Autosomal Dominant Hereditary Spastic Paraparesis Research Articles

Three novel mutations in 20 patients with hereditary spastic paraparesis.

Hereditary spastic paraparesis (HSP) constitutes both genetic and clinically heterogeneous group of upper motor neuron diseases. Half of the individuals with autosomal dominant (AD) HSP have mutations in SPAST, ATL1, and REEP1 genes. This study was conducted to elucidate the genetic etiology of patients with the pure type AD-HSP diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In the first step of work, Sanger sequencing (SS) was performed in ATL1, SPAST, and REEP1 genes and the second phase whole-exome sequencing (WES) was performed following SS analysis for the patients with no detected mutations in these genes. The results of this study revealed that in ATL1, 6 patients have previously reported c.776C > A mutation and 6 patients have novel c.470T > C mutation. In SPAST, 3 patients have novel c.1072G > C mutation and 2 patients have novel c.1099-1G > C mutation. WES was performed in three patients, who had no detected mutation in these genes with SS analysis. In this approach, as previously reported c.1859T > C mutation in KIAA0196 was detected, and it was confirmed with the patient's relatives by SS. In three of patients, no HSP-associated variant could be identified in SS and WES. With this study, the molecular genetic etiology in 20 of 23 (87%) individuals that were included in this study with the utilization of SS and WES was elucidated. Utilization of SS and WES methods have enabled the identification of genetic etiology of HSP further with appropriate genetic counseling that was provided to the patients.

Does calf muscle spasticity contribute to postural imbalance? A study in persons with pure hereditary spastic paraparesis

ObjectivesThe contribution of spasticity to postural imbalance in patients with upper motor neuron syndrome is still unclear. This study aimed to evaluate the responses to support-surface perturbations in patients with hereditary spastic paraparesis (HSP). These patients typically suffer from bilateral spasticity with relatively preserved muscle strength of the lower limbs. Particularly toes-up rotations were expected to be destabilizing due to insufficient suppression of calf muscle stretch reflexes. MethodsParticipants were seventeen symptomatic community-dwelling patients with autosomal dominant pure HSP and seventeen healthy controls. All patients had increased muscle tone of the triceps surae (TS) but no muscle contractures. Perturbations were applied by rotating or translating a platform with increasing intensity in four sagittal-plane directions. The primary outcome was maximum intensity (‘limit of stability’) sustained without stepping or grabbing in each type of perturbation. Leg muscle tone and strength were assessed with the Modified Ashworth Scale and Medical Research Council (MRC) scale, respectively. ResultsFor toes-up perturbations, limits of stability in patients were substantially lower than in controls, which were related to TS muscle tone but not to tibialis anterior (TA) strength. Toes-down rotations were indiscriminative. For backward perturbations, patients also had lower limits of stability, unrelated to TA strength or TS muscle tone. In forward perturbations, patients with TS strength MRC 4 were less stable than patients with normal TS strength and controls. ConclusionCalf muscle spasticity and weakness differently contribute to postural imbalance in patients with HSP. This notion could have implications for the clinical management of spasticity.

Dementia in SPG4 hereditary spastic paraplegia

Cognitive impairment and dementia has been reported in autosomal dominant hereditary spastic paraparesis (HSP) linked to the SPG4 locus. There has only been one postmortem examination described; not all accept that progressive cognitive decline is a feature of this disorder. A family with SPG4-HSP known to have a deletion of exon 17 in the spastin gene (SPG4delEx17) was cognitively assessed over a 7-year period. The index family member died and a postmortem examination was performed. Thirteen family members older than 40 years were clinically and cognitively assessed using the Cambridge Cognitive Assessment over a 7-year period. The presence of SPG4delEx17 was assessed; a neuropathologic examination of the brain of the index family member was performed. Cognitive decline occurred in 6 of the 13 family members and in all 4 older than 60 years. Two genetic deletions were identified: SPG4delEx17 in 12 of the 13 family members and a deletion of SPG6 (SPG6del) in 5. Eight individuals had the SPG4delEx17 deletion only; 4 had evidence of progressive cognitive impairment. Four family members had both SPG4delEx17 and SPG6del; 2 of these had cognitive impairment. One family member with the SPG6del alone had neither HSP nor cognitive impairment. The index case with both deletions died with dementia; the brain showed widespread ubiquitin positivity within the neocortex and white matter. Cognitive decline and dementia is a feature of SPG4-HSP due to a deletion of exon 17 of the spastin gene.

Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4

The aim of our study was to evaluate Motor Evoked Potentials (MEPs) and cortical excitability, using Transcranial Magnetic Stimulation (TMS) as well as short latency Somatosensory Evoked Potentials (SEPs) in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) patients. MEPs were recorded from upper and lower limb muscles in 12 patients (7 m and 5 f) affected by ADHSP with spastin mutation (SPG4). We measured: (i) motor threshold (MTh); (ii) total motor conduction time (TMCT); (iii) direct and indirect central motor conduction time (d-CMCT and i-CMCT) calculated by subtracting from the cortical latency those obtained on magnetic spinal stimulation (d-PMCT) and via the F-wave method (i-PMCT); (iv) MEP amplitude (MEP/Mmax ratio%) and (v) duration of the cortical silent period (CSP). Latency, amplitude and persistence of the F-wave obtained with electrical nerve stimulation were also considered; H reflex was also tested from lower extremities. SEPs were recorded from spine and scalp sites following median and posterior tibial nerve stimulation; conventional latency and amplitude measurements were performed. In a comparison with the control group, the MTh recording from lower limbs was significantly higher (67.5 ± 7.7% versus 52.5 ± 6.9%), MEPs were absent in one case and showed reduced amplitude in the remainders (22.9 ± 12.6% versus 66.3 ± 25.9% of M wave); TMCT resulted to be abnormal (36.5 ± 3.9 ms versus 27.1 ± 1.4 ms) and d-CMCT as well as i-CMCT were significantly prolonged (23.1 ± 3.5 ms versus 13.8 ± 1.3 ms; and 20.1 ± 3.4 ms versus 10.6 ± 1.3 ms, respectively). The CSP, which was normal from the hands, was significantly shortened from the legs and correlated with spasticity scoring (Ashworth scale). Cortical SEPs from lower limbs were abnormal in all cases, whereas SEPs by stimulation of median nerves were normal; F-wave parameters from upper limbs showed no abnormalities, whereas an increased persistence was detected from lower limbs; H reflex amplitudes resulted larger compared with controls. Moreover, shortening of the CSP, being correlated with the Ashworth scale, can be considered an electrophysiological marker of spasticity that seems to arise from impairment of the supraspinal or intracortical inhibitory pathways with an additional contribution of increased segmental motor neuron excitability. These data prove the existence of comparable neurophysiological abnormalities in ADHSP with spastin mutation (SPG4) when long ascending and descending pathways are involved.

A Missense Mutation in the Coiled-Coil Domain of the KIF5A Gene and Late-Onset Hereditary Spastic Paraplegia

To our knowledge, up to now, only 2 mutations in the KIF5A gene, a member of the kinesin superfamily, have been identified as the molecular cause of early-onset autosomal dominant hereditary spastic paraparesis (ADHSP). To assess the genetic defect in a family with late-onset ADHSP. Only the proband agreed to undergo complete neurological testing and mutational analysis. The proband was screened for mutations in the spastin, atlastin, NIPA1, and KIF5A genes, either by denaturing high-performance liquid chromatography or sequence analysis. The history of the family was consistent with ADHSP characterized by late onset of the disease. Mutational analysis results were negative for the spastin, atlastin, and NIPA1 genes but identified a missense mutation (c.1082C>T) in the coiled-coil coding region of the KIF5A gene. This finding enlarges the phenotypic spectrum of ADHSP linked to KIF5A and enhances the role of that gene in the epidemiology of this disease. We propose that the KIF5A gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations.

Further evidence of genetic heterogeneity in autosomal dominant distal motor neuronopathy

Distal hereditary motor neuronopathy is a genetically and clinically heterogeneous disorder. To date, five loci, and their relative genes, have been mapped on chromosomes 7p14, 7q11, 9q34, 11q12 and 12q24, respectively. We describe an Italian family with autosomal dominant distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis on chromosomes 7p14, 9q34, 11q12 and 12q24. Moreover we sequenced the genes mapped to 7q11 and 12q24. Negative LOD scores excluded linkage to 7p14, 9q34, and 11q12 chromosomes in our family. No mutations were found in genes mapped to 7q11 and 12q24. In addition, because of pyramidal features, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis. The analysis was negative thus excluding a complicated form of autosomal dominant hereditary spastic paraparesis. These data further confirm a genetic heterogeneity within inherited motor neuronopathy.

Further evidence of genetic heterogeneity in autosomal dominant distal motor neuronopathy

Distal hereditary motor neuronopathy (distal HMN) is a genetically and clinically heterogeneous disorder. To date three loci have been identified on chromosomes 7p14, 9q34 and 12q24. We describe a four generation Italian family with distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis with microsatellites on chromosomes 7p14, 9q34 and 12q24. Negative LOD scores excluded any evidence of linkage to the above‐mentioned chromosomes in the family. Moreover, because of pyramidal features in our patients, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis (ADHSP). The analysis was negative thus excluding that our patients were affected by a complicated form of ADHSP. These data further confirm a genetic heterogeneity within inherited motor neuronopathy disorders.

Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation

The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symptoms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense mutation in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and increased tone in the legs. The mean age of onset was 32.2 +/- 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 +/- 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hyperreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals affected with SPG4 from family members with nonspecific neurological findings.

Novel spastin mutations and their expression analysis in two Italian families.

Mutations in spastin cause the most common form of pure autosomal dominant hereditary spastic paraparesis (SPG4). Here, we report two Italian families affected with SPG4-linked HSP harboring two novel spastin mutations. SSCP/sequencing analysis of the spastin gene showed a single base pair deletion causing a frame-shift in one family (1442delT) and a missense mutation (1726T>C) resulting in a leucine to proline amino-acid change (L534P) in the other family. Total RNA from the mutant and the wild-type spastin allele in muscle biopsies from patients from the two affected families was quantitated. RNA expression was almost absent from the spastin allele harboring the single base pair deletion, while it was nearly normal for the spastin allele harboring the missense mutation. These data suggest that varying spastin RNA levels are found in out-of-frame and missense spastin mutations and imply different mechanisms involved in the molecular pathology of SPG4 linked HSP.

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...

The prevalence of “pure” autosomal dominant hereditary spastic paraparesis in the island of Ireland

Objectives: Hereditary spastic paraparesis (HSP) is clinically and genetically heterogeneous. “Pure” autosomal dominant (AD) HSP is most common and eight genetic loci are identified to date. Previous studies have included...

Phenotype of AD-HSP due to mutations in the SPAST gene

"Pure" autosomal dominant hereditary spastic paraparesis (AD-HSP) is clinically and genetically heterogeneous. There are at least seven genetic loci with varying ages at onset and disability. The SPAST gene at the SPG4 locus on chromosome 2p is the major disease gene for AD-HSP. To investigate whether there are distinct clinical features among families with AD-HSP due to SPAST mutations compared with families excluded from SPG4. Nineteen families with "pure" AD-HSP were identified, and the clinical features of family members were compared using a standard protocol. With use of genetic studies, the families were divided into two groups for comparison: those with mutations in SPAST, the "mutation-positive" group, and those excluded from SPG4 on the basis of linkage studies, the "SPG4-excluded" group. Twenty-nine individuals from four families had mutations in SPAST, whereas 22 individuals from three families comprised the SPG4-excluded group; in 11 families, the pattern of linkage was unknown. In the one remaining family, no mutations were found despite strong linkage to SPG4. Different mutations were identified in the four SPAST pedigrees, but the clinical picture was similar in each. Comparison of the mutation-positive group with the SPG4-excluded group revealed an older age at onset (p = 0.03), more disability (p = 0.001), more rapidly progressive paraparesis (p = 0.044), and more cognitive impairment (p = 0.024) among affected individuals with SPAST mutations, not confounded by disease duration. Despite different mutations, SPAST families have a similar phenotype that can be distinguished from other genetic groups.

Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation.

To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.

Age-related cognitive decline in hereditary spastic paraparesis linked to chromosome 2p.

To investigate whether cognitive decline is part of the phenotype of SPG4-linked hereditary spastic paraparesis (HSP) and to determine whether cognitive changes are present in haplotype carriers before the onset of paraparesis. The major locus for "pure" autosomal dominant HSP is the SPG4 locus on chromosome 2p. Cognitive impairment linked to this locus has been described in two families. The authors identified 19 families with "pure" autosomal dominant HSP. Five had linkage to the SPG4 locus (maximum lod score for D2S2374: 5.99 at zero recombination in four smaller families and 3.86 at zero recombination in the largest family). Haplotype construction identified a disease haplotype for all families; 41 individuals carried this haplotype (30 affected by HSP, 11 unaffected). All haplotype carriers and 41 matched controls underwent Cambridge Cognitive (CAMCOG) examination. Nonparametric significance tests were used comparing total and subset scores. Haplotype carriers affected by HSP had lower total CAMCOG scores than control subjects (85.86/107 versus 96.2/107; p < 0.0005). The subsets of orientation, memory, language expression, and comprehension were also significantly lower. Ten individuals had scores < or =80/107, indicating mild dementia. Unaffected haplotype carriers had mean total CAMCOG scores lower than control subjects (91.82/107 versus 98. 09/107; p = 0.016). In both groups cognitive decline was age-dependent and scores diverged from control subjects from age 40. All SPG4-linked families showed the effect. Mild, age-related cognitive impairment is a feature common to these families. It illustrates variable phenotypic expression at this locus and may be the first manifestation of the disease gene in individuals as yet unaffected by paraparesis.

Cognitive impairment in families with pure autosomal dominant hereditary spastic paraparesis.

In the course of a study of a large family with pure autosomal dominant hereditary spastic paraparesis (AD-HSP), mild cognitive impairment was found in older family members. In order to determine if cognitive impairment occurred more frequently in families with pure AD-HSP than normally expected, a case control study of cognitive function in HSP was undertaken. Thirty-one patients, from 12 kindreds with pure AD-HSP, matched with 31 healthy control subjects for age, sex and years of education, were assessed for evidence of cognitive impairment using the Cambridge Cognitive Examination (CAMCOG). Twenty unaffected siblings matched with twenty healthy control subjects were similarly assessed. The total CAMCOG score in the affected group (mean 89.26/107, SD 11.08, 95% confidence interval 85.2-94.49) compared with the control group (mean 96.52/107, SD 5.52, 95% confidence interval 94.49-98.54) was significantly reduced (P = 0.0003). There were also significant abnormalities in three out of the nine subsets including memory (P = 0.0002), language comprehension (P = 0.0166) and language expression (P = 0.0025). The differences between the groups were due to cognitive impairment appearing after the age of 50 years in patients with AD-HSP; CAMCOG scores before this age were similar to control scores. There was also a minor non-significant difference in total CAMCOG score for the unaffected siblings (mean 93.7/107, SD 8.54, 95% confidence interval 89.70-97.70) compared with the control group (mean 97.9/107, SD 4.61, 95% confidence interval 95.7-100.1) (P < 0.02). This study demonstrates that mild cognitive impairment develops after the age of 50 years in patients with pure AD-HSP and is further evidence of degeneration in other systems in this disorder.

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance.

We report linkage of a family affected with autosomal dominant hereditary spastic paraparesis (HSP) and/or cognitive impairment to the HSP locus on chromosome 2p. To date all families linked to this locus have been affected with 'pure' HSP. The specific pattern of cognitive impairment in this family is characterised primarily by deficits in visuo-spatial functions. We also present genetic studies that indicate variable expression and low or delayed penetrance. We have constructed a haplotype flanked by polymorphic markers D2S400 and D2S2331 that was present in 12 individuals affected with spastic paraparesis. The severity of spasticity varied markedly among these individuals. In addition four of these individuals (aged 62-70) also had a specific form of cognitive impairment. The disease haplotype was also present in an individual (age 57) who had an identical pattern of cognitive impairment as the only sign of the disease supporting the hypothesis that spastic paraparesis and cognitive impairment are the result of variable expression of a single gene (rather than a co-incidental occurrence). Haplotype reconstruction for all participating family members revealed the presence of this disease haplotype in six individuals who had normal neurological and neuropsychological examinations. All six are below the maximal age of onset in the family--60 years. This is evidence for low or late penetrance of the AD HSP gene in this family. The identification of normal individuals carrying the disease haplotype demonstrates the importance of genetic studies in combination with clinical examination when counselling at risk family members.

Pure hereditary spastic paraparesis: an exclusion map covering more than 40% of the autosomal genome

Pure hereditary spastic paraparesis (HSP) is an upper motor neuron syndrome clinically characterized by slowly progressive weakness and spasticity of the legs. To determine the chromosomal location of the genetic defect, a five-generational Dutch family with autosomal dominant pure HSP was subjected to linkage studies. Analysis was carried out on 48 members spanning three generations, of whom 23 individuals are definitely affected. By screening the genome with a total of 167 microsatellite markers distributed over all autosomes, an exclusion map for HSP was constructed. Depending on the actual size of the human genome, our exclusion map covered between 40% and 65% of its autosomal length. Loci on chromosomes 1, 8, 13, 14, and 18 showed slightly positive lod scores. The areas around these loci were investigated more closely, but no conclusive evidence for, or against, linkage could be obtained.