Evaluation of MTHFR C677T polymorphism in ischemic and hemorrhagic stroke patients. A case-control study in a Northern Indian population

The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity. Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by a slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the most frequent gene associated with HSP-TCC, encodes spatacsin, a protein of unknown function. We describe two siblings from an Arabic consanguineous family with slowly progressive spastic paraparesis, mental retardation, seizures, thin corpus callosum and periventricular white matter abnormalities. Homozygosity mapping identified a novel single candidate region of 7.3 Mb on chromosome 1p13.2-1p12. The finding of a new locus for AR-HSP-TCC further demonstrates the extensive genetic heterogeneity of this condition.     

Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity

BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) is an autosomal recessive form of complicated HSP mainly characterized by slowly progressive spastic paraparesis and mental deterioration beginning in the second decade of life. The locus for HSP-TCC, designated SPG11, was mapped to chromosome 15q13-15 in some of the affected families from Japan, Europe, and North America, spanning an interval of 17.5 megabases (Mb). OBJECTIVE: To perform a clinical and genetic study of HSP-TCC. DESIGN AND SETTING: Case series; multi-institutional study. PATIENTS: Seven patients with HSP-TCC who belong to 3 consanguineous families of Arab origin residing in Israel. RESULTS: The 7 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain magnetic resonance imaging. After excluding the SPG7 locus, we tested the 3 families for linkage to the SPG11, SPG21/MAST, and ACCPN loci associated with autosomal recessive disorders with TCC. Two families showed evidence for linkage to SPG11 (Z(max) = 5.55) and reduced the candidate region to 13 Mb. CONCLUSIONS: Our findings in HSP-TCC further confirm its worldwide distribution and genetic heterogeneity, and they significantly reduce the candidate SPG11 interval.     

遗传性痉挛性截瘫伴薄型胼胝体的临床特征

目的 探讨遗传性痉挛性截瘫伴薄型胼胝体（HSP-TCC）的临床特征。方法 对4例HSP-TCC患者的临床资料进行回顾性分析。结果 4例患者均于青少年起病，表现为智能低下，痉挛步态，双下肢痉挛，无力，腱反射亢进，病理征阳性，无感觉障碍，2例有共济失调及大小便障碍；1例有双上肢痉挛及肌肉萎缩，头颅MRI显示胼胝体变薄。结论 HSP-TCC的主要临床特征为青少年起病的痉挛性截瘫，智能低下，头颅MRI显示胼胝体变薄。     

Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.     

Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early‐onset levodopa‐responsive Parkinsonism

Background: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia. Methods: We describe one Italian autosomal recessive hereditary spastic paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism‐like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T₂‐weighted lesions in periventricular regions, and the ¹²³I‐ioflupane single‐photon emission coupled tomography was abnormal. Results: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11. Discussion: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary spastic paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients. © 2011 Movement Disorder Society     

Spastic paraplegia 15: Linkage and clinical description of three Tunisian families

Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16‐Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity. © 2007 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.     

Troyer syndrome revisited

Abstract. Troyer syndrome, originally described in 1967 in an Old Order Amish population, is a complicated form of hereditary spastic paraplegia (HSP) inherited in an autosomal recessive fashion and slowly progressive. The cardinal features are spastic paraparesis, pseudobulbar palsy and distal amyotrophy, together with mild developmental delay and subtle skeletal abnormalities. We report a detailed evaluation of 21 cases of Troyer syndrome in the same Amish population, including three from the original study. Imaging of the brain revealed white matter abnormalities, particularly in the temporoparietal periventricular area. This study, coupled with the recent identification of the gene responsible (SPG20, encoding spartin), increases our understanding of this form of HSP.     

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.     

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.     

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 novel SPG11 mutations in a cohort of Chinese families with hereditary spastic paraplegia

Aim of the study: To investigate the mutation frequency of SPG11, SPG15, SPG5 and SPG7 in China.

Materials and methods: We have scanned the whole exons of KIAA1840, ZFYVE26, SPG7 and CYP7B1 genes in a group of 36 unrelated Chinese ARHSP families.

Results: SPG11 mutations were found in 33.33% (12/36) of ARHSP patients in our study, and no mutation was identified in SPG15, SPG5 or SPG7 genes. Among the SPG11 mutations detected, c.1755_1758delAGCA/p. P585PfsX623, c.29832984delTA/p.L934LfsX1010, c.1845_1848delGTCT/p.F617Lfs*5, c.6478+1G>T and c.3662_3665delTCAA/p.I1221RfsX1230 were novel mutations, they all introduced premature termination codons which were predicted to leading to the absence of the spastacsin protein in the patients' cells. All the SPG11 patients in our study presented with spastic paraparesis and/or mental impairment at initial time, and most patients showed thin corpus callosum (TCC) and white matter abnormalities (WMA) in brain MRI. After years' duration, they gradually manifested with dysarthria, dysphagia, peripheral neuropathy, amyotrophy, skeletal deformity, cerebellar signs, ophthalmoplegia, decreased vision, sphincter disturbance and tremor.

Conclusions: SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare. The core symptoms of Chinese SPG11 patients showed no difference when compared to SPG11 in western countries, and clinical heterogeneity also existed in our SPG11 patients. We suggested that ARHSP patients with mental impairment, especially combined with TCC, should be excluded SPG11 first in China.     

A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene

Abstract

Hereditary spastic paraplegia (HSP) is a group of rare neurodegenerative disorder with genetic and clinical heterogeneity. It has autosomal dominant (AD), autosomal recessive (AR) and X-linked forms. HSPs are clinically classified into ‘pure’ and ‘complicated’ (complex) forms. SPG11 (KIAA1840) and SPG15 (ZFYVE26) are the most common ARHSPs with thin corpus callosum (TCC). They typically present with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life. Here, we present a patient girl, born to a couple who were first cousins, was admitted to the pediatric neurology outpatient clinic at 14?years of age because of walking with help, dysarthria and forgetfulness. Her examination revealed a motor mental retardation, bilateral leg spasticity, increased deep tendon reflexes in lower limbs, bilateral pigmentary retinopathy; TCC and white matter hyperintensities on brain MRI, sensorimotor axonal polyneuropathy findings in lower limbs on electromyography. Based on the clinical features and the imaging studies, the diagnosis of HSP was suspected. Targeted next generation sequencing (NGS) was performed using Inherited NGS Panel that consists of 579 gene associated with Mendelian disorders. Analysis of the patient revealed a c.6398_6401delGGGA(p.Arg2133Asnfs*15)(Exon35) homozygous novel change in ZFYVE26 gene. Genotype-phenotype correlation of HSP is complicated due to heterogeneity. The clinical similarity of HSP types increases the importance of genetic diagnosis. There are few reports about pathogenic variants in ZFYVE26 gene in the literature. This case report is one of the few studies that revealed a novel pathogenic variant in ZFYVE26 gene using NGS.     

Genetics of hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are clinically and genetically highly heterogeneous. The key symptom of spastic paraparesis of lower limbs can be complicated by a variety of signs and symptoms including cognitive impairment, optic atrophy, cerebellar ataxia, peripheral nerve involvement, or seizures. At least 48 loci have been identified, termed SPG1-SPG48. Ten genes for autosomal dominant HSP are currently known, SPG4 being by far the most common subtype accounting for ～50% of cases. SPG3 is especially common in young-onset cases. Autosomal recessive HSP seems to be even more heterogeneous. The known 12 autosomal recessive HSP genes collectively explain about one third of cases only. The most common causes for pure autosomal recessive HSP are SPG7 and SPG5. Mental retardation and thin corpus callosum on magnetic resonance imaging point toward SPG11 and SPG15. The authors provide an overview on clinical, neurophysiologic, and neuroradiologic characteristics of the more common HSP subtypes. More details are given in the tables for quick reference, and a genetic testing strategy is proposed.     

A new locus for autosomal recessive spastic paraplegia (SPG32) on chromosome 14q12-q21

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. Here, we performed a genome-wide linkage analysis on a consanguineous family presenting an autosomal recessive form of HSP associated with mild mental retardation, brainstem dysraphia, and clinically asymptomatic cerebellar atrophy. We have mapped the disease locus SPG32 to chromosome 14q12-q21 within a 30-cM interval, which excludes the atlastin gene.     

SPG11: a consistent clinical phenotype in a family with homozygous Spatacsin truncating mutation

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Here, we describe clinical and genetic features in an Italian family affected by autosomal recessive HSP (ARHSP) with mental impairment and thin corpus callosum (TCC). In both affected subjects, genetic analysis revealed the presence of a homozygous small deletion (733_734delAT) leading to a frameshift (M245VfsX) within the coding region of SPG11 gene, encoding spatacsin. This finding is the first independent confirmation that spatacsin loss of function mutations cause ARHPS-TCC. Roberto Del Bo and Alessio Di Fonzo, These two authors equally contributed to the present work.     

Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families

Hereditary spastic paraplegia (HSP) type 15 is an autosomal recessive (AR) form of complicated HSP mainly characterized by slowly progressive spastic paraplegia, mental retardation, intellectual deterioration, maculopathy, distal amyotrophy, and mild cerebellar signs that has been associated with the Kjellin syndrome. The locus for this form of HSP, designated SPG15, was mapped to an interval of 19 cM on chromosome 14q22-q24 in two Irish families. We performed a clinical-genetic study of this form of HSP on 147 individuals (64 of whom were affected) from 20 families with AR-HSP. A genome-wide scan was performed in three large consanguineous families of Arab origin after exclusion of linkage to several known loci for AR-HSP (SPG5, SPG7, SPG21, SPG24, SPG28, and SPG30). The 17 other AR-HSP families were tested for linkage to the SPG15 locus. Only the three large consanguineous families showed evidence of linkage to the SPG15 locus (2.4 > Z (max) > 4.3). Recombinations in these families reduced the candidate region from approximately 16 to approximately 5 Mbases. Among the approximately 50 genes assigned to this locus, two were good candidates by their functions (GPHN and SLC8A3), but their coding exons and untranslated regions (UTRs) were excluded by direct sequencing. Patients had spastic paraplegia associated with cognitive impairment, mild cerebellar signs, and axonal neuropathy, as well as a thin corpus callosum in one family. The ages at onset ranged from 10 to 19 years. Our study highlights the phenotypic heterogeneity of SPG15 in which mental retardation or cognitive deterioration, but not all other signs of Kjellin syndrome, are associated with HSP and significantly reduces the SPG15 locus.     

Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene

BACKGROUND: Hereditary spastic paraparesis (HSP) denotes a group of inherited neurological disorders with progressive lower limb spasticity as their clinical hallmark; a large proportion of autosomal dominant HSP belongs to HSP type 4, which has been linked to the SPG4 locus on chromosome 2. A variety of mutations have been identified within the SPG4 gene product, spastin. OBJECTIVE: Correlation of genotype and electrophysiological phenotype. MATERIAL: Two large families with HSP linked to the SPG4 locus with a very similar disease with respect to age of onset, progression, and severity of symptoms. METHODS: Mutation analysis was performed by PCR from genomic DNA and cDNA, and direct sequencing. The motor system was evaluated using transcranial magnetic stimulation. RESULTS: Patients differ in several categories depending on the type of mutation present. CONCLUSIONS: For the first time in hereditary spastic paraparesis, a phenotypic correlate of a given genetic change in the spastin gene has been shown.     

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.     

New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP)

The hereditary spastic paraplegias (HSP) are a heterogeneous group of conditions in which the main feature is a progressive spastic paraparesis. Mutations in the receptor expression enhancing protein 1 (REEP1) gene have recently been reported to be associated with an autosomal dominant HSP phenotype (SPG31). The objective of this study was to identify the frequency of REEP1 mutations in both autosomal dominant HSP (ADHSP) and sporadic spastic paraparesis (SSP) cases and to analyse the genotype/phenotype correlation of mutations so far described in REEP1. One hundred thirty-three index cases from large ADHSP pedigrees and 80 SSP cases were screened for mutation in REEP1 by direct sequencing. Three mutations were identified in REEP1 in the ADHSP group. A novel nonsense mutation in exon 5, c.[337C>T] (p.[Arg113X]), was associated with spastic paraparesis, amyotrophy and mitochondrial dysfunction. A second previously reported mutation, c.[606+43G>T], was identified in two pedigrees. The index case of one of these pedigrees had a peripheral neuropathy in association with spastic paraparesis, and the proband of the second pedigree had a severe spastic tetraparesis and bulbar dysfunction. No mutations were detected in the SSP cases. We report a mutation frequency of 2.3% in REEP1 in ADHSP, suggesting REEP1 mutation is a relatively uncommon cause of ADHSP in a population of patients drawn from the UK. The phenotype of ADHSP associated with REEP1 mutation is broader than initially reported. The spastic paraparesis in SPG31 may be complicated by the presence of amyotrophy, bulbar palsy and/or peripheral neuropathy.