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Gene: Association with Multiple Sclerosis in Two Avected Siblings and Epilepsy in Other Avected Family Members

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Gene: Association with Multiple Sclerosis in Two Avected Siblings and Epilepsy in Other Avected Family Members 788 J Neurol Neurosurg Psychiatry 2001;71:788–791 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.6.788 on 1 December 2001. Downloaded from SHORT REPORT A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two aVected siblings and epilepsy in other aVected family members S H Mead, C Proukakis, N Wood, A H Crosby, G T Plant, T T Warner Abstract spastin gene in families with SPG4 linked Hereditary spastic paraparesis (HSP) is a HSP.5–8 clinically and genetically heterogeneous There is evidence of considerable genetic neurodegenerative disorder characterised susceptibility in multiple sclerosis (MS), with by progressive lower limb spasticity and involvement of HLA haplotypes and some weakness. Some forms have been associ- uncharacterised genetic loci.9 Our neuroge- ated with white matter lesions and com- netic report was prompted by the identification plex phenotypes. This study was prompted of two siblings with clinical history and investi- by the diagnosis of multiple sclerosis (MS) gation findings consistent with the concurrence in two sisters from a large pedigree with of both MS and HSP. Our aims were to hereditary spastic paraparesis. Twelve characterise the clinical phenotype in the aVected members of the extended family copyright. MRC Prion Unit, extended family and determine the genetic Imperial College at were examined (MRI and EEG were abnormality to clarify any susceptibility rela- St Mary’s Hospital, carried out and evoked potentials tion between HSP and MS. Norfolk Place, London measured in five), and historical infor- W2 1PG, UK mation was obtained from six aVected S H Mead deceased persons. The inherited disease National Hospital for phenotype was confirmed as autosomal Methods Neurology and dominant hereditary spastic paraparesis The family was approached through the Neurosurgery, Queen associated with epilepsy in four aVected proband (fig 1). Informed written consent was Square, London persons. None of the extended family had obtained from all participants. Twenty six WC1N 3BG, UK evidence of MS. Genetic analysis of the members of the extended family were exam- C Proukakis family has shown linkage to chromosome http://jnnp.bmj.com/ T T Warner ined by one of us (SHM). Diagnosis of HSP 2p and sequencing of the spastin gene has was based on established criteria of lower limb University identified a 1406delT frameshift mutation hyperreflexia plus either progressive spastic Department of Clinical in exon 10. This kindred demonstrates the gait abnormality, bilateral extensor plantars, or Neurosciences, Royal clinical heterogeneity of HSP associated bilateral ankle clonus.10 Diagnosis of MS was Free Campus, Royal with spastin mutations. The possible rel- based on established criteria (table 1).11 Five Free and University evance of the concurrence of HSP and MS College Medical members of the family were admitted to the School, Rowland Hill in the sib pair is discussed. National Hospital for Neurology for detailed Street, London (J Neurol Neurosurg Psychiatry 2001;71:788–791) investigation and a further two members had on September 26, 2021 by guest. Protected NW3 2PF, UK brain MRI as outpatients. Keywords: hereditary spastic paraparesis; multiple scle- N Wood Blood was obtained from family members G T Plant rosis; spastin T T Warner after informed consent and DNA was extracted using standard procedures. Linkage analysis Department of Hereditary spastic paraparesis (HSP) is a using microsatellite markers around the SPG4 Medical Genetics, disease characterised by progressive lower limb locus was performed. For one aVected member St Georges’s Hospital spasticity and weakness. Autosomal dominant with aVected oVspring (IV-10), the 17 exons of Medical School, Cranmer Terrace, HSP is the most common form and eight the SPG4 gene were amplified together with London SW17 0RE, UK genetic loci have been identified. It is estimated the flanking intronic regions using novel prim- A H Crosby that around 40% of autosomal dominant HSP ers (Proukakis et al, unpublished data). kindreds are linked to a locus on chromosome Polymerase chain reaction (PCR) products Correspondence to: 2p (SPG4).12 There is considerable pheno- were sequenced directly on an ABI377 auto- Dr G T Plant [email protected] typic heterogeneity within pedigrees linked to mated DNA sequencer. To confirm the muta- the SPG4 locus, with evidence of epilepsy, cog- tion, PCR products obtained from genomic Received 2 February 2001 nitive impairment, and neurological abnor- DNA were subcloned (TOPO-TA cloning kit, and in revised form 34 3 July 2001 malities from birth in some pedigrees. Invitrogen) and products derived from both Accepted 6 July 2001 Recently, mutations have been identified in the parental chromosomes sequenced. Mutation www.jnnp.com Hereditary spastic paraparesis and frame shift mutation of the spastin (SPG4) gene 789 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.6.788 on 1 December 2001. Downloaded from detection in other family members was per- formed by PCR amplification and sequencing of exon 10. Lower limb loss of vibration sense Results PROBAND CASE HISTORY (IV-13) The proband presented at the age of 22 with Lower limb UMN signs rapid onset of visual disturbance. On examina- tion she had impaired visual acuity, an incongruous left sided hemianopia, mild dysar- thria, and impaired joint position sense in the Upper limb sensory loss left hand. These signs improved slowly over 6 weeks. At 3 months she had a residual left hemianopia, impaired colour vision, and a mild left hemiparesis. Fifteen years later she devel- Upper limb ataxia oped over 2 weeks a loss of balance, slurring dysarthria, and incoordination of her right hand. Examination in hospital recorded addi- tional signs of a spastic paraparesis, with brisk lower limb reflexes and extensor plantars. A Upper limb UMN signs diagnosis of multiple sclerosis was made and intravenous methylprednisolone was given with some response. Over the subsequent years her spastic gait Urinary problems deteriorated with increasing spasticity, eventu- ally limiting her to a wheelchair. She developed urge incontinence, nocturia, and severe pains related to leg muscle spasms. On examination, aged 47, she had a left relative aVerent Gastro- intestinal compaints pupillary defect with an acuity of 3/24, 3/24, and severely impaired colour vision. Pursuit eye movements were broken and jaw jerk was copyright. brisk. Tone was slightly increased in the arms +++000+++ but power was full with only a mild cerebellar ataxia. Tendon reflexes in the upper limb were brisk. In the lower limb there was markedly increased tone with sustained ankle clonus and hip flexion weakness of 4/5. Deep tendon reflexes were brisk with extensor plantars responses. Brain MRI was markedly abnormal (fig 2). Analysis of CSF demonstrated oligo- clonal immunoglobulin bands that were absent Relapsing- remitting Epilepsy Back pain in serum. http://jnnp.bmj.com/ PROBAND’S SISTER’S CASE HISTORY (IV-12) The proband’s sister presented aged 25 when Age requiring wheelchair she began to drag her left foot on the ground and she complained of a tight, heavy sensation aVecting the upper thighs, back, and shoulders. The symptoms gradually progressed involving both lower limbs, although the left leg re- on September 26, 2021 by guest. Protected Age requiring aid mained worse than the right. Her balance became impaired, and she was unable to stand on one leg. She also had been diagnosed with anxiety depression. Aged 50, she was unable to walk outside more than 100 m with a walking stick and climbing stairs was diYcult. Exam- ination at age 50 showed brisk upper limb reflexes with bilateral HoVman’s sign. She had a spastic paraparesis with hypertonicity of both legs, ankle clonus, and a mild pyramidal type weakness. There were distal sensory abnor- malities aVecting all modalities in all four Age Sex Onset limbs. A brain MRI showed white matter lesions (fig 2). Analysis of CSF showed the presence of oli- goclonal immunoglobulin bands, which were absent in serum. V15F5600++++0++++ 00++++00++++ 00+00+00+++ 0++0+000+++ 0+000 00+0++00+++ 00000000++0 00000 00+0+000++0 00+00+00+++ 00+000+0++0 0+++++00++++ II-4V-332F32 V-930F0 V-11V-732F24 67V-139M37 V-236M34 V-638F35 29V-840M35 MIV-13IV-1250F2546 ++0 IV-1057F35 MIV-1158F50 48IV-664F34 30IV-467F4060 IV-271F45556500++++00++++ 27III-12 F 82 22 F 23 60 0 40 0 70 + + 0 0 + 0 + 0 0 0 0 + + ++ + ++ ++ 0 ++ 0=normal, +=mildly abnormal, ++=severely abnormal. Table 1 Phenotype table www.jnnp.com 790 Mead, Proukakis, Wood,et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.6.788 on 1 December 2001. Downloaded from I 1 245 3 II 1 2 3 4 5 6 7 8 9 10 11 12 13 III 1 2 3 4 5 6 7 8 9 10 11 12 13 V 1 2 3 4 5 6 7 8 9 10 11 12 13 Figure 1 Pedigree. Filled circles represent aVected people. Examined people are detailed in table 1. The details have been modified to preserve anonymity. THE EXTENDED FAMILY II-4 described this member’s lifelong general- Inheritance of HSP was compatible with an ised tonic-clonic seizures with onset at age 12. autosomal dominant trait with no evidence of Patient IV-6 had generalised tonic-clonic sei- incomplete penetrance. The mean age of zures between the ages of 14 and 24. Patient symptom onset was 36 (range 22 to 60) IV-11 had a high frequency of seizures between excluding one patient with abnormalities from the ages of 8 months and 5 years. Occasionally birth. None of the extended family had a clini- these consisted of tonic spasms and cyanosis, at cal history or examination findings suggestive other times there were jerking movements of copyright.
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