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Brain Advance Access originally published online on December 13, 2007
Brain 2008 131(3):772-784; doi:10.1093/brain/awm293
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration

Giovanni Stevanin1,2,3,*, Hamid Azzedine1,2,4,*, Paola Denora1,2,5,*, Amir Boukhris1,2,3,6, Meriem Tazir7, Alexander Lossos8, Alberto Luis Rosa9, Israela Lerer10, Abdelmadjid Hamri11, Paulo Alegria12, José Loureiro13, Masayoshi Tada14, Didier Hannequin15,16, Mathieu Anheim17, Cyril Goizet1,2,18, Victoria Gonzalez-Martinez19, Isabelle Le Ber1,2, Sylvie Forlani1,2, Kiyoshi Iwabuchi20, Vardiela Meiner10, Goekhan Uyanik21, Anne Kjersti Erichsen22, Imed Feki6, Florence Pasquier23, Soreya Belarbi7, Vitor T. Cruz13, Christel Depienne1,2,3, Jeremy Truchetto1,2, Guillaume Garrigues19, Chantal Tallaksen22, Christine Tranchant17, Masatoyo Nishizawa14, José Vale12, Paula Coutinho13, Filippo M. Santorelli5, Chokri Mhiri6, Alexis Brice1,2,3, Alexandra Durr1,2,3 and on behalf of the SPATAX consortium{dagger}

1INSERM, U679, 2Université Pierre et Marie Curie - Paris 6, UMR S679, 3APHP, Département de Génétique et Cytogénétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, 4Centre de Référence de Neurogénétique, CHU d’Angers, France, 5Unit of Molecular Medicine, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy; 6Service de Neurologie, Hôpital Habib Bourguiba, Sfax, Tunisia, 7Service de Neurologie, Hôpital Mustapha, Algiers, Algeria, 8Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 9Laboratorio de Biologia Cellular y Molecular, Fundacion Allende and Sanatorio Allende, Cordoba, Argentina, 10Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 11Hôpital Benbadis, Constantine, Algeria 12Serviço Neurologia, Hospital De Egas Moniz, Lisboa, 13Departamento de Neurologia, Hospital S. Sebastiao, Santa Maria da Feira, Portugal, 14Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan, 15Department of Neurology, Rouen University Hospital and 16INSERM, U614, Rouen, France, 17Neurology Department, Hôpital Civil, Strasbourg, France, 18Service de Génétique, Hôpital Pellegrin, Bordeaux, France, 19Service de Neurologie, CHU de Montpellier, Hôpital Gui de Chauliac, Montpellier, France, 20Neurological Clinic of Yokohama, Yamate, Japan, 21Department of Neurology, University of Regensburg, Germany, 22Ulleval University Hospital, Oslo, Norway and 23Centre Hospitalier Régional Universitaire, EA2691, Lille, France

Correspondence to: Prof Alexis Brice, INSERM U679, IFR de Neurosciences, Pitié-Salpêtrière Group, 47 Bd de l'Hôpital, 75013 Paris, France E-mail: brice{at}ccr.jussieu.fr


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Introduction
 Materials and Methods
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Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

Key Words: spastic paraplegias; SPG11; thin corpus callosum; mental retardation; lower motor neuron degeneration

Abbreviations: AR, autosomal recessive; HSP, hereditary spastic paraplegias; IQ, intellectual quotient; LL, lower limbs; MMSE, Mini Mental State Evaluation; UL, upper limbs; SPG, spastic paraplegia gene; TCC, thin corpus callosum; WMA, white matter abnormalities

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Received September 28, 2007. Revised November 3, 2007. Accepted November 8, 2007.


   Introduction
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 Summary
 Introduction
Materials and Methods
 Results
 Discussion
 Supplementary materials
 Appendix
 References
 
Hereditary spastic paraplegias (HSP) are neurodegenerative conditions in which the main clinical features are progressive spasticity and weakness of the lower limbs associated with posterior column or bladder involvement (Harding, 1983Go; Filla et al., 1992Go; Tallaksen et al., 2001Go). This phenotype can be complicated by the presence of a wide range of additional neurological and non-neurological signs or symptoms including mental retardation, deafness, cerebellar ataxia, epilepsy, dysarthria, ichthyosis, optic atrophy, peripheral neuropathy, retinitis pigmentosa, cataract, etc. These diseases are inherited in an autosomal dominant, autosomal recessive (AR) or X-linked manner and a wide genetic heterogeneity has been demonstrated with the identification of more than 33 loci and 15 genes (Fink, 2006Go; Mannan et al., 2006Go; Valdmanis et al., 2007Go; Stevanin et al., 2007Go). The most common forms of autosomal dominant HSP, accounting for about 50% of patients, are caused by mutations in the SPG4 and SPG3A genes that encode for spastin and atlastin, respectively (Hazan et al., 1999Go; Zhao et al., 2001Go).

In AR-HSP, observed more frequently than autosomal dominant HSP in inbred populations (Coutinho et al., 1999Go), the first three genes identified that encode paraplegin (SPG7), spartin (SPG20) and maspardin (SPG21) (Casari et al., 1998Go; Patel et al., 2002Go; Simpson et al., 2003Go), as well as the gene responsible for the related spastic ataxia of Charlevoix Saguenay (Engert et al., 2000Go), represent only a small proportion of all cases (Fink, 2003Go). Strikingly, about one-third of AR-HSP index patients have a thin or atrophied corpus callosum (ARHSP-TCC) visualized by MRI with different degrees of cognitive deficit (Franca et al., 2007Go). This form of AR-HSP was initially mapped to chromosome 15q13-15 [SPG11, (Martinez et al., 1999Go)] and accounts for 41–77% of reported ARHSP-TCC families (Shibasaki et al., 2000Go; Casali et al., 2004Go; Stevanin et al., 2006Go). Recently, the SPG11 gene, also known as KIAA1840/FLJ21439, that encodes spatacsin, was identified and was mutated in 11 of 12 ARHSP-TCC index patients (Stevanin et al., 2007Go). Ten different mutations were identified in the 11 families. They were either nonsense mutations, deletions or insertions in the SPG11 coding sequence, resulting theoretically in an abnormally truncated protein in all cases.

The aims of the present study were to estimate the frequency of SPG11 mutations in a large series of patients with ARHSP with or without TCC, mental retardation or cognitive impairment, to define the spectrum of the mutations in this gene and to describe the associated phenotypes.


   Materials and Methods
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 Summary
 Introduction
 Materials and Methods
Results
 Discussion
 Supplementary materials
 Appendix
 References
 
Subjects
Forty-three kindreds with an autosomal recessive inheritance and 33 isolated cases with no family history of the disease were selected, 22 and 5 of which were consanguineous, respectively. Index patients presented with either (i) spastic paraplegia with a mental retardation or cognitive impairment and TCC visualized at MRI (n = 26), (ii) spastic paraplegia with TCC without mental retardation and cognitive impairment (n = 11) or (iii) spastic paraplegia with mental retardation or cognitive impairment without TCC (n = 22). In addition, 17 index patients presenting with spastic paraplegia and mental retardation or cognitive impairment for which MRI was not available were also analysed. This study has been approved by the local Bioethics committee (approval no 03-12-07 of the Comité Consultatif pour la Protection des Personnes et la Recherche Biomédicale Paris-Necker to Drs A. Durr and A. Brice). Informed written consent has been given by all participating members of the families before blood samples were collected for DNA extraction. All clinical evaluations were performed according to a protocol established by the European and Mediterranean network for spinocerebellar degenerations (SPATAX, coordinator: Dr A. Durr) that included: full medical history and examination, estimation of the age at onset by the patient, presence or absence of additional neurological symptoms/signs, electroneuromyographic (ENMG) studies and brain MRI when possible. IQ or Mini Mental State Evaluations (MMSE) (Folstein et al., 1975Go) were available for 12 patients, two of whom had detailed neuropsychological evaluations including Standard Progressive Matrices [PM38, (Raven, 1982Go)] and the Wechsler Memory Scale (Wechsler, 1987Go). According to the DSM-IV criteria (Diagnosis and statistical Manual of Mental disorders, 2000Go), mental retardation was considered when the patient had an IQ < 70 before the age of 18 years.

Most patients were French (n = 37) or North-African (n = 15), or originated from other European countries (n = 13), the Middle-East (n = 6) and elsewhere (n = 5). Eleven of the 33 sporadic subjects previously tested negative for mutations or rearrangements in the SPG4 gene (Depienne et al., 2006Go, 2007Go); mutations in the SPG7 gene were also excluded in a subset (n = 20/43) of families (Elleuch et al., 2006Go).

Genotyping
Linkage to SPG11 was investigated in 33 AR-HSP families using the polymorphic markers D15S781, D15S537, D15S516 and D15S659 after DNA amplification by polymerase chain reaction (PCR); the amplicons were sized on an ABI Prism 3730 automated sequencer with GenMapper software (Applied Biosystems, Foster City, CA, USA), as previously described (Stevanin et al., 2006Go). After haplotype reconstruction, putative linkage was established on the basis of common haplotypes by descent in affected relatives of the same pedigree.

Mutation detection
The coding sequence and splice site boundaries of the 40 exons of the SPG11 gene were amplified by PCR and sequenced in both directions as described previously (Stevanin et al., 2007Go).

Numbering of new mutations/polymorphisms was performed relative to the ATG codon of the first coding exon, as recommended by the Human Genome Variation Society (http://www.hgvs.org/mutnomen/). Segregation of the mutations/polymorphisms with the disease was verified by direct sequencing in 64 additional family members whose DNA samples were available. In addition, unrelated healthy subjects were screened to evaluate the frequency of nucleotidic changes: 80 French Caucasians, 31 North-Africans, 103 Palestinians and 48 individuals from Argentina. Synonymous, missense and splice-site variations were systematically evaluated for modifications of exonic splicing enhancers (ESEfinder algorithm available at http://www.rulai.cshl.edu/cgi-bin/tools/ESE/esefinder.cgi) or consensus splicing sequences (at http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html and http://www.fruitfly.org/seq_tools/splice.html). Multiple alignment with spatacsin orthologs in various species was performed using ClustalW software (http://www.ebi.ac.uk/clustalw/) to evaluate conservation of missense variants.

The effect on mRNA splicing of a variant affecting the last codon of exon 15 was analysed by RT-PCR on RNA extracted from the lymphoblasts of patient FSP670-5, as reported elsewhere (Stevanin et al., 2007Go) using primers cDNAF—GCTCTGTGGTGGGATCAACT (exon 14) and cDNAR—TGCTTACACTGGCCTGATTG (exon 18) at an annealing temperature of 60°C, followed by direct sequencing of the PCR product.


   Results
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 Summary
 Introduction
 Materials and Methods
 Results
Discussion
 Supplementary materials
 Appendix
 References
 
Linkage studies
We initially analysed the segregation of four microsatellite markers tightly flanking the SPG11 gene in 33 kindreds, in which at least two affected patients were sampled. Twelve families were excluded because no common haplotypes segregated with the disease in affected relatives. In 21 families (64%), the reconstruction of the haplotypes was compatible or did not exclude linkage to SPG11. In these 21 families, the SPG11 gene was sequenced.

SPG11 mutation screening
Direct sequencing of the SPG11 gene was performed in 64 unrelated index patients, including the probands of the 21 putatively linked families mentioned earlier and 43 index patients not analysed by linkage studies. We identified 22 truncating mutations in the index patients of 20 families, 19 were newly identified variants (Table 1). In 14 of these families, the mutations were homozygous. In six kindreds, the patients had two compound heterozygous mutations. The mutations segregated with the disease in the families where this could be tested (Supplementary figure). Unaffected relatives (n = 47) never had two mutations in the SPG11 gene.


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  		Table 1 SPG11 mutations

 
Most mutations were nonsense mutations (n = 4, three new); small deletions (n = 13, 11 new) or insertions (one new). In addition, we identified four new mutations predicted to affect the splicing of the KIAA1840 mRNA and that were not found on at least 160 and 62 Caucasian and North-African control chromosomes, respectively. In the Israeli-Arab family FSP670, the homozygous c.2833A>G mutation in the last conserved codon of exon 15, leading to the missense variation p.R945G, was also shown to affect the 5' splice consensus site (score of +2.7 versus +4.9 for the wild-type sequence). This in silico prediction was confirmed on mRNA isolated from lymphoblasts of an affected family member (FSP670-5) in which an alternative donor splice site is generated downstream in intron 15 leading to a 65 bp insertion and a premature stop codon (Fig. 1; r.2834 + 1_2834 + 65ins, p.R945GfsX5). The c.2833A>G mutation was also absent from 103 healthy unrelated Palestinians. In families FSP847 and FSP892, homozygous G>A transitions at positions c.869 + 1 and c.2316 + 1 in intron 4 and intron 12 were predicted to strongly alter the consensus sequence score from +9.8 to –0.9 and from +6.2 to –4.5, respectively. The c.869 + 1G>A mutation, found in family FSP847, was also absent from 48 healthy unrelated Argentineans. The single patient from family FSP830, who carried a heterozygous nonsense mutation in exon 6 (c.1282A>T, p.K428X), also carried an A>G transition at position c.6477 + 4 in intron 34 for which the splice score (http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html) was reduced from +9.6 to +6.6. Living cells were not available, however, to confirm the in silico predictions of missplicing in families FSP847, FSP892 and FSP830.


Figure 1
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  		Fig. 1 Mutation c.2833A>G in family FSP670 alters SPG11 mRNA splicing. (A) The electrophoregram shows the c.2833A>G mutation. (B) Pedigree and segregation of the mutation in the family. Square symbols represent men, the circles represent women. The filled symbols are affected individuals. The numbers are an internal reference for each sampled individual. Stars indicate sampled subjects. M = mutation; + = wild type. (C) Agarose gel separation of the PCR products generated from SPG11 cDNA from an affected subject and controls showing abnormal processing of the mRNA (D) Graphical representation of the effect of the mutation. Exons are boxed. An alternative donor splice site in intron 15 is used in the mutant allele leading to a 65 bp insertion and a premature stop codon.

 
The 22 identified mutations were located in—or close to—15 different exons throughout the gene, from exon 1 to exon 37. However, two of these mutations were found in more than one family. Mutation c.6100C>T/p.R2034X was found in four different kindreds from Algeria, Morocco and Tunisia and was previously reported in three North African families (Stevanin et al., 2007Go). Portions of the haplotypes reconstructed with four closely flanking markers were similar in the four new kindreds and in families previously reported, indicating a common ancestral mutational event (Table 2). The new mutation c.6737_6740delTTGA/p.I2246_E2247>S2246fsX was found in two families from Japan (homozygous) and from Algeria (heterozygous) associated with different haplotypes as expected. In addition, the c.529_533delATATT/p.I177_I178del>S177fsX mutation (Stevanin et al., 2007Go), previously found in two Portuguese families, was found in another kindred from the same country (FSP831), associated with the same haplotype (Table 2). In contrast, the c.733_734delAT/p.M245VfsX mutation, previously found on two different ancestral chromosomes in Italian and French families (Del Bo et al., 2007Go), was homozygous in patients from a Tunisian kindred associated with different haplotypes, suggesting independent mutational events or a very ancient mutation.


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  		Table 2 Haplotypes of four close flanking markers segregating with the recurrent mutations in the SPG11 gene in this study and in previous reports (Stevanin et al., 2007Go; Del Bo et al., 2007Go)

 
Four exonic nucleotide variants present in patients but also in >2% of control chromosomes from France and North Africa are likely to be polymorphisms: c.808G>A/p.V270I (1.5 versus 2.3% in controls), c.1388T>C/p.F463S (47 versus 51%), c.3420G>A/p.L1140L (2.3 versus 3.3%) and c.7023C>T/p.Y2341Y (1.5 versus 7.1%). The p.F463S and p.L1140L variants have already been described in the NCBI (http://www.ncbi.nlm.nih.gov) and Ensembl (http://www.ensembl.org) human genome databases, and the silent changes at residues 1140 and 2341 occurred in the presence of homozygous truncating mutations in the SPG11 gene. None of them were shown to modify splice sites. Three additional intronic polymorphisms were detected at positions –139A>G and –141A>C upstream exon 8, and +62C>T downstream exon 37 but were not predicted to cause missplicing of the SPG11 gene.

Clinical characteristics of the 20 new SPG11 families (38 patients)
Six families were North African (two Algerian, two Tunisian and two Moroccan), eight European (four from Portugal, two from France, one from Romania and one from Norway), four Middle-Eastern (two Israeli, one of which of Arabic origin, one Turkish and one Saudi-Arabian) and one each from Argentina and Japan.

Most of the families (65%) had a clear autosomal recessive mode of inheritance, whereas seven index patients (35%), including five without consanguinity, had no family history of neurological disorders.

Age at onset in 37 SPG11 patients ranged from 2 to 27 with a mean of 14.0 ± 5.9 years. Onset was, in most cases, characterized by gait disorders (30/38, 79%), or less frequently by mental retardation (6/38, 16%), rarely dysarthria and tremor (one each). After a mean disease duration of 14.9 ± 6.6 years (range: 2–35), all patients had a severe clinical picture that included progressive spastic paraplegia (Table 3): most were at least wheelchair bound (20/38, 53%) or needed assistance for walking (6/38, 16%), but 12 could still walk without help (Fig. 2). While only 12% of the patients were confined to a wheelchair or bedridden after <10 years of disease, 60% were in this condition after 18 years of evolution (Fig. 2). Patients were wheelchair bound after a mean disease duration of 16.5 ± 5.8 years (range 9–35, n = 20). Lower limb spasticity was severe in 25/37 (67%), associated with severe weakness in 19/37 (51%). Distal or generalized wasting was also noted in 20/38 (53%). Dysarthria was frequently observed (n = 16/38, 42%). Mental retardation, illustrated by learning difficulties in childhood, was present in 12 patients and confirmed in eight who had a mean IQ of 58 ± 9 (range: 45–69). In addition, in 80% (24/30) of the patients, cognitive decline was evident on examination and worsened with time. MMSE scores were low in 4/5 patients tested (<23/30). Only one patient, who had the shortest disease duration (FSP683-3, 2 years), had no mental retardation and cognitive decline. Two patients underwent detailed neuropsychological evaluation (FSP522-1 and FSP75-21). The non-verbal evaluation of global cognitive efficiency in patient FSP522-1 was normal (PM38 = 46/60), but she had a severe memory impairment (Wechsler Memory Quotient = 72/140) associated with reduced verbal fluency and an attention deficit indicative of executive dysfunction. A second evaluation, 5 years later, showed deterioration of her cognitive status. Patient FSP75-21, who had mental retardation (IQ = 56), showed a MMSE score of 21/30 at 35 years with psychiatric and cognitive difficulties that included auditory hallucinations and executive dysfunctions.


Figure 2
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  		Fig. 2 Severity according to disease duration in SPG11 patients.

 

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  		Table 3 Clinical features of 38 patients with mutations in the SPG11 gene

 
Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus were noted in seven patients, most of whom had disease durations >15 years (5/21 versus 2/17). There was pes cavus in eight patients, scoliosis in five and other signs were occasionally observed: parkinsonism, orthostatic hypotension, macular excavation or degeneration, strabismus. Four patients, all with disease durations of >18 years, had swallowing difficulties.

Interestingly, ENMG detected lower motor neuron involvement in 13/16 (81%) after a mean disease duration of 14.4 ± 4.9 years (Table 4). In two patients, there was clear anterior horn involvement, while in the others there was axonal neuropathy. Brain MRI showed a TCC (20/21, 95%), with cortical atrophy (17/21, 81%) and associated with diffuse white matter hyperintensities on T2 images (13/19, 69%). The atrophy of the corpus callosum was found in all but one patient (FSP400-5, 7-year disease duration), but with variable intensity (Fig. 3). Leucoencephalopathy was periventricular and confluent, and its severity increased with disease duration. In mild cases, only frontal and occipital periventricular damage was seen (Fig. 3). Finally, visual evoked potentials were abnormal in three out of five patients, indicating an even more diffuse distribution of the lesions.


Figure 3
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  		Fig. 3 Brain MRI images of three patients with different disease durations. (A) T1-weighted sagittal image showing thin corpus callosum and global cortical atrophy, (B) T2–Fast Spin Echo weighted axial and coronal images showing periventricular hyperintensities of variable severity according to disease duration.

 

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  		Table 4 Paraclinical investigations in 27 SPG11 patients

 

   Discussion
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 Introduction
 Materials and Methods
 Results
 Discussion
Supplementary materials
 Appendix
 References
 
The identification of 22 different truncating mutations (19 new) distributed throughout the SPG11 gene (Fig. 4) emphasizes the need to analyse the whole gene in clinical practice. Only two of these mutations were found in more than two families in this study and previous studies, suggesting regional founders in these populations (Stevanin et al., 2007Go): the recurrent mutation c.6100C>T/p.R2034X in families from North Africa where it accounted for 70% of the reported cases (7/10 mutated families); the c.529_533delATATT/p.I177_F178>S177fsX mutation in Portuguese families (3/6 mutated families). Conserved haplotypes for flanking microsatellite markers were associated with these mutations.


Figure 4
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  		Fig. 4 Schematic representation of the SPG11 gene showing the location of the known (up) and new (down) mutations. # reported by Stevanin et al., 2007Go and DelBo et al., 2007Go.

 
Most of the 20 new SPG11 families originated from the Mediterranean basin, but mutations were also found in families from Scandinavia, Japan and South America, indicating a worldwide distribution of this clinico-genetic entity, as previously suggested (Shibasaki et al., 2000Go; Casali et al., 2004Go; Winner et al., 2006Go; Stevanin et al., 2006Go; Olmez et al., 2006Go).

When the eleven previously reported cases (Stevanin et al., 2007Go) from our series are taken into account, SPG11 mutations are found in ~26% (9/35) of apparently sporadic HSP with TCC patients and ~40% (22/53) of subjects with complex AR-HSP. Interestingly, the frequency varies widely according to the phenotype (Table 5). SPG11 mutations were found in 59% of patients with TCC and mental impairment collected by our network, a frequency very close to the 41–77% of families from Italy, Japan and Mediterranean countries found in previous linkage analyses (Shibasaki et al., 2000Go; Casali et al., 2004Go; Stevanin et al., 2006Go). Mutations in SPG11 accounted for only a single family (1/22, 4.5%) of the subgroup of patients with HSP and cognitive impairment without TCC, but patients from this kindred had mild white matter changes and cortical atrophy after a short disease duration of 7 years. SPG11 is therefore the major identified cause of HSP-TCC and, when taking into account the proportion of 1/3 of HSP-TCC among ARHSP (Franca et al., 2007Go), SPG11 is responsible for ~21% of families with ARHSP, making it the most frequent cause of this disease.


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  		Table 5 Frequency of SPG11 mutations according to the phenotype

 
The clinical features of the SPG11 patients studied here were similar to previous reports (Shibasaki et al., 2000Go; Casali et al., 2004Go; Winner et al., 2006Go; Stevanin et al., 2006Go; Lossos et al., 2006Go), with a broader range of ages at onset (2–27 years). SPG11 is severe since patients were wheelchair bound after a mean disease duration of 16.5 ± 5.8 years (range 9–35, n = 20) compared to 26.6 ± 15 years (range 5–49, n = 5) in SPG4 patients (Depienne et al., 2006Go, 2007Go). Mental retardation or cognitive impairment and atrophy of the corpus callosum are the hallmarks of this disorder, but they may be lacking in patients with short disease durations (<10 years). Another frequent sign is axonal neuropathy, sometimes associated with anterior horn signs, observed in 81% of affected subjects. This is indicative of lower motor neuron degeneration and may clinically mimic amyotrophic lateral sclerosis when wasting is marked. White matter abnormalities are also frequently observed on MRI (69%). They start in the periventricular regions close to the frontal and occipital horns and increase in frequency and severity with disease duration, which may lead to a misdiagnosis of leucodystrophy. Finally, cerebellar ocular signs may also occur as the disease progresses.

The phenotype of 21 patients from 15 kindreds with TCC and mental impairment but no mutations in SPG11 did not differ from SPG11 patients except for an earlier mean age at onset of 9.6 ± 13.0 (range: 6 months to 50 years). Gait instability was the sign at onset in all patients and cerebellar signs were present in 5. Eight of these 15 individuals were sporadic.

In summary, the presence of HSP-TCC is the best single indicator that SPG11 should be tested in patients with onset in the first to third decade, but the presence of one or more other signs, such as mental retardation and later cognitive deterioration, lower motor neuron involvement and white matter lesions, increases the chance of identifying SPG11 mutations. Additionally, evidence of white matter abnormalities in the periventricular regions increases even further the probability that SPG11 is the cause of the disease, rather than other causes of leucodystrophy. HSP mainly affects the corticospinal axons by a dying back mechanism but lesions in SPG11 are wider, as suggested by the identification of TCC and other white matter abnormalities, signs of lower motor neuron degeneration, cerebellar ataxia and abnormal visual evoked potentials. Further studies are now required to understand the effects of these mutations, all truncating, causing the loss of spatacsin function in upper and lower motor neurons as well as in other regions of the nervous system.


   Supplementary materials
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 Introduction
 Materials and Methods
 Results
 Discussion
 Supplementary materials
Appendix
 References
 
Supplementary materials are available at Brain online.


   Appendix
Top
 Summary
 Introduction
 Materials and Methods
 Results
 Discussion
 Supplementary materials
 Appendix
References
 
Members of the Spastic Paraplegia and ATAXia network (SPATAX): Dr A. Durr (Hôpital Pitié-Salpêtrière, Paris, France), Pr B. Fontaine (Hôpital Pitié-Salpêtrière, Paris, France), Pr J.P. Azulay (Hôpital de la Timone, Marseille, France), Pr A. Benomar (CHU, Rabat, Morocco), Pr E. Bertini (Osp. Bambino Gesù, Roma, Italy), Dr O. Boespflug-Tanguy (Faculté de Médecine, Clermont-Ferrand, France), Pr P. Coutinho (Hospital San Sebastião, Santa Maria da Feira, Portugal), Pr A. Filla (Università Degli Studi Di Napoli Federico II, Napoli, Italy), Pr D. Hannequin (Hôpital Charles Nicolle, Rouen, France), Dr A. Hamri (Hôpital Benbadis, Constantine, Algeria), Pr Michel Koenig (IGBMC, Illkirch, France), Pr P. Labauge (Hôpital Caremeau, Nimes, France), Pr A. Lossos (Hadassah Hebrew University Hospital, Jerusalem, Israel), Pr A. Megarbane (Université Saint-Joseph, Beirut, Lebanon), Pr J.E. Nielsen (The Panum Institute, Copenhagen, Denmark), Pr A.M. Ouvrard Hernandez (CHU, Grenoble, France), Dr E. Reid (Addenbrooke's Hospital, Cambridge, UK), Dr D. Rodriguez (Hôpital St Vincent De Paul, Paris, France) Pr S. Roumani (Dpt of Neurology, Damascus, Syria), Pr M. Salih (University Hospital, Ryadh, Saudi Arabia), Pr J. Sequeiros (University of Porto, Porto, Portugal), Dr C. Tallaksen (Ullevål University Hospital, Oslo, Norway), Pr M. Tazir (CHU Mustapha, Algiers, Algeria), Pr F. Tison (Groupe Hospitalier Sud, Pessac, France), Dr C. Goizet (Hôpital Pellegrin, Bordeaux, France), Dr E.M. Valente (Istituto Di Genetica Medica, Roma, Italy), Pr N. Wood (The National Hospital, London, UK), Dr C. Verny (CHU, Angers, France) and Pr T. Warner (Royal Free and University College Medical School, London, UK).


   Footnotes
 
*The first three authors contributed equally to this work. Back

{dagger}The members of the SPATAX consortium are listed in the Appendix. Back


   Acknowledgements
 
The authors are grateful to the families and to the clinicians who referred patients to us, to Drs Samir Belal, Sebahattin Cirak, Michel Koenig, Clotilde Lagier-Tourenne and Merle Ruberg for their contribution in this study, to Drs Nizar Elleuch, Mohamed Imed Miladi, Catherine Lubetzki, Pilar Mazetti and Frederic Sedel for additional clinical investigations and to Nawal Benammar, Elodie Denis, Estelle Ferdiko and the DNA and cell bank of IFR70 for technical assistance. The study was funded by the Agence Nationale pour la Recherche (France, to A.D. and G.S.), the Verum foundation (Germany, to A.Br), the Hadassah France Fund for studies in spastic paraplegia (France, to A.L.) and the Groupement d’Intérêt Scientifique – Institut des Maladies Rares (France, A04180DS/A04139DS to G.S.). P.D. and F.M.S. were supported by grants from Fondazione Mariani ONLUS and Telethon Italy (GGP06188).


   References
Top
 Summary
 Introduction
 Materials and Methods
 Results
 Discussion
 Supplementary materials
 Appendix
 References
 
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