paraplegia with hypoplastic corpus callosum are inheritance consistent with autosomal recessive trait, slowly progressive spastic paraparesis and mental detoriation, hypoplasia of corpus callosum revealed by brain computerized tomography or magnetic resonance imaging, and exclusion of other disorders by magnetic resonance imaging of the spine and brain as well as other laboratory tests. In this report, the authors present the case of 3 affected siblings in a family from Turkey, whereas 1 child and the con-sanguineous parents were healthy. To the authors' knowledge, it is the first reported case of autosomal recessive hereditary spastic paraplegia with hypoplastic corpus callosum from Turkey.     

Levodopa-responsive parkinsonism in hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegia with thin corpus callosum is a rare degenerative disease, which is characterized by a progressive weakness of the lower limbs with a hypoplastic corpus callosum, and is often associated with other symptoms such as mental impairment, amyotrophy, sensory disturbances, dysuria, nystagmus and cataract. We describe two siblings (brother and sister) who showed a thin corpus callosum on MRI, one of whom showed the pure form of progressive spastic paraplegia, while the other showed predominant levodopa-responsive parkinsonism. The present cases are illustrative of a phenotypic heterogeneity in the same family of spastic paraplegia with a thin corpus callosum, despite the identical neuroimaging findings, and also presented another form of autosomal recessive juvenile levodopa-responsive parkinsonism.     

Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13–15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.Electronic Supplementary Material  Supplementary material is available for this article at     

Complicated hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) and childhood onset

The hereditary spastic paraplegias (HSPs) are a group of rare disorders with the predominant clinical feature of progressive spastic paraplegia. They are subdivided into pure and complicated forms according to whether the disorder is associated with other neurological abnormalities. We report on two unrelated female Caucasian patients with complicated HSP, aged 16 and 24 years, who showed progressive gait disturbance with spasticity and ataxia as well as cognitive impairment. Onset of symptoms was at age 3 and 10 years, respectively. MRI revealed mild diffuse non-progressive T (2)-signal alterations of cerebral white matter and thinning of the body and genu of the corpus callosum. Some similarity of clinical symptoms and MRI patterns with the phenotype of Mast syndrome prompted a mutation analysis of the SPG21 gene, encoding maspardin, which revealed a wild-type sequence in both patients. Clinical and neuroradiological features in our patients are diagnostic for complicated autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC, SPG11). This disorder, characterized by a typical MRI pattern and a progressive spastic paraplegia that may be associated with dementia and ataxia, may have an onset in early childhood and probably is one of the more common forms of complicated HSP.     

Immunohistochemical localization of spatacsin in α‐synucleinopathies

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP‐TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α‐synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti‐spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin‐positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α‐synuclein‐containing inclusions suggests that spatacsin may be involved in the pathogenesis of α‐synucleinopathies.     

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult‐onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss‐of‐function of the paraplegin‐AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7‐HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP. © 2010 Movement Disorder Society     

Hereditary spastic paraplegia type 11: Clinicogenetic lessons from 339 patients

Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype of autosomal recessive hereditary spastic paraplegia (HSP), to date, there are more than 181 different KIAA1840 gene mutations detected, and yet the genetic landscape of SPG11 is far from complete. To find the clinical and genetic characteristics of SPG11, we performed a reanalysis of the clinical features and genotype-phenotype correlations in all reported studies exhibiting SPG11 mutations. A total of 339 patients were collected, their mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and mental retardation (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%). The most common brain MRI abnormality is thinning of the corpus callosum (TCC) (173/190, 91.05%), followed by periventricular white matter changes (130/158, 82.28%), cerebral or cerebellar cortical atrophy (55/107, 51.40%). The mutational spectrum associated with KIAA1840 gene is wide, and frameshift mutations are the most common type followed by nonsense mutations. Our reanalysis demonstrated that SPG11 exhibited significant clinical and genetic heterogeneity, and no clear genotype-phenotype correlation was observed. There is no mutational hot spot in the KIAA1840 gene, which emphasizes the need to analyse the whole gene in clinical practice. In addition to conventional genetic testing methods, further mRNA analysis should be conducted on some cases to yield a definitive diagnosis.     

Hereditary spastic paraplegia with thin corpus callosum and cataract: a clinical description of two siblings

We report two siblings with autosomal recessive hereditary spastic paraplegia and thin corpus callosum. These patients had a similar history of progressive spastic gait, followed by mental impairment in the second decade. In addition to rigospasticity, ataxia, and foot deformity, both patients had congenital cataract on ophthalmologic examination. The association of cataract and thin corpus callosum suggests a distinct genetic disorder involving these structures in complicated spastic paraplegia.     

Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia

Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514_1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.     

Targeted disruption of the Mast syndrome gene SPG21 in mice impairs hind limb function and alters axon branching in cultured cortical neurons

Mast syndrome (SPG21) is a childhood-onset, autosomal recessive, complicated form of hereditary spastic paraplegia (HSP) characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product maspardin underlies this disorder, likely leading to loss of protein function. In this study, we generated SPG21−/− knockout mice by homologous recombination as a possible animal model for SPG21. Though SPG21−/− mice appeared normal at birth, within several months they developed gradually progressive hind limb dysfunction. Cerebral cortical neurons cultured from SPG21−/− mice exhibited significantly more axonal branching than neurons from wild-type animals, while comprehensive neuropathological analysis of SPG21−/− mice did not reveal definitive abnormalities. Since alterations in axon branching have been seen in neurons derived from animal models of other forms of HSP as well as motor neuron diseases, this may represent a common cellular pathogenic theme.     

Identification of a Mutation in SPG11 in an Iranian Patient with Spastic Paraplegia and Ears of the Lynx Sign

Hereditary spastic paraplegia (HSP) includes a number of inherited disorders which are characterized by stiffness in the lower extremities and progressive gait disturbance. Mutations in terms of spastic gait genes (SPGs) are responsible for occurrence of different types of HPS with autosomal recessive, X-linked recessive, and autosomal dominant modes of inheritance. In the current case report, we identified a mutation in SPG11 gene in a female patient with progressive stiffness of lower extremities and atrophy of corpus callosum and the “lynx ear” sign in brain MRI. Whole exome sequencing (WES) revealed a homozygote frameshift deletion variant in SPG11 gene (NM001160227: exon 28: c.4746delT, p.N1583Tfs*23). This variant is a null variant classified as a pathogenic variant (PVS1) according to ACMG standards and guidelines. The frequency of this variant in 1000G, ExAC, and Iranome databases was 0. This study shows the role of WES in the identification of disease-causing mutations in a disease such as HSP which can be caused by diverse mutations in several genes.     

Hereditary spastic paraplegias: an update

PURPOSE OF REVIEW: Hereditary spastic paraplegias are a genetically heterogeneous group of diseases. Recent advances concerning their nosology and molecular bases have greatly improved the genetic diagnosis of these diseases, with implications for genetic counselling. The recent identification of new genes and loci, however, has blurred the distinction between hereditary spastic paraplegias and other entities, such as cerebellar ataxias or leucodystrophies. Cerebral MRI and the familial history of each patient with spastic paraplegia are the minimal clinical elements needed to orient genetic testing. RECENT FINDINGS: For SPG4, the gene most frequently involved in hereditary spastic paraplegias, a novel mutational mechanism was described, which allows detection of an increased number of cases. In autosomal recessive forms, mutations in the recently identified SPG11 gene seem to account for a majority of the complex forms of the disease with atrophy of the corpus callosum. In addition, the SACS gene has been implicated in an increasing number of cases of various origins. SUMMARY: Genetic testing is progressively more complex and clinical and other information concerning the phenotype is now crucial for choosing an appropriate genetic testing procedure for each patient.     

Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus

Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs. They are inherited as autosomal dominant, autosomal recessive, and X-linked traits. Four Italian families with autosomal recessive pure spastic paraplegia are reported. We show evidence of linkage to the SPG5 locus on chromosome 8p and our data reduce the candidate interval for SPG5 to the11-cM interval spanned by D8S285 and D8S544. We also report the search for mutations in five genes located in the region and their exclusion as candidates for SPG5.