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Background Hereditary spastic paraplegia (HSP), a genetically and clinically heterogeneous group of neurodegenerative disorders, is characterized by progressive lower limb weakness and spasticity. Among the 8 loci associated with the autosomal dominant uncomplicated HSP (AD-HSP), the spastin (SPG4) and atlastin (SPG3A) genes have been known to account for approximately 40% and 10% of all cases, respectively. Objective To investigate the contribution of these 2 genes in the occurrence of HSP in Korean patients. Design Clinical and genetic study. Setting Tertiary care center. Patients Eighteen patients with uncomplicated HSP (11 AD and 7 sporadic) underwent screening for gene mutation. Main Outcome Measures Mutations in the SPG4 and SPG3A genes as detected by direct sequencing of all coding exons and flanking intronic sequences. Results We identified 8 different SPG4 mutations, 7 of which have not been reported elsewhere. Among the detected mutations were 3 missense mutations, 2 in-frame deletions, 2 frameshift mutations, and 1 splice-site mutation. No mutation was found in the SPG3A gene. Conclusion Compared with previous studies, a higher frequency of SPG4 gene mutations in AD-HSP (7/11; 64%) was observed, suggesting that a mutation analysis for the SPG4 gene might be helpful for molecular diagnosis of AD-HSP in Korean patients. [ABSTRACT FROM AUTHOR]

Background Hereditary spastic paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic paraplegia. Atlastin1 mutations have been identified in 8 families so far. Objectives To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years. Patients and Methods We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients. Results We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 ± 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations. Conclusions This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A. [ABSTRACT FROM AUTHOR]

Background Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts for approximately 10% to 15% of all autosomal dominant hereditary spastic paraplegia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established. Objective To describe a kindred with an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene. Patients Complete neurological examination and genetic analysis were performed on 6 affected members of a small African American kindred. Linkage analysis to genetic markers near autosomal dominant hereditary spastic paraplegia loci on chromosomes 2p and 14q was performed. The coding sequence of the SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal controls. Results Every affected individual had signs of uncomplicated spastic paraparesis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis suggested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene revealed a missense mutation C635T, predicted to result in a threonine to isoleucine substitution at codon 156. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. Conclusion We report a novel mutation in the SPG3A gene in an African American family with an infantile onset of autosomal dominant hereditary spastic paraplegia. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia is a group of genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs. The most common form of hereditary spastic paraplegia is caused by mutations in the spastin gene (SPG4), which encodes spastin, an adenosine triphosphatase associated with various cellular activities protein. Objective: To investigate the Chinese patients with hereditary spastic paraplegia for mutations in SPG4. Methods: DNA samples from 31 unrelated patients were analyzed for mutations in SPG4 by single-strand conformation polymorphism analysis and direct sequencing. All DNA samples were screened for mutations by the polymerase chain reaction, followed by electrophoresis and silver staining. Each new variant identified was analyzed in 50 control subjects to determine whether it is a polymorphism or a mutation. Results: Three novel mutations were detected in 4 affected individuals, including 2 missense mutations (T1258A and A1293G) and 1 deletion mutation (1668-1670delCTA). Conclusions: To our knowledge, this is the first report of SPG4 mutations in the People's Republic of China. The percentage of involved Chinese families with autosomal dominant hereditary spastic paraplegia with an SPG4 mutation is 18% (4/22), lower than the estimated 40% linked to this locus. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia (HSP) with thin corpus callosum (CC) is a rare neurodegenerative disorder classified as a complicated form of spastic paraplegia. Some patients with HSP with thin CC have previously been described in Japanese families, and the genetic locus was linked to chromosome 15q13-15. Objective: Our objective was to further clinically and genetically characterize HSP with thin CC. Patients: We describe the clinical, structural, and functional follow-up and the genetic characterization of 2 sisters aged 26 and 31 years who had severe spastic paraplegia and cognitive impairment. Results: Magnetic resonance imaging revealed a thin CC with progressing frontoparietal cortical atrophy paralleled by cognitive decline. Using transcranial magnetic stimulation, we delineated a lack of transcallosal inhibition. Images obtained withfluorodeoxyglucose positron emission tomography showed reduced cortical and thalamic hypometabolism that decreased further within 4 years. Additionally, combined axonal loss and demyelinating sensorimotor polyneuropathy were present. Because other family members were not affected, autosomal recessive inheritance was considered likely. Genetic analysis of this autosomal recessive HSP was consistent with the linkage to 15q13-15 (markers D15S971, D15S118, D15S994, and D15S659). No mutation was found within the SLC12A6 gene. Conclusion: Progressive axonal degeneration occurs in the corticocortical projections, corticospinal tract, and peripheral nerves in HSP with thin CC linking to chromosome 15q13-15 in a German pedigree. [ABSTRACT FROM AUTHOR]

Background: Mutations in the ALS2 gene cause juvenile-onset autosomal recessive amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia. Objective: To assess the role of ALS2 among more common forms of ALS. Methods: DNA from 95 unrelated familial, 95 unrelated sporadic, and 11 early-onset ALS patients was screened for mutations in ALS2 by denaturing high-performance liquid chromatography and direct sequencing of polymerase chain reaction–amplified fragments. Each variant identified was also analyzed among control subjects. All 34 exons of ALS2 plus the 5′ and 3′ untranslated region were screened. Results: We detected 23 novel sequence variants; however, none is disease-associated. Conclusion: Mutations of ALS2 are not a common cause of ALS. [ABSTRACT FROM AUTHOR]

The hereditary spastic paraplegias (HSPs) are inherited neurologic disorders in which the primary symptom is insidiously progressive difficulty walking due to lower extremity weakness and spasticity. There have been great strides in our knowledge of this group of disabling disorders; 20 HSP loci and 9 HSP genes have been discovered. Insights into the molecular causes of HSPs are beginning to emerge. This review summarizes these advances in HSPs' genetics. [ABSTRACT FROM AUTHOR]

The article presents information on hereditary spastic paraplegias. Hereditary spastic paraplegias can be categorized as noncomplicated or complicated depending on whether additional neurologic signs, such as amyotrophy, ataxia, optic atrophy, or mental retardation, are present. Certain forms of complicated HSP may also manifest systemic abnormalities, including cataracts, gastroesophageal reflux, or gastrointestinal dysfunction. The continuing discovery of genes associated with HSP is the crucial initial step in developing powerful animal models of disease that should allow better understanding of basic pathophysiologic mechanisms.

Presents a letter to the editor about Charcot-Marie-Tooth disease type 2.

Presents a letter to the editor about Allan-Herdon-Dudley Syndrome.