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Feb 9, 2009 - Mathieu Anheim. Clotilde Lagier-Tourenne ... Michel Koenig. Christine Tranchant ... Mathieu Anheim · C. Lagier-Tourenne ·. J. L. Mandel · M.
J Neurol (2009) 256:104–108 DOI 10.1007/s00415-009-0083-3

Mathieu Anheim Clotilde Lagier-Tourenne Giovanni Stevanin Marie Fleury Alexandra Durr Izzie Jacques Namer Paola Denora Alexis Brice Jean-Louis Mandel Michel Koenig Christine Tranchant

Received: 4 April 2008 Received in revised form: 26 July 2008 Accepted: 8 August 2008 Published online: 9 February 2009

ORIGINAL COMMUNICATION

SPG11 spastic paraplegia A new cause of juvenile parkinsonism

G. Stevanin · A. Durr · A. Brice Assistance Publique-Hôpitaux de Paris (AP-HP) Groupe Hospitalier Pitié-Salpêtrière Département de Génétique et de Cytogénétique Paris, France I. J. Namer Service de Biophysique et Médecine Nucléaire Hôpital de Hautepierre CHU Strasbourg, France

Dr. M. Anheim (쾷) · M. Fleury · C. Tranchant Dépt. de Neurologie Hôpital Civil Centre Hospitalier Universitaire de Strasbourg 1 place de l’Hôpital 67000 Strasbourg, France Tel.: +33-388/116662 Fax: +33-388/116343 E-Mail: [email protected] Mathieu Anheim · C. Lagier-Tourenne · J. L. Mandel · M. Koenig Institut de Génétique de Biologie Moléculaire et Cellulaire CNRS/INSERM/Université Louis Pasteur Illkirch, France G. Stevanin · A. Durr · P. Denora · A. Brice INSERM UMR_S679 Paris, France

JON 3083

G. Stevanin · A. Durr · P. Denora · A. Brice UPMC Univ Paris 06 UMR_S679 Groupe Hospitalier Pitié-Salpêtrière Paris, France

■ Abstract Autosomal recessive hereditary spastic paraplegia (AR HSP) with thin corpus callosum (TCC) is a rare neurodegenerative disorder often caused by mutations in the gene encoding for spatacsin at the SPG11 locus on chromosome 15q. The disease is characterized by progressive spastic paraparesis and mental retardation which occur during the first two decades of life and frequently with peripheral neuropathy. Brain magnetic resonance imaging (MRI) reveals typical TCC with periventricular white matter changes. We describe two patients, of Turkish descent, from the same consanguineous family and affected with SPG11 in association with unusual early-onset parkinsonism. Parkinsonism occurred

during the very early stages of SPG11 in both patients, being in one the inaugural symptom of the disease presented as a resting tremor with akinesia, rigidity and expressing an initial moderate levodopa-response that progressively weakened. The second patient presented a resting tremor with mild akinesia and no levodopa-response. Both patients were affected with progressive spastic paraparesis which had initially occurred at 15 and 12 years of age, respectively, in association with mild mental retardation and an axonal polyneuropathy. TCC with periventricular white matter changes (PWMC) was evident by MRI and 123I-ioflupane SPECT was abnormal. Genetic analysis detected for both patients a new c.704_705delAT, p.H235RfsX12 homozygous mutation in SPG11. This report provides evidence that parkinsonism may initiate SPG11linked HSP TCC and that SPG11 may cause juvenile parkinsonism. ■ Key words parkinsonism · spastic paraplegia · SPG11 · thin corpus callosum

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Introduction Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurodegenerative diseases leading to progressive spasticity of the lower limbs. AR HSP with thin corpus callosum (TCC) (MIM 604360) is a rare disorder characterized by gradual spastic paraparesis, mental retardation and peripheral neuropathy [10, 18]. Onset usually occurs within the second decade of life [10]. Magnetic resonance imaging (MRI) reveals a thinning of the anterior corpus callosum (TCC) and periventricular white matter changes (PWMC) that often appear during the course of the disease [6]. Most AR HSP TCC patients have been proved to be linked to the SPG11 locus on chromosome 15q [9] and to be the result of mutations in the SPG11 gene, encoding spatacsin [13, 15, 17]. AR HSP TCC is considered clinically to be a relatively homogeneous disease. We report two patients from a Turkish consanguineous family with a truncating mutation in the SPG11 gene, who display early-onset parkinsonism, inaugural in one case, with 123I-ioflupane SPECT evidence of bilateral asymmetrical nigro-striatal loss.

Patients and methods ■ Case 1 Patient 1 is a 28 year-old girl of Turkish origin born from a second degree consanguineous marriage. At 12 years, she was referred because of a bilateral, marked resting tremor which predominated on the right side, while a moderate postural tremor was also present along with moderate akinesia and rigidity. She had mild mental retardation. Neurological examination revealed brisk reflexes, bilateral Babinski sign and a reduced sense of vibration. Fundus was normal. Levodopa responsiveness had been moderate at the onset of the disease. The UPDRS motor score improved from 44 to 33 following treatment with 200 mg levodopa when she was 22 years old. A daily dose of 300 mg of levodopa was administered though the patient’s tolerance limit had been reached, as signalled by vomiting and dizziness despite the use of domperidone. Both extrapyramidal and pyramidal

syndromes worsened progressively and the patient became wheelchair-bound at 22 years. The response to levodopa weakened and the reduction in the UPDRS motor score decreased (e. g., from 50 to 45) following intake of 200 mg levodopa when 28. At 15 years of age, brain MRI had detected TCC with PWMC (Fig. 1 a) though the spinal cord MRI was normal. Electroneuromyography revealed axonal sensory peripheral neuropathy of the lower limbs. Exhaustive laboratory investigations proved negative and genetic analysis excluded Friedreich’s ataxia. ■ Case 2 Patient 2, the youngest brother of patient 1 displayed, when aged 15, spastic paraparesis with bilateral Babinski sign and brisk reflexes, though none at the ankles, in association with mental deterioration. The corresponding mini mental state examination (MMSE) score was 21/30, while the Frontal Assessment Battery result was 10/18. At 16, a bilateral, moderate upper limb resting tremor appeared accompanied by mild akinesia. The UPDRS motor score which had been 12 at baseline showed no improvement following the administration of 200 mg of levodopa. The patient had a mild decrease in the sense of vibration as well as gaze-evoked nystagmus to the right. No cerebellar signs or sphincter disturbances were present. Fundus was normal. Since a lack of efficacy following a single dose does not exclude an ultimate response to levodopa, treatment (600 mg/d) was initiated but proved of limited benefit, becoming the cause of nausea and vomiting and was therefore discontinued. Both extrapyramidal and pyramidal syndromes worsened progressively and by the age of 20 the patient was unable to walk without bilateral assistance. When aged 15, brain MRI had detected TCC in association with bilateral PWMC (Fig. 1 b and c). Spinal cord MRI was normal. Electroneuromyography was consistent with axonal sensori-motor peripheral neuropathy. An exhaustive range of laboratory investigations proved normal. A deltoid muscle biopsy revealed neurogene atrophy but no indications of mitochondriopathy. The parents of patients 1 and 2 were not expressing either spastic paraplegia, nor suffering any other serious complaint. ■ SPECT methods Intravenous administration of 150 MBq of [123I]ioflupane (DaTSCAN, Amersham GE Health) was carried out 30 min following thyroid blockade (200 mg KClO4 per os) in two patients. Brain SPECT was performed approx. 4 h later by means of a double-head gamma camera (Siemens E-CAM) with high-resolution collimators, matrix size 128 × 128, 40 frames, 40 s/frame.

Fig. 1 a Sagittal T1-weighted brain magnetic resonance imaging of patient 1 at 15 years of age. Cerebral global atrophy and severe atrophy of the corpus callosum. b Sagittal T1-weighted brain magnetic resonance imaging of patient 2 at 15 years of age. Cerebral global atrophy and severe atrophy of the corpus callosum. c Axial FLAIR brain magnetic resonance imaging of patient 2 at 15 years of age. Cerebral global atrophy and severe atrophy of the corpus callosum. Hypersignal of the periventricular anterior white matter

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Four adjacent transaxial slices from the basal ganglia having the highest radiotracer count were summed for semi-quantitative analysis of striatal specific dopamine transporter binding of [123I]ioflupane. Fixed regions of interest (ROI) were drawn over the summed transaxial slices of each hemisphere over the whole striatum. Tracerspecific striatum uptake was calculated using the formula: (count density striatum ROI – count density occipital ROI) / count density occipital ROI. ■ Genetic analysis Both patients were analyzed with GeneChip Human Mapping 50K Xba arrays from Affymetrix to identify common regions of homozygosity by descent as defined by more than 30 consecutive homozygous single nucleotide polymorphisms (SNPs). To orientate the mutation analysis, an overlap was sought between these regions of homozygosity and the loci or genes described for autosomal recessive spastic paraplegia or parkinsonism. The detection method for mutations of SPG11 gene has been described previously [17].

Results Patients 1 and 2 were 28 and 21 years of age, respectively, when the 123I-ioflupane SPECT was undertaken. The 123Iioflupane SPECT of the two patients revealed bilateral, statistically significant reduction of striatal ligand uptake (normal control ratio > 2) with a comparative severity on the left side (Fig. 2 a and b). In both cases, the value of striatal ligand uptake was below 2. Standard deviations of the age-matched, normal control and the putamen/caudate uptake ratio were reduced (normal control ratio: 0.85) (Fig. 2 a and b). The two patients were identical and homozygous for 197 successive single nucleotide polymorphisms at the SPG11 locus on chromosome 15q spanning 9.3 Mb. In contrast, both patients were heterozygous at the following SPG loci: SPG 5, 7, 14, 15, 20, 21, 23, 24, 25, 26, 27, 28 and 30. Both patients were also heterozygous at the parkin (PARK2) locus on 6q, heterozygous at the DJ1 (PARK7), Pink1 (PARK6) and Kufor Rabek syndrome (PARK9) loci on chromosome 1p and heterozygous at the dopa-responsive dystonia (DYT5) locus on 14q. No mutation in the parkin gene was identified. The patients were heterozygous at the ATP7B, PANK2, and ChAc loci linked to Wilson’s disease, pantothenate kinase-associated neurodegeneration and choreoacanthocytosis, respectively. Direct sequencing of the SPG11 gene in both patients revealed an undescribed homozygous mutation c.704_705delAT in exon 4 leading to a frameshift and premature stop codon p.H235RfsX12 (Fig. 3).

Discussion We report two patients of Turkish origin from the same consanguineous family affected with AR HSP TCC due to a newly discovered homozygous mutation in SPG11

Fig. 2 a 123I-ioflupane SPECT of patient 1 revealed bilateral severe loss of uptake in the striatum. The mean specific striatum uptake was 0.45 (left) and 0.57 (right), respectively, corresponding to a 75 % (left) and 70 % (right) statistically significant decrease in comparison with the age-matched normal control. The putamen/caudate uptake ratio was 0.64 (left) and 0.67 (right). b 123I-ioflupane SPECT of patient 2 showed marked bilateral loss of uptake of caudate and putamen, greater in the putamen compared with the caudate and in the left side compared with the right. This is a characteristic appearance observed in Parkinson disease. The mean specific striatum uptake was 1.17 (left) and 1.39 (right), respectively, corresponding to a 41 % (left) and 31 % (right) statistically significant decrease. The putamen/caudate uptake ratio was 0.10 (left) and 0.25 (right)

and who display unusual early-onset parkinsonism, inaugural in one case and with dopaminergic denervation confirmed by 123I-ioflupane SPECT. In general patients affected with SPG11-linked HSP TCC usually present spastic paraparesis of gradual progression, display brisk reflexes and bilateral Babinski sign in association with mental retardation and/or moderate cognitive impairment. The mean age at onset is 12 years (range 2–23) [17], with the initial symptoms manifesting difficulties in locomotion through motor impairment (57 %), which may be preceded by mental retardation in 19 % of sufferers. Some patients have pseudobulbar dysarthria (54 %). Other clinical signs are moderate upper and lower limb amyotrophy, urinary incontinence, dysphagia and less frequently, cerebellar signs, cataracts, retinitis pigmentosa or optic atrophy. The cognitive profile corresponds to short-term memory impairment, along with attention and concentration deficiency. Disability worsens with progression of the disease and patients may be-

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Fig. 3 Direct sequencing of the SPG11 gene of patient 1 (SPD199-1, forward), patient 2 (SPD19916, reverse) and of a control subject (forward and reverse). Homozygous mutation c.704_705delAT in exon 4 leading to a frameshift and premature stop codon p.H235RfsX12 is present in patients 1 and 2 but not in control subject

Reference Reference-AA SPD199-1 Forward

SPD199-16 Reverse

Control Forward

Control Reverse

come wheelchair-bound during their fourth decade [16, 17]. Electroneuromyography is consistent with motor axonal polyneuropathy in 72 % of patients. Sural nerve biopsy revealed axonal degeneration and accumulation of intraaxonal pleomorphic membranous material [4]. Quadriceps muscle biopsy is characterized by unspecific chronic neurogenic atrophy. The 18-fluorodeoxyglucose PET may reveal progressive cortical and thalamic hypometabolism [4]. Brain MRI detected TCC in all but one [13] SPG11-patients and may reveal cortical atrophy as well as PWMC. TCC may be seen in other HSP, including SPG7 [2], SPG21 [14] and SPG4 [12] and in peripheral neuropathy with agenesis of the corpus callosum [5]. Parkinsonism is unusual in SPG11 linked spastic paraplegia [4, 15] and 123I-ioflupane SPECT has never been studied in this disease. Extrapyramidal signs, occurring more than 20 years following disease onset, have been reported in 6 patients without genetic evidence for SPG11 [11] and detected in 1 patient nine years after onset in a series of 20 patients with genetically confirmed SPG11 [4]. In 4 other SPG11 patients, hand tremor without clear evidence for parkinsonism was noted at examination 8 to 27 years after the onset of the disease [1, 13]. Early parkinsonism has been reported in only two patients: one with rigidity and mild tremor in the hands and the other with levodopa-responsive youngonset parkinsonism but without spastic paraplegia [7]. However, neither SPG11 sequencing nor 123I-ioflupane

SPECT have been performed for these two patients. In our cases, the 123I-ioflupane SPECT was consistent with bilateral asymmetrical nigro-striatal neuron loss. Cooccurrence in this consanguineous family of SPG11linked HSP TCC with parkin, DJ1 or Pink1-linked Parkinson’s disease as well as with Kufor Rabek syndrome or other possible etiologies of spastic paraplegia associated with parkinsonism was ruled out by the lack of homozygosity at the corresponding locus. It is not established whether parkinsonism is due to the new SPG11 mutation that we identified. Indeed, no clear correlation between genotype and phenotype has yet been reported [1, 3, 4, 8, 13, 15, 19]. The human SPG11 gene contains 40 exons on chromosome 15q21.1 and encodes for a protein [3] comprising 2443 amino acids and termed spatacsin [17]. The specific role of this peptide remains unknown though it appears to be essential to the function and the survival of many neurons [3] and a certain degree of basal ganglia involvement cannot, at present, be excluded in this disorder. This is the first report of a proven SPG11-linked HSP TCC, responsible for an atypical phenotype with juvenile parkinsonism and abnormal 123I-ioflupane SPECT. In conclusion, parkinsonism, especially resting tremor, may be the inaugural presentation of SPG11linked HSP TCC and therefore SPG11 should be considered in patients with juvenile-onset parkinsonism accompanied by a limited response to levodopa.

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■ Conflict of interest The authors declare no conflict of interest.

d’Intérêt Scientifique – Rare Diseases Institute and the Verum Foundation. We are grateful to Dr. S. Forlani for her help.

■ Acknowledgements The authors’ work was financially supported by the French National Agency for Research (ANR), the Groupement

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