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Hereditary Spastic Paraplegia with Thin Corpus Callosum Reduction of the SPG11 Interval and Evidence for Further Genetic Heterogeneity

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Hereditary Spastic Paraplegia with Thin Corpus Callosum Reduction of the SPG11 Interval and Evidence for Further Genetic Heterogeneity ORIGINAL CONTRIBUTION Hereditary Spastic Paraplegia With Thin Corpus Callosum Reduction of the SPG11 Interval and Evidence for Further Genetic Heterogeneity Alexander Lossos, MD; Giovanni Stevanin, PhD; Vardiella Meiner, MD; Zohar Argov, MD; Naima Bouslam, MS; J. P. Newman, PhD; John M. Gomori, MD; Stephan Klebe, MD; Israela Lerer, MSc; Nizar Elleuch, MD; Shira Silverstein, MSc; Alexandra Durr, MD; Oded Abramsky, MD, PhD; Ziva Ben-Nariah, MD; Alexis Brice, MD Background: Hereditary spastic paraplegia (HSP) Patients: Seven patients with HSP-TCC who belong to 3 with thin corpus callosum (TCC) is an autosomal reces- consanguineous families of Arab origin residing in Israel. sive form of complicated HSP mainly characterized by Results: The 7 patients manifested a relatively similar com- slowly progressive spastic paraparesis and mental dete- bination of adolescence-onset cognitive decline and spas- rioration beginning in the second decade of life. The tic paraparesis with TCC on brain magnetic resonance im- locus for HSP-TCC, designated SPG11, was mapped to aging. After excluding the SPG7 locus, we tested the 3 chromosome 15q13-15 in some of the affected families families for linkage to the SPG11, SPG21/MAST, and ACCPN from Japan, Europe, and North America, spanning an loci associated with autosomal recessive disorders with TCC. interval of 17.5 megabases (Mb). Two families showed evidence for linkage to SPG11 (Zmax=5.55) and reduced the candidate region to 13 Mb. Objective: To perform a clinical and genetic study of HSP-TCC. Conclusions: Our findings in HSP-TCC further confirm its worldwide distribution and genetic heterogeneity, and they significantly reduce the candidate SPG11 interval. Design and Setting: Case series; multi-institutional study. Arch Neurol. 2006;63:756-760 EREDITARY SPASTIC variability. Later studies defined a paraplegia (HSP) with thin 20-centimorgan interval in this region in 10 Author Affiliations: corpus callosum (TCC) of 13 Japanese families with HSP-TCC7 and Department of Neurology, (Online Mendelian Inher- in 5 of 12 Italian families with HSP-TCC,8 Agnes Ginges Center for itance in Man [OMIM] demonstrating genetic heterogeneity. We Human Neurogenetics #604360) is an autosomal recessive form of present the results of genetic analysis in 3 (Drs Lossos, Argov, Newman, H complicated HSP characterized clinically by Arab families from Israel with HSP-TCC. and Abramsky), and Departments of Human slowly progressive spastic paraparesis and Genetics (Drs Meiner and mental deterioration beginning in the sec- 1 METHODS Ben-Nariah and Mss Lerer and ond decade of life. Additional manifesta- Silverstein) and Radiology tions include urinary incontinence, sen- (Dr Gomori), Hadassah-Hebrew sory deficit in the legs, late distal We evaluated 7 patients with HSP-TCC who University Medical Center, amyotrophy, occasional seizures, extrapy- belong to 3 consanguineous families of Arab Jerusalem, Israel; and Institut ramidal signs, and cerebellar ataxia. Al- origin residing in Israel. Of the 31 living fam- National de la Sante´etdela though the appearance of TCC on cerebral ily members, 8 parents and 11 clinically unaf- Recherche Me´dicale Unit 679 magnetic resonance imaging is typical of fected siblings ranging in age from 15 to 35 (formerly Unit 289), Federative 1 years (mean age, 23 years) were also available Institute for Neuroscience HSP-TCC, it also occurs in some of the for the study. The study was approved by the Research (IFR70) other HSPs, including those related to Ethics Committee, Hadassah Medical Organi- 2 3 4 (Drs Stevanin, Klebe, Elleuch, SPG7, SPG21, and SPG4, and in periph- zation, Jerusalem, Israel. Durr, and Brice and eral neuropathy with agenesis of the cor- Diagnosis of HSP-TCC was established ac- Ms Bouslam), Department of pus callosum,5 making genetic analysis es- cording to the published criteria.6,7 Age at symp- Genetics, Cytogenetics, and sential for diagnosis. tom onset was obtained from the parents or the Embryology, AP-HP The locus for HSP-TCC, designated available medical records. Because of lan- (Drs Stevanin, Durr, and Brice), SPG11, was originally assigned to chromo- guage limitations, we used the Test of Non- Federation of Neurology, AP-HP verbal Intelligence9 for the assessment of men- (Dr Brice), and Pitie´-Salpeˆtrière some 15q13-15 overlapping the ACCPN tal status. This language-free test of visual Medical School, Pierre and locus in 7 families from Italy and North logical reasoning yields predicted IQ scores 6 Marie Curie University America. Onset in early childhood, nor- when other batteries cannot be applied. (Dr Brice), Salpeˆtrière Hospital, mal intelligence, and the absence of TCC High-molecular-weight DNA was ex- Paris, France. in some of these families suggested clinical tracted from peripheral blood samples of 26 (REPRINTED) ARCH NEUROL / VOL 63, MAY 2006 WWW.ARCHNEUROL.COM 756 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table. Clinical and Imaging Findings in 7 Patients With Hereditary Spastic Paraplegia With Thin Corpus Callosum Family 670 Family 672 Family 671 Finding Patient 4 Patient 5 Patient 3 Patient 5 Patient 10 Patient 4 Patient 5 Sex/age at examination, y Female/31 Male/30 Male/27 Female/25 Female/23 Female/24 Female/23 Age at onset, y Cognitive decline 12 12 14 15 Ͻ10 20 20 Gait disturbance 17 17 16 17 13 18 19 Disability stage* 444 4332 Nonverbal IQ 61 69 78 75 65 78 77 Pseudobulbar dysarthria ϩϩϩ ϩϩϩϩ LL hyperreflexia ϩϩϩ ϩϩϩϩ LL spasticity ϩϩϩ ϩϩϩϩ UL hyperreflexia ϩϩϩ ϩϩϩϩ UL spasticity − − − − − − Rigidity Extensor plantar response ϩϩϩ ϩϩϩϩ Distal amyotrophy ϩϩϩ ϩϩϩϩ Urinary problems − − − − ϩϩ − Cerebral MRI Thin corpus callosum ND R, G, B, S R, G, B, S ND NA R, G, B, S R, G, B, S WMA ND F, O, Pv F, O, Pv ND NA F, O, Pv F, O, Pv Mild frontal atrophy ND ϩϩND NA ϩ − Peroneal nerve MNCV, m/s 47 43 49 ND 46 37 47 CMAP, mV 1.1 3.2 2.6 ND 4.1 3.0 4.5 Sural nerve SNCV, m/s 44 45 48 ND 48 36 46 SNAP, µV 4 5 10 ND 9 16 12 Abbreviations: B, body; CMAP, compound motor action potential amplitude; F, frontal; G, genu; LL, lower limb; MNCV, motor nerve conduction velocity; MRI, magnetic resonance imaging; NA, not available; ND, not done; O, occipital; Pv, periventricular; R, rostrum; S, splenium; SNAP, sensory nerve action potential amplitude; SNCV, sensory nerve conduction velocity; UL, upper limb; WMA, white matter abnormalities; ϩ, presence; −, absence. *Disability stage at last examination: 2 indicates moderate gait stiffness without consistent use of assistive device; 3, marked gait stiffness with consistent use of assistive device; and 4, wheelchair bound. subjects. Coding exons of the SPG7 gene were screened by de- ciated with mild hand tremor, and patient 671-4 devel- naturing high-performance liquid chromatography, showing oped urinary incontinence late in the course of her disease. no abnormal profile in the affected representatives from each 7,8 Additional features included high-arched palate in pa- family. Twelve microsatellite markers covering the SPG11, tients 670-4, 670-5, and 671-4, obesity with a body mass SPG21/MAST,3 and ACCPN5 loci were selected for linkage analy- sis. Genotypes were determined using standard methods in an index above 33 (where BMI is the weight in kilograms di- ABI 3730 automated sequencer and the GeneMapper version vided by the height in meters squared) in patients 672-3 3.5 software (Applied Biosystems, Foster City, Calif). Linkage and 672-5, and wide interdental spaces and Raynaud phe- analysis was performed using Allegro software (deCODE Ge- nomenon in patient 671-4. netics, Reykjavik, Iceland) assuming a fully penetrant reces- Consistent with the clinical findings, all of the 4 pa- sive disease with a frequency of 0.00005, similar male-female tients studied by magnetic resonance imaging had TCC recombination frequencies, and equal allele frequencies. most prominent in the rostrum, genu, and body associ- ated with confluent and symmetric signal hyperintensi- RESULTS ties on T2-weighted and fluid-attenuated inversion re- covery sequences in the cerebral white matter (Table). CLINICAL FINDINGS Widening of the anterior interhemispheric fissure was present in the 3 oldest patients, possibly the conse- Clinical findings at last examination are summarized in the quence of a mild frontal atrophy. Basal ganglia, brain- Table. All of the 7 patients manifested slowly progressive stem, cerebellum, and the cervical spinal cord appeared spastic paraparesis, distal hand and foot muscle atrophy and normal. Only brain computed tomography was avail- weakness, signs of pseudobulbar dysfunction, and pro- able in patient 671-10, and it showed TCC. Results of gressive mental impairment. The functional disability tended peripheral nerve conduction studies were consistent with to correlate with age. While no patients had sensory defi- borderline-to-mild predominantly axonal polyneuropa- cit, seizures, signs of cerebellar dysfunction, or cataracts, thy in patients 670-4, 670-5, and 671-4 and were nor- some clinical variability was apparent in family 671. Al- mal in patients 671-10 and 671-5. Sural nerve biopsy in though patient 671-10 initially had gait disturbance and patients 670-4 and 671-4 showed signs of axonal degen- urinary incontinence at age 13 years, she was reported to eration, and a quadricep muscle biopsy specimen in pa- have mild mental retardation since early childhood. Pa- tient 670-5 showed chronic neurogenic changes with- tient 671-5 had extrapyramidal rigidity in
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