J Neurol (2009) 256:1714–1718 DOI 10.1007/s00415-009-5189-0
ORIGINAL COMMUNICATION
Novel compound heterozygous mutations of the SPG11 gene in Korean families with hereditary spastic paraplegia with thin corpus callosum Sung-Min Kim Æ Jeong-Seon Lee Æ Suhyun Kim Æ Hyun-Jung Kim Æ Man-Ho Kim Æ Kyoung-Min Lee Æ Yoon-Ho Hong Æ Kyung Seok Park Æ Jung-Joon Sung Æ Kwang-Woo Lee
Received: 18 December 2008 / Revised: 23 April 2009 / Accepted: 18 May 2009 / Published online: 10 June 2009 Ó Springer-Verlag 2009
Abstract Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is one of the most common complicated forms of autosomal recessive hereditary spastic paraplegia (HSP). Mutation in SPG11 gene, which is mapped to chromosome 15q21, was recently found to be a major cause of this variant form of HSP. The aim of this study is to investigate SPG11 mutations and clinical manifestations in two Korean families with HSP-TCC. Direct sequencing of the 40 coding exons and boundaries of exon–intron in SPG11 gene, and descriptions of clinical findings in two nonconsanguineous families with HSPTCC are presented. Three novel and one known compound heterozygous mutations were found in two affected families, which were not found in controls, including one deletion in exon (c.5410_5411delTG), two insertions (c.1834_1835InsT and c.2163_2164InsT), and one
Electronic supplementary material The online version of this article (doi:10.1007/s00415-009-5189-0) contains supplementary material, which is available to authorized users. S.-M. Kim J.-S. Lee S. Kim H.-J. Kim M.-H. Kim K.-M. Lee K. S. Park J.-J. Sung K.-W. Lee Department of Neurology, College of Medicine, Seoul National University, Seoul, Korea Y.-H. Hong Department of Neurology, Seoul Boramae Hospital, Seoul, Korea J.-J. Sung (&) Burnham Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, and the University of California, 10901, North Torrey Pines Road, La Jolla, San Diego, CA 92037, USA e-mail:
[email protected]
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missense mutation (c.3291?1G[T). Both of our patients had impairments in frontal lobe functions. We present the first SPG11 mutations in Korean families, three of which are novel. SPG11 mutation should be suspected in Korean patients having HSP with TCC and executive dysfunction. Keywords Hereditary spastic paraplegia SPG11 Thin corpus callosum Autosomal recessive
Introduction Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited neurodegenerative diseases that share the common clinical feature of progressive development of spastic weakness in both legs. The inheritance pattern can be autosomal dominant, autosomal recessive or X-linked recessive, and HSP can be classified as pure (uncomplicated) or complex (complicated) form according to the absence or presence of neurologic deficits other than spastic paraplegia [1]. HSP with thin corpus callosum (HSP-TCC) is a clinically distinctive form that has an autosomal recessive inheritance pattern, spastic paraplegia, cognitive impairment, and thin corpus callosum. Mutations in the SPG11 gene, which encodes spatacsin and is mapped to chromosome 15q21, have recently been identified to be a major cause of HSP-TCC [1–3]. The function of spatacsin is not yet known, but a recent experimental study showed that it might be biologically essential because this protein is expressed in all brain tissues and is highly conserved among species [2]. This mutation was initially reported frequently among Japanese and Mediterranean families [2, 3], but recently it has shown a worldwide distribution, and to date more than
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67 mutations have been reported in European, Brazilian, African, Pakistan, Indian, Japanese, and Chinese families [1–4, 8, 10–12]. We found two sets of compound heterozygous mutations in SPG11 in three autosomal recessive Korean patients with HSP-TCC, three of which were novel.
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(MEP) showed a central conduction defect (data not shown). Brain MRI of this patient also showed diffuse atrophy of corpus callosum (Fig. 2d).
Methods and results Mutation analysis
Case reports Patient A: A 25-year-old male with healthy nonconsanguineous parents and an affected sister presented with progressive weakness of both legs (Fig. 1). He had normal motor and mental developments in early childhood, but developed progressive weakness of both legs and mild dysarthria at the age of 15 years. He was a college student when he visited our clinic. Neurologic examination revealed a mini-mental state examination (MMSE) score of 28/30 (impaired at serial 7), a frontal assessment battery score of 15/18 [5], spastic dysarthria, spastic weakness of both legs, and brisk deep tendon reflex (DTR) of both legs with positive Babinski’s sign. Motor power and DTR of the arms were normal. Diffuse abnormal spontaneous activities and large-amplitude long-duration motor unit action potentials (MUAPs) were observed in cervical, thoracic, and lumbar segments by electromyography. Brain magnetic resonance imaging (MRI) revealed extreme thinning of corpus callosum (Fig. 1d). Detailed clinical and laboratory evaluation of his sister was not performed because she was treated in another hospital and did not want to undergo repeated work-up. Patient B: A 21-year-old female with healthy nonconsanguineous parents presented with a progressive weakness of both legs (Fig. 1). She had normal motor and mental developments in early childhood, but relatively poor performance at school. At the age of 15 years, she began to have progressive gait disturbance. On neurologic examination, she revealed spasticity and ataxia of both legs with brisk DTR and ankle clonus, and wide-based ataxic gait. Cranial nerve function and the motor function of her arms were normal, and the motor power of her legs was relatively preserved (Medical Research Council grade IV?). Though her MMSE score was normal (30/30), it took her 35 s to name 24 rectangles, 35 s to read 24 color words in the simple condition, and 60 s to name 24 color words in the interference condition (Stroop test), she could generate only three words beginning with ‘‘S’’ in 1 min (word fluency test), and she could learn only 8 of 15 unrelated words after fifth learning trial (Rey auditory verbal learning test), all of which imply severely impaired executive function and working memory in this patient [6]. Both somatosensory evoked potential (SSEP) and motor evoked potential
Genomic DNA was extracted from peripheral blood lymphocytes of patients and their families using a DNA extraction kit (NucleospinÒ Blood L kit, Macherey-Nagel, Germany). The entire 40 coding exons, and the boundaries of the exon–intron of SPG11 gene were amplified by polymerase chain reaction (PCR). The primers for PCR were designed according to the information from Primer3 input 0.4.0 (http://frodo.wi.mit.edu) (see supplementary table for detail). The conditions for PCR amplification were as follows: 94°C for 3 min, followed by 36 cycles of 94°C for 30 s, 60°C/65°C for 1 min, 72°C for 1 min, and final extension at 72°C for 10 min. Sequence analyses were performed by Big Dye terminator technology (ABI 3100 Perkin-Elmer, Warrington, UK). Genomic DNA samples from 50 healthy people, who visited the clinic for the health screening, without other neurologic disease or spastic paraplegia were used as controls with informed consents.
Results In patient A, mutation analysis revealed compound heterozygous mutations, a heterozygous T insertion in exon 11 (c.2163_2164insT), which created a frameshift change at the 722 amino acid position and caused a premature stop codon at the 731 amino acid (p.I722YfsX731), and a heterozygous T insertion in exon 9 (c.1834_ 1835InsT), which created a premature stop codon at the 612 amino acid (p.N612X). His father and sister also had T insertion in exon 11, and the mother and the sister also had T insertion in exon 9 (Fig. 1a, b, c). By contrast, these mutations were not observed in our 50 control patients (supplementary data 1). In patient B, we found compound heterozygous mutations, a heterozygous transposition in exon 18 (c.3291?1G[T), which might create an aberrant splicing, and a heterozygous deletion in exon 30 (c.5410_5411delTG/p.C1804P), which created a frameshift change at the 1,803 amino acid and caused a premature stop codon at the 1,828 amino acid (p.L1803LfsX1828). The father also had a transposition mutation at exon 18, and the mother had a deletion at exon 30. Patient B had an unaffected sister who did not undergo genetic testing (Fig. 2a, b, c). These
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Fig. 1 Sequence chromatography and family pedigree for patient A and family. a Sequence of part of exon 11 shows mutated allele with insertion of T in patient A and his sister and father. b Sequence of part of exon 9 shows mutated allele with insertion of T in patient A
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and his sister and mother. c Pedigree of patient A and his family. d Sagittal brain MRI image in this patient shows thinning of corpus callosum
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Fig. 2 Sequence chromatography and family pedigree for patient B and family. a Sequence of part of exon 18 shows mutated allele with insertion of T in patient B and her father. b Sequence of part of
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exon 30 shows mutated allele with deletion of TG in patient B and her mother. c Pedigree of patient B and her family. d Sagittal brain MRI image in this patient shows thinning of corpus callosum
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mutations were not observed in our 50 control patients (supplementary data 2).
Comments Mutations in SPG11 are common in patients with autosomal recessive (AR) HSP-TCC, and are thought to be a major cause of this disease. Previous studies, which were performed mostly on European, Mediterranean, and Brazilian families, reported the incidence of SPG11 mutations to be 40–50% among patients with AR HSP-TCC [3, 11]. The incidence of SPG11 mutations in Asian patients with AR HSP-TCC has been unknown, but considering that linkage analysis on Japanese AR HSP-TCC patients showed that 77% of these patients were mapped to chromosome 15, and that SPG11 mutations were frequently found in families from Pakistan, India [8], China [10], and Japan [8], we can assume that the incidence of this mutation might also be high in Asian countries. Therefore we expect that more Korean patients with SPG11 mutations will be found in the near future. We found two sets of heterozygous compound mutations in SPG11 gene in two nonconsanguineous Korean families with HSP-TCC. Among those, the mutation in the exon 11 (c.2163_2164insT) had been found in Chinese [10], but the other three mutations in exons 9, 18, and 30 were all novel. Both of our patients showed relatively severe frontal lobe dysfunction compared with their MMSE scores, and patient B even had completely normal MMSE score (30/30) despite severe impairments in frontal lobe functions. Low sensitivity of MMSE to frontal lobe functions might account for this discrepancy [7], and these result are consistent with previous reports on functional images in patients with HSP-TCC, which reported decreased brain metabolism and perfusion in the medial frontal lobe and thalamus on 18F-fluorodeoxyglucose positron emission tomography (PET) [8]. It is also consistent with a previous study, which reported executive dysfunction in 80% of patients with SPG11 mutation [3]. Our patients also had other clinical features of spastic dysarthria, widespread lower motor neuron degeneration, progressive spastic paraplegia, and thin corpus callosa, all of which were also similar with the clinical characteristics of patients in previous studies [1–4, 10]. Patients with SPG11 mutations can have various diffuse white-matter hyperintensities on T2 brain magnetic resonance imaging (MRI), which can mimic other immune, metabolic diseases such as multiple sclerosis and leukodystrophies [9]. Patients with diffuse white-matter changes with unknown causes should undergo tests for SPG11 mutation, especially when they have TCC. However, those
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abnormalities on brain MRI were not observed in our patients. In conclusion, we report three novel and one known heterozygous compound SPG11 mutations including two insertions, one deletion, and one missense mutation; these are the first cases of genetically confirmed SPG11 mutations in the Korean population. SPG11 mutation should be suspected in Korean patients having HSP with TCC and executive dysfunction. Acknowledgment This work was supported by Grant No. A091226 from Korean Ministry for health welfare and family affairs funds.
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