Spastic Paraplegia 11, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-11 (SPG11) is caused by homozygous or compound heterozygous mutation in the gene encoding spatacsin (SPG11; 610844) on chromosome 15q21.

Biallelic mutation in the SPG11 gene can also cause autosomal recessive juvenile-onset amyotrophic lateral sclerosis-5 (ALS5; 602099) and autosomal recessive Charcot-Marie-Tooth disease type 2X (CMT2X; 616668), different neurodegenerative disorders with overlapping features.

Description

Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition to spasticity.

For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

Clinical Features

Nakamura et al. (1995) reported 2 families with autosomal recessive hereditary spastic paraplegia, mental impairment, and thin corpus callosum. In the first family, 3 affected brothers had onset in the second decade of gait disturbance resulting in wheelchair use by age 21 years. All 3 patients had an IQ less than 60. Other features included lower limb spasticity, slight ataxia, and mild sensory impairment. Three sisters from a second family, in which the parents were first cousins, had similar features to the affected brothers in the first family. Brain CT and MRI of 4 patients showed mild frontal and temporal cortical atrophy, mild ventricular dilatation, and widening of the frontal longitudinal fissure. All patients had a markedly thin corpus callosum which was not consistent with a degenerative process and was distinct from congenital agenesis (ACC; 217990) and partial agenesis (e.g., 304100) of the corpus callosum. Peripheral nerve biopsies showed decreased numbers of myelinated fibers, axonal degeneration, and abnormal Schwann cell inclusions.

Ueda et al. (1998) reported 2 Japanese sibs with SPG11 who showed thalamic glucose hypometabolism on positron emission tomography (PET) scan.

Winner et al. (2004) reported 2 German sisters with SPG11. The more severely affected sister had onset at age 24 years of a slowly progressive spastic paraplegia with increasing urinary urge incontinence and slow cognitive decline. Both sisters were obese, whereas no other family members were overweight. Serial MRIs showed a tendency toward progressive atrophy of the rostral corpus callosum, as well as symmetric white matter lesions. Transcranial stimulation showed a lack of transcallosal inhibition, and PET scan showed cortical and thalamic hypometabolism that decreased further within 4 years. Combined axonal loss and demyelinating sensory neuropathy were also present. No mutations were identified in the SLC12A6 gene (604878), which is mutated in agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000).

Casali et al. (2004) reported 18 patients from 12 Italian families with HSP-TCC; 2 of the families were consanguineous. The clinical phenotype was homogeneous, with gait difficulties beginning at a median age of 13 years (range 4 to 20 years) and progressing to loss of ambulation within approximately 10 years. Neurologic features included spasticity, pyramidal signs, hyperreflexia, and severe mental deterioration. MRI studies showed thin corpus callosum in all patients and periventricular white matter changes in 15 of 18 patients.

Lossos et al. (2006) reported 2 consanguineous Arab-Israeli families in which 2 sibs in each family had autosomal recessive HSP-TCC. All patients had onset of clinical symptoms during the second decade of life, with cognitive decline preceding gait disturbance by 2 to 5 years. Cardinal signs included pseudobulbar dysarthria, spastic paraparesis with lower limb hyperreflexia, upper limb hyperreflexia, extensor plantar responses, and distal amyotrophy. Brain imaging of 1 affected sib from each family showed thin corpus callosum, white matter abnormalities, and mild frontal atrophy. Two of 3 patients examined had mild axonal peripheral neuropathy. Two affected sibs in 1 family were obese.

Stevanin et al. (2007) reviewed the features of autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP-TCC). Cognitive impairment is first noticed in childhood and progresses insidiously to severe functional disability of a frontal type over a period of 10-20 years (Nakamura et al., 1995; Winner et al., 2004). Some affected individuals develop a pseudobulbar involvement, with dysarthria, dysphagia, and upper limb spasticity, associated with bladder dysfunction and signs of predominantly axonal, motor, or sensorimotor peripheral neuropathy. PET scan shows cortical and thalamic glucose hypometabolism. MRI shows thin corpus callosum that predominates in the rostral third, with hyperintensities in periventricular white matter and cerebral cortical atrophy predominating in the frontal region.

Del Bo et al. (2007) reported 27-year-old Italian opposite-sex dizygotic twins with autosomal recessive SPG11. The sibs had onset of ataxia and cognitive impairment at ages 12 and 15 years, respectively. The disorder progressed rapidly, leading to spastic paraplegia, dysarthria, and peripheral neuropathy. Both were wheelchair-bound in their early twenties. Brain MRI showed thin corpus callosum and cortical atrophy in both sibs. Both parents were healthy and came from the same small town in Sicily but denied consanguinity. Genetic analysis identified a homozygous mutation in the SPG11 gene (733delAT; 610844.0004).

Hehr et al. (2007) reported clinical details of 18 patients from 9 families with genetically confirmed SPG11. Several of the families had previously been reported by Olmez et al. (2006). The mean age at onset of walking impairment was 16 years (range, 8 to 31). Patients had predominantly lower limb paresis with proximal spasticity and hyperreflexia with extensor plantar responses. The gait was slow, spastic, and slightly ataxic. Dysarthria was noted in 85% of patients, and amyotrophy of the hypothenar and thenar muscles was commonly present. General mental impairment of varying degrees was present in 83%, and was associated with hypometabolism of the frontal cortex and thalamus on PET scan. MRI performed in at least 1 member of each family showed rostral atrophy of the corpus callosum and supratentorial white matter changes. Peripheral nerve biopsy showed hypomyelination of large fibers and loss of unmyelinated fibers, consistent with a clinical picture of mixed axonal and demyelinating polyneuropathy. Evidence also suggested disturbed axonal transport. The long-term course of 1 patient followed for 10 years showed progression of the disorder. Hehr et al. (2007) concluded that the disease process in SPG11 affects the corticospinal tract, major corticocortical connections via the corpus callosum, and the peripheral nervous system, and likely involves impaired axonal transport.

Samaranch et al. (2008) reported 4 Spanish patients with SPG11 confirmed by genetic analysis. All had some degree of mental retardation and a thin corpus callosum on brain imaging. The 3 older individuals had spastic paraparesis since late childhood and decreased brain metabolism on PET studies, predominantly in the thalamus and paracentral cortex of the hemispheres. Samaranch et al. (2008) postulated that the thalamic dysfunction may contribute to impaired attention.

Clinical Variability

Crimella et al. (2009) identified homozygous or compound heterozygous mutations in the SPG11 gene in 4 (40%) of 10 patients with SPG and thin corpus callosum and in 3 (8.5%) of 35 patients with SPG without thin corpus callosum. The molecular findings were consistent with a loss-of-function mechanism.

Orlen et al. (2009) reported 5 patients from 4 unrelated families with 5 truncating mutations in the SPG11 gene (see, e.g., 610844.0007-610844.0009). Two patients had delayed psychomotor development, 2 had onset at ages 3 and 4 years, respectively, and 1 had onset at age 14 years. Four patients were wheelchair-bound in the third or fourth decades; the fifth patient was only 14 at the time of the study and had a milder phenotype overall. The 4 older patients (ages 29 to 48) had lower limb spasticity, hyperreflexia with extensor plantar responses, sphincter disturbances, amyotrophy of the hands or calves, thin corpus callosum, cerebral atrophy, and periventricular white matter changes. All patients had some degree of cognitive dysfunction or mental retardation. Three were obese. An unusual finding in the 4 older patients was progressive central retinal degeneration, which was reminiscent of the phenotype for Kjellin syndrome (SPG15; 270700). Orlen et al. (2009) concluded that central retinal degeneration may be a previously unrecognized late-onset feature of this disorder.

Mapping

Martinez Murillo et al. (1999) performed genetic linkage analysis in 8 recessive familial spastic paraparesis families from America and Europe. The known recessive SPG loci, SPG5A, SPG7 (607259), as well as X-linked types of spastic paraplegia, SPG1 (303350) and SPG2 (312920), were excluded in 7 families; 1 family showed data consistent with linkage to the chromosome 8 locus. The other families showed positive lod scores for markers on 15q. The maximum multipoint combined lod score for non-chromosome 8 families was 3.14 for markers D15S1007, D15S971, D15S118, and D15S1012, at a distance of 6.41 cM from the marker D15S1007, in a region between D15S971 and D15S118. The data indicated a new locus for autosomal recessive familial spastic paraparesis on 15q13-q15, and the authors suggested that this may be a common form. Two of the 7 families linked to chromosome 15q had a complicated form of SPG with attenuation of the corpus callosum and mental deterioration; 3 families had SPG and pes cavus, but no abnormalities of the corpus callosum, and 2 families had a pure form of HSP.

In 10 of 13 Japanese families with complicated HSP with mental impairment and thin corpus callosum, Shibasaki et al. (2000) found linkage to chromosome 15q13-q15 (maximum multipoint lod score of 9.68 at a position 1.2 cM telomeric from D15S994 to D15S659).

Casali et al. (2004) demonstrated linkage to 15q13-q15 in 5 of 12 Italian families with HSP-TCC (maximum cumulative lod score of 3.35 at marker D15S659). Haplotype analysis excluded a founder effect. The absence of strong linkage to the SPG11 locus in 7 families indicated genetic heterogeneity.

By linkage and haplotype analysis of 2 consanguineous Arab-Israeli families with SPG and thin corpus callosum, Lossos et al. (2006) refined the candidate SPG11 locus to a 13-Mb (17-cM) interval on chromosome 15q13-q15 between markers D15S971 and D15S143 (maximum multipoint lod scores of 3.1 and 2.5 for the 2 families, respectively). A third consanguineous Arab-Israeli family with a similar phenotype was excluded from the SPG11 locus, indicating genetic heterogeneity.

Stevanin et al. (2006) reported 6 Mediterranean families with autosomal recessive HSP-TCC showing linkage to the SPG11 locus (positive lod scores at marker D15S659). Haplotype reconstruction allowed refinement of the locus to a 6-cM interval. Genetic analysis excluded mutations in the MAP1A (600178) and SEMA6D (609295) genes in the index patients from 5 families showing linkage to SPG11. Linkage to the SPG11 locus was excluded in 4 additional families with HSP-TCC, indicating genetic heterogeneity.

Stevanin et al. (2007) genotyped 12 families with ARHSP-TCC using 34 microsatellite markers in the candidate interval for SPG11 and the adjacent and overlapping loci for SPG21 (248900) and agenesis of corpus callosum with polyneuropathy (218000). Maximal positive multipoint lod scores ranging from 0.60 to 3.85, which corresponded to the maximal expected values in the pedigrees, were obtained in 10 families in the SPG11 interval. The combined multipoint lod score reached the value of 17.32 for these families. Linkage was not conclusive in the 2 remaining kindreds. Haplotype reconstructions in 2 consanguineous families with strong evidence for linkage to SPG11 further restricted the region most likely to contain the responsible gene to a 3.2-cM homozygous region between D15S778 and D15S659. This interval contains approximately 40 genes.

Molecular Genetics

Stevanin et al. (2007) analyzed 18 genes in the 3.2-cM SPG11 candidate interval by direct sequencing of all exons and their splicing sites, and identified 10 mutations in the KIAA1840 gene (610844) in 11 families. The KIAA1840 gene, encoding spatacsin, is expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus, and pineal gland. The mutations were either nonsense or insertions or deletions leading to a frameshift, suggesting a loss-of-function mechanism. All mutations were in the homozygous state except in 2 kindreds, in which affected individuals were compound heterozygous. Only 2 mutations were found in more than 1 pedigree: R2034X (604360.0001) in 3 consanguineous North African kindreds, and a 5-bp deletion in exon 3 (604360.0002) in 2 Portuguese families.

The SPG11 gene appears to be the one most frequently responsible for ARHSP-TCC. Only a single family (8%) in the cohort studied by Stevanin et al. (2007) did not have a mutation in SPG11, indicating that there is at least one other responsible gene. On the other hand, whether the SPG11 gene accounts for other clinical phenotypes of ARHSP remained to be determined.

Spastic paraplegias are believed to result from a dying back of exons. Mitochondrial metabolism, endosomal and trans-Golgi trafficking and axonal transport have been implicated in several HSPs (Crosby and Proukakis, 2002). Although the function of spatacsin remains unknown, the experimental evidence that it is expressed in all tissues and is highly conserved among species suggests that it has an essential biologic function. The possible presence of at least one transmembrane domain suggested that spatacsin may be a receptor or transporter.

In 18 patients from 9 unrelated families with SPG11, Hehr et al. (2007) identified 11 different mutations, including 10 novel mutations, in the SPG11 gene (see, e.g., 610844.0005-610844.0006) in the homozygous or compound heterozygous state. Four of the families were consanguineous, including 3 Turkish families initially reported by Olmez et al. (2006). Mutations were distributed throughout the entire spatacsin gene without obvious clustering.

Bauer et al. (2009) used high-resolution comparative genomic hybridization (HRCGH) to identify deletions in the SPG11 gene in 3 patients with SPG11 in whom only 1 mutant SPG11 allele had been identified by gene sequencing. HRCGH analysis suggested heterozygous genomic deletion in all 3 patients; however, quantitative PCR confirmed an 8.23-kb deletion in only 1 patient. The 8.23-kb deletion resulted in loss of exons 31 to 34 and was also found in the proband's affected sister and their unaffected father. The clinical features in the brother and sister did not differ from those of patients with point mutations.

Population Genetics

Boukhris et al. (2009) identified a molecular basis for hereditary spastic paraplegia in 13 (34.2%) of 38 unrelated families from southern Tunisia with the disorder. The most common forms of SPG were SPG11 in 7 (18.4%) families and SPG15 (270700) in 4 (10.5%) families. SPG4 (182601) and SPG5 (270800) were present in 1 family each.