- Email: [email protected]
Novel compound heterozygous mutations in sacsin-related ataxia
Journal of the Neurological Sciences 239 (2005) 101 – 104 www.elsevier.com/locate/jns
Novel compound heterozygous mutations in sacsin-related ataxia Yoichi Yamamoto a,*, Kotaro Hiraoka a, Mutsuko Araki a, Seiichi Nagano a, Haruo Shimazaki b, Yoshihisa Takiyama b, Sabro Sakoda a a
Department of Neurology D4, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan b Department of Neurology, Jichi Medical School, Tochigi 329-0498, Japan Received 31 March 2005; received in revised form 9 August 2005; accepted 10 August 2005 Available online 29 September 2005
Abstract High prevalence of a form of autosomal recessive spastic ataxia with early onset was originally described among French Canadians in the Charlevoix-Saguenay region, in northeastern Quebec. Since the responsible gene (SACS) was identified, mutations in the SACS gene have been described in Tunisia, Italy, Turkey, and Japan. The mutation sites found outside Quebec are different from the ones in Quebec. All patients outside Quebec, except one Italian patient, have been reported to have homozygous mutations. The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951_2952delAG]+[3922delT]) in the SACS gene. D 2005 Elsevier B.V. All rights reserved. Keywords: Autosomal recessive; Spastic ataxia; Sacsin; Compound heterozygotes; Deletion
1. Introduction Autosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS; OMIM 270550) is a neurodegenerative disease characterized by the early onset of gait unsteadiness, often at the age of 12 to 18 months combined with spasticity [1]. More than 300 patients with ARSACS have been described in the Charlevoix-Saguenay region of Quebec. Recently, the gene responsible for ARSACS (SACS) was identified on chromosome 13 [2]. The SACS gene has a single giant exon of 12,794 base pairs which contains an open reading frame encoding a 3829-amino-acid protein, sacsin [2]. All the mutations of SACS gene reported so far are listed in Table 1. In the patients in Quebec, two mutations in the SACS gene, one frameshift (p.Pro2198ProfsX2202) and one nonsense (p.Arg1752X), both leading to protein truncation, have been reported. Recently, new mutations in the SACS gene have been identified in Tunisia [3], Italy [4,5], Turkey [6], and Japan [7,8]. In all these patients, with the exception of * Corresponding author. Tel.: +81 6 6879 3571; fax: +81 6 6879 3579. E-mail address: [email protected] (Y. Yamamoto). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.08.005
one Italian patient [5], the mutations were homozygous. All these patients had the core clinical features of earlyonset difficulty in walking and gait unsteadiness with spastic ataxia, dysarthria, nystagmus, and sensory and motor neuropathy. Mental retardation and retinal myelination are considered to be variable features. Recently, patients without spastic ataxia, which has been considered a core feature, were reported in Japan (homozygous p.Phe304Ser) [9]. In this report, we describe a case of Japanese identical twins with novel compound heterozygous mutations in the SACS gene.
2. Materials and methods 2.1. Patients After obtaining informed consent, we analyzed identical twin sisters in a Japanese family with hereditary spastic ataxia. There was no consanguinity, and the parents were from different prefectures in Japan. The family members, including the parents and elder sister of the patients, were free of neurologic symptoms (Fig. 1).
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Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Table 1 Clinical features of SACS gene mutations Mutation
Cerebellar ataxia
Spastic paraplegia
Peripheral neuropathy
Dementia
Retinal hypermyelination
[Homozygous mutations] p.Phe304Ser p.Ile360AsnfsX361 p.Ile445MetfsX457 p.Gln595ProfsX599 p.Cys648Arg p.Trp1196Arg
+ + + + + +
+ + + + +
+ + + + + +
+ ND ND + + ND
+ + ND ND + +
pThr1667ArgfsX1678 p.Arg1752X p.Lys2181AsnfsX2202 p.Pro2198ProfsX2202 p.Trp2498Arg p.Thr2683LysfsX2709 p.Leu3193LeufsX3200 p.Ala3324Pro p.Asn3799Asp
+ + + + + + + + +
+ + + + + + + + +
+ + + + + + + + +
[Compound heterozygous mutations] p.[Gln620X]+[Lys1529LysfsX1541] + p.[Glu984GlyfsX986]+ + [Ser1308LeufsX1326]
+ +
+ +
Others
Later onset 10 – 14 years old
+ +
Ophthalamoplegia
+ + + ND T
+ + + + ND +
+
Amenorrhea hyperlipidemia
Country
Reference
Japan Tunisia Tunisia Italy Turkey Tunisia
[9] [3] [3] [4] [6] [3]
Italy Quebec Japan Quebec Japan Turkey Turkey Tunisia Turkey
[5] [1] [8] [1] [7] [6] [6] [3] [6]
Italy Japan
[5] This report
ND = not described.
2.2. Molecular genetic analysis
3. Results
Blood samples were obtained with informed consent from the two patients and their parents. Genomic DNA was extracted from peripheral blood leukocytes. Using 28 appropriate primer pairs (each primer sequence is available on request), the coding exon of the SACS gene (GenBank/EMBL/DDBJ accession number AF193556) was amplified by PCR from 200 ng of genomic DNA, and then sequenced directly with an ABI PRISM 310 genetic analyzer. We have adopted HUGO Mutation Database Initiative (MDI)/Human Genome Variation Society (HGVS) Mutation Nomenclature Recommendations in which the A of the starting Met codon is nucleotide + 1. To confirm the mutations, the amplified fragments were subcloned into a TA-cloning plasmid vector (TOPO TA Cloning Kit; Invitrogen) and then sequenced on both strands using each universal primer. Analysis was performed with the use of GeneScan analysis software, ver. 3.4.1 (ABIPerkin Elmer). This study was approved by the Medical Ethics Committee of Jichi Medical School.
3.1. Clinical findings
Fig. 1. The family tree of the patients.
3.1.1. Patient 1 This 35-year-old woman could not run fast and had been prone to tumble since early childhood. At age 5, her speech was slow and dysarthric. At age 20, gait disturbance and pollakiuria became apparent, and her menstrual cycle became irregular. The gait disturbance progressed slowly, and she became more prone to tumble. At age 24, her feet often scraped the floor when she walked and she often tumbled. At age 25, she often fell down while she was standing. At age 28, she became amenorrheic. At age 31, she was admitted to our hospital for diagnosis. Neurologic examination revealed spasticity in all four limbs and mild weakness in the lower extremities. Patella tendon reflexes were increased with Babinski and Chaddock signs, but Achilles tendon reflexes were decreased. She showed mild limb ataxia and gaze-evoked nystagmus. Vibratory sensation in the ankles was decreased. Low compliance bladder was suggested by the cystometrogram. Fundscopy did not reveal hypermyelinated retinal fibers. In the left post-tibial nerve, the motor nerve conduction velocity was 32.6 m/s and the compound motor action potential was 1.14 mV. The sensory nerve conduction velocity was 35.0 m/s in the left median nerve, and a sensory wave was not evoked in the sural nerve. Brain MRI revealed slight cerebral atrophy and atrophy of the cerebellar superior vermis. Verbal IQ and performance IQ were 70 and 64, respectively (Wechsler
Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Adult Intelligence Scale-Revised). Serological tests revealed hyperlipidemia, with total cholesterol 306 mg/dl (normal 150 –220) and triglyceride 316 mg/dl (normal 30 –150). The oral glucose tolerance test was normal. She was judged to have secondary amenorrhea, because menstruation occurred upon taking norgestrel and ethinylestradiol. At age 35, she was re-admitted to our hospital. Neurological re-examination revealed mildly progressed spasticity and ataxia of all four limbs. Brain MRI revealed atrophy of the cerebellar superior vermis and cervical spine (Fig. 2). Trans-vaginal ultrasonography revealed a polycystic-ovarylike appearance. Luteinizing hormone was 13.4 mIU/ml (normal 1.7– 13.3) and testosterone was 0.89 ng/ml (normal 0.1 –0.9). 3.1.2. Patient 2 Patient 2 (a 35-year-old woman) and patient 1 are identical twins (Fig. 1). She could not run fast and had been prone to tumble since early childhood. At age 16, her menstrual cycle became irregular. At age 20, pollakiuria appeared. At age 35, she was also admitted to our hospital, and the findings of her neurological examination were similar to those of patient 1. Brain MRI revealed atrophy of the cerebellar superior vermis and cervical spine. Her verbal IQ and performance IQ were 81 and 69, respectively (Wechsler Adult Intelligence Scale-Revised). Serologic tests revealed hypercholestemia of total cholesterol 300 mg/dl and triglyceride 708 mg/dl. The oral glucose tolerance test revealed impaired glucose tolerance. Trans-vaginal ultrasonography showed a polycystic-ovary-like appearance. Luteinizing hormone was 12.5 mIU/l and testosterone was 0.97 ng/ml. 3.2. Molecular genetic study The sequence analyses of the two genomes of the patients revealed compound heterozygous deletion mutations, c.[2951_2952delAG]+[3922delT], in the SACS gene, both of which result in premature termination of the predicted sacsin protein (p.[Glu984GlyfsX986]+[Ser1308LeufsX1326]). c.2951_2952delAG was found in the unaffected mother, and c.3922delT in the unaffected father.
A
B
Fig. 2. Brain magnetic resonance imaging. Sagittal (A) and axial (B) slices of T1-weighted images. The atrophy of the superior vermis and cervical spinal cord are demonstrated.
103
Thus, the c.[2951_2952delAG]+[3922delT] mutations of the SACS gene were found to cosegregate with the disease in the present family with autosomal recessive transmission. The healthy sister of the two patients refused genetic analyses.
4. Discussion Mutations in SACS are increasingly being recognized outside Quebec, the region where ARSACS was originally described (Table 1). Our patients showed the core clinical features of ARSACS, such as early-onset spastic ataxia, dysarthria, nystagmus, and sensory and motor neuropathy. Brain MRI revealed marked atrophy of the superior vermis, which is a characteristic feature of ARSACS. Recently, patients without spastic ataxia, which has been considered a core feature, were reported [9]. Concerning the variable features, hypermyelination of retinal fibers was absent in our patients. ARSACS without hypermyelination of retinal fibers was reported in 2 Italian families [5] and a Japanese family [8]. In our cases, mental retardation was indicated by the reduced verbal IQ and performance IQ, although the low score of performance IQ may have been partly related to the physical handicap, since the test requires speed and good motor control of fine movements. As shown in Table 1, the sites of reported mutations in the SACS gene are spread over the whole gene. Although the high carrier frequency shown in Quebec [2] is not likely to happen outside Quebec, specific mutations seem to reside in a specific geographic region or ethnic population. Genetic analysis of our patients revealed novel compound heterozygous mutations in the SACS gene, producing truncated proteins due to frameshifts (p.[Glu984GlyfsX986]+[Ser1308LeufsX1326]). However, transcripts with such premature termination codons can be specifically degraded by a mechanism called nonsensemediated mRNA decay. In this case, the transcripts do not generally lead to the synthesis of truncated proteins [10]. Whether mutant SACS mRNA is degraded by this mechanism is a question that needs further study. Sacsin accomplishes a still unknown function. On the basis of protein sequence homologies, sacsin is believed to act as a chaperone important in protein folding or in the stabilization of nucleotide binding [2,6]. It is presently unclear if this role might also affect some metabolic pathway and lead to its dysregulation. Such a possibility might explain the associated features manifested by our two patients. Interestingly, other forms of inherited ataxia, including ataxia with ocular-motor apraxia type 1, Marinesco-Sjogren, and infantile-onset cerebellar ataxia, also present complicated clinical features such as hypogonadism and hyperlipidemia [11 – 13]. It is tempting to speculate that the defective proteins in these disorders are all related to some form of metabolic dysregulation.
104
Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Acknowledgements This work was supported by a Research Grant for Nervous and Mental Disorders (14B, Y.T.) and a grant from the Research Committee for Ataxic Diseases (Y.T.) of the Ministry of Health, Labor, and Welfare, Japan.
References [1] Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1978;5:61 – 9. [2] Engert JC, Be´rube´ P, Mercier J, Dore´ C, Lepage P, Ge B, et al. ARSACS, a spastic ataxia common in northeastern Que´bec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 2000;24:120 – 5. [3] El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY, et al. Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol 2003;60:982 – 8. [4] Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, et al. A novel mutation in SACS gene in a family from southern Italy. Neurology 2004;62:100 – 2. [5] Grieco GS, Malandrini A, Commanducci G, Leuzzi V, Valoppi M, Tessa A, et al. Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type. Neurology 2004;62:103 – 6.
[6] Richter AM, Ozgul RK, Poisson VC, Topaloglu H. Private SACS mutations in autosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS) families from Turkey. Neurogenetics 2004;5: 165 – 70. [7] Ogawa T, Takiyama Y, Sakoe K, Mori K, Namekawa M, Shimazaki H, et al. Identification of a SACS gene missense mutation in ARSACS. Neurology 2004;62:107 – 9. [8] Hara K, Onodera O, Endo M, Kondo H, Shiota H, Miki K, et al. Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan. Mov Disord 2004;20:380 – 2. [9] Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I. A phenotype without spasticity in sacsin-related ataxia. Neurology 2005;64:2129 – 31. [10] Vasudevan S, Peltz SW. Nuclear mRNA surveillance. Curr Opin Cell Biol 2003;15:332 – 7. [11] Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia. The aprataxin gene mutations. Neurology 2002;59:590 – 5. [12] Izatt L, Neme´th HA, Meesaq A, Mills KR, Taylor AMR, Shaw CE. Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised a-fetoprotein. J Neurol 2004;251:805 – 12. [13] Nikali K, Suomalainen A, Terwilliger J, Koskinen T, Weissenbach J, Peltonen L. Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus. Am J Hum Genet 1995;56:1088 – 95.
Novel compound heterozygous mutations in sacsin-related ataxia Yoichi Yamamoto a,*, Kotaro Hiraoka a, Mutsuko Araki a, Seiichi Nagano a, Haruo Shimazaki b, Yoshihisa Takiyama b, Sabro Sakoda a a
Department of Neurology D4, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan b Department of Neurology, Jichi Medical School, Tochigi 329-0498, Japan Received 31 March 2005; received in revised form 9 August 2005; accepted 10 August 2005 Available online 29 September 2005
Abstract High prevalence of a form of autosomal recessive spastic ataxia with early onset was originally described among French Canadians in the Charlevoix-Saguenay region, in northeastern Quebec. Since the responsible gene (SACS) was identified, mutations in the SACS gene have been described in Tunisia, Italy, Turkey, and Japan. The mutation sites found outside Quebec are different from the ones in Quebec. All patients outside Quebec, except one Italian patient, have been reported to have homozygous mutations. The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951_2952delAG]+[3922delT]) in the SACS gene. D 2005 Elsevier B.V. All rights reserved. Keywords: Autosomal recessive; Spastic ataxia; Sacsin; Compound heterozygotes; Deletion
1. Introduction Autosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS; OMIM 270550) is a neurodegenerative disease characterized by the early onset of gait unsteadiness, often at the age of 12 to 18 months combined with spasticity [1]. More than 300 patients with ARSACS have been described in the Charlevoix-Saguenay region of Quebec. Recently, the gene responsible for ARSACS (SACS) was identified on chromosome 13 [2]. The SACS gene has a single giant exon of 12,794 base pairs which contains an open reading frame encoding a 3829-amino-acid protein, sacsin [2]. All the mutations of SACS gene reported so far are listed in Table 1. In the patients in Quebec, two mutations in the SACS gene, one frameshift (p.Pro2198ProfsX2202) and one nonsense (p.Arg1752X), both leading to protein truncation, have been reported. Recently, new mutations in the SACS gene have been identified in Tunisia [3], Italy [4,5], Turkey [6], and Japan [7,8]. In all these patients, with the exception of * Corresponding author. Tel.: +81 6 6879 3571; fax: +81 6 6879 3579. E-mail address: [email protected] (Y. Yamamoto). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.08.005
one Italian patient [5], the mutations were homozygous. All these patients had the core clinical features of earlyonset difficulty in walking and gait unsteadiness with spastic ataxia, dysarthria, nystagmus, and sensory and motor neuropathy. Mental retardation and retinal myelination are considered to be variable features. Recently, patients without spastic ataxia, which has been considered a core feature, were reported in Japan (homozygous p.Phe304Ser) [9]. In this report, we describe a case of Japanese identical twins with novel compound heterozygous mutations in the SACS gene.
2. Materials and methods 2.1. Patients After obtaining informed consent, we analyzed identical twin sisters in a Japanese family with hereditary spastic ataxia. There was no consanguinity, and the parents were from different prefectures in Japan. The family members, including the parents and elder sister of the patients, were free of neurologic symptoms (Fig. 1).
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Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Table 1 Clinical features of SACS gene mutations Mutation
Cerebellar ataxia
Spastic paraplegia
Peripheral neuropathy
Dementia
Retinal hypermyelination
[Homozygous mutations] p.Phe304Ser p.Ile360AsnfsX361 p.Ile445MetfsX457 p.Gln595ProfsX599 p.Cys648Arg p.Trp1196Arg
+ + + + + +
+ + + + +
+ + + + + +
+ ND ND + + ND
+ + ND ND + +
pThr1667ArgfsX1678 p.Arg1752X p.Lys2181AsnfsX2202 p.Pro2198ProfsX2202 p.Trp2498Arg p.Thr2683LysfsX2709 p.Leu3193LeufsX3200 p.Ala3324Pro p.Asn3799Asp
+ + + + + + + + +
+ + + + + + + + +
+ + + + + + + + +
[Compound heterozygous mutations] p.[Gln620X]+[Lys1529LysfsX1541] + p.[Glu984GlyfsX986]+ + [Ser1308LeufsX1326]
+ +
+ +
Others
Later onset 10 – 14 years old
+ +
Ophthalamoplegia
+ + + ND T
+ + + + ND +
+
Amenorrhea hyperlipidemia
Country
Reference
Japan Tunisia Tunisia Italy Turkey Tunisia
[9] [3] [3] [4] [6] [3]
Italy Quebec Japan Quebec Japan Turkey Turkey Tunisia Turkey
[5] [1] [8] [1] [7] [6] [6] [3] [6]
Italy Japan
[5] This report
ND = not described.
2.2. Molecular genetic analysis
3. Results
Blood samples were obtained with informed consent from the two patients and their parents. Genomic DNA was extracted from peripheral blood leukocytes. Using 28 appropriate primer pairs (each primer sequence is available on request), the coding exon of the SACS gene (GenBank/EMBL/DDBJ accession number AF193556) was amplified by PCR from 200 ng of genomic DNA, and then sequenced directly with an ABI PRISM 310 genetic analyzer. We have adopted HUGO Mutation Database Initiative (MDI)/Human Genome Variation Society (HGVS) Mutation Nomenclature Recommendations in which the A of the starting Met codon is nucleotide + 1. To confirm the mutations, the amplified fragments were subcloned into a TA-cloning plasmid vector (TOPO TA Cloning Kit; Invitrogen) and then sequenced on both strands using each universal primer. Analysis was performed with the use of GeneScan analysis software, ver. 3.4.1 (ABIPerkin Elmer). This study was approved by the Medical Ethics Committee of Jichi Medical School.
3.1. Clinical findings
Fig. 1. The family tree of the patients.
3.1.1. Patient 1 This 35-year-old woman could not run fast and had been prone to tumble since early childhood. At age 5, her speech was slow and dysarthric. At age 20, gait disturbance and pollakiuria became apparent, and her menstrual cycle became irregular. The gait disturbance progressed slowly, and she became more prone to tumble. At age 24, her feet often scraped the floor when she walked and she often tumbled. At age 25, she often fell down while she was standing. At age 28, she became amenorrheic. At age 31, she was admitted to our hospital for diagnosis. Neurologic examination revealed spasticity in all four limbs and mild weakness in the lower extremities. Patella tendon reflexes were increased with Babinski and Chaddock signs, but Achilles tendon reflexes were decreased. She showed mild limb ataxia and gaze-evoked nystagmus. Vibratory sensation in the ankles was decreased. Low compliance bladder was suggested by the cystometrogram. Fundscopy did not reveal hypermyelinated retinal fibers. In the left post-tibial nerve, the motor nerve conduction velocity was 32.6 m/s and the compound motor action potential was 1.14 mV. The sensory nerve conduction velocity was 35.0 m/s in the left median nerve, and a sensory wave was not evoked in the sural nerve. Brain MRI revealed slight cerebral atrophy and atrophy of the cerebellar superior vermis. Verbal IQ and performance IQ were 70 and 64, respectively (Wechsler
Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Adult Intelligence Scale-Revised). Serological tests revealed hyperlipidemia, with total cholesterol 306 mg/dl (normal 150 –220) and triglyceride 316 mg/dl (normal 30 –150). The oral glucose tolerance test was normal. She was judged to have secondary amenorrhea, because menstruation occurred upon taking norgestrel and ethinylestradiol. At age 35, she was re-admitted to our hospital. Neurological re-examination revealed mildly progressed spasticity and ataxia of all four limbs. Brain MRI revealed atrophy of the cerebellar superior vermis and cervical spine (Fig. 2). Trans-vaginal ultrasonography revealed a polycystic-ovarylike appearance. Luteinizing hormone was 13.4 mIU/ml (normal 1.7– 13.3) and testosterone was 0.89 ng/ml (normal 0.1 –0.9). 3.1.2. Patient 2 Patient 2 (a 35-year-old woman) and patient 1 are identical twins (Fig. 1). She could not run fast and had been prone to tumble since early childhood. At age 16, her menstrual cycle became irregular. At age 20, pollakiuria appeared. At age 35, she was also admitted to our hospital, and the findings of her neurological examination were similar to those of patient 1. Brain MRI revealed atrophy of the cerebellar superior vermis and cervical spine. Her verbal IQ and performance IQ were 81 and 69, respectively (Wechsler Adult Intelligence Scale-Revised). Serologic tests revealed hypercholestemia of total cholesterol 300 mg/dl and triglyceride 708 mg/dl. The oral glucose tolerance test revealed impaired glucose tolerance. Trans-vaginal ultrasonography showed a polycystic-ovary-like appearance. Luteinizing hormone was 12.5 mIU/l and testosterone was 0.97 ng/ml. 3.2. Molecular genetic study The sequence analyses of the two genomes of the patients revealed compound heterozygous deletion mutations, c.[2951_2952delAG]+[3922delT], in the SACS gene, both of which result in premature termination of the predicted sacsin protein (p.[Glu984GlyfsX986]+[Ser1308LeufsX1326]). c.2951_2952delAG was found in the unaffected mother, and c.3922delT in the unaffected father.
A
B
Fig. 2. Brain magnetic resonance imaging. Sagittal (A) and axial (B) slices of T1-weighted images. The atrophy of the superior vermis and cervical spinal cord are demonstrated.
103
Thus, the c.[2951_2952delAG]+[3922delT] mutations of the SACS gene were found to cosegregate with the disease in the present family with autosomal recessive transmission. The healthy sister of the two patients refused genetic analyses.
4. Discussion Mutations in SACS are increasingly being recognized outside Quebec, the region where ARSACS was originally described (Table 1). Our patients showed the core clinical features of ARSACS, such as early-onset spastic ataxia, dysarthria, nystagmus, and sensory and motor neuropathy. Brain MRI revealed marked atrophy of the superior vermis, which is a characteristic feature of ARSACS. Recently, patients without spastic ataxia, which has been considered a core feature, were reported [9]. Concerning the variable features, hypermyelination of retinal fibers was absent in our patients. ARSACS without hypermyelination of retinal fibers was reported in 2 Italian families [5] and a Japanese family [8]. In our cases, mental retardation was indicated by the reduced verbal IQ and performance IQ, although the low score of performance IQ may have been partly related to the physical handicap, since the test requires speed and good motor control of fine movements. As shown in Table 1, the sites of reported mutations in the SACS gene are spread over the whole gene. Although the high carrier frequency shown in Quebec [2] is not likely to happen outside Quebec, specific mutations seem to reside in a specific geographic region or ethnic population. Genetic analysis of our patients revealed novel compound heterozygous mutations in the SACS gene, producing truncated proteins due to frameshifts (p.[Glu984GlyfsX986]+[Ser1308LeufsX1326]). However, transcripts with such premature termination codons can be specifically degraded by a mechanism called nonsensemediated mRNA decay. In this case, the transcripts do not generally lead to the synthesis of truncated proteins [10]. Whether mutant SACS mRNA is degraded by this mechanism is a question that needs further study. Sacsin accomplishes a still unknown function. On the basis of protein sequence homologies, sacsin is believed to act as a chaperone important in protein folding or in the stabilization of nucleotide binding [2,6]. It is presently unclear if this role might also affect some metabolic pathway and lead to its dysregulation. Such a possibility might explain the associated features manifested by our two patients. Interestingly, other forms of inherited ataxia, including ataxia with ocular-motor apraxia type 1, Marinesco-Sjogren, and infantile-onset cerebellar ataxia, also present complicated clinical features such as hypogonadism and hyperlipidemia [11 – 13]. It is tempting to speculate that the defective proteins in these disorders are all related to some form of metabolic dysregulation.
104
Y. Yamamoto et al. / Journal of the Neurological Sciences 239 (2005) 101 – 104
Acknowledgements This work was supported by a Research Grant for Nervous and Mental Disorders (14B, Y.T.) and a grant from the Research Committee for Ataxic Diseases (Y.T.) of the Ministry of Health, Labor, and Welfare, Japan.
References [1] Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1978;5:61 – 9. [2] Engert JC, Be´rube´ P, Mercier J, Dore´ C, Lepage P, Ge B, et al. ARSACS, a spastic ataxia common in northeastern Que´bec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 2000;24:120 – 5. [3] El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY, et al. Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol 2003;60:982 – 8. [4] Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, et al. A novel mutation in SACS gene in a family from southern Italy. Neurology 2004;62:100 – 2. [5] Grieco GS, Malandrini A, Commanducci G, Leuzzi V, Valoppi M, Tessa A, et al. Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type. Neurology 2004;62:103 – 6.
[6] Richter AM, Ozgul RK, Poisson VC, Topaloglu H. Private SACS mutations in autosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS) families from Turkey. Neurogenetics 2004;5: 165 – 70. [7] Ogawa T, Takiyama Y, Sakoe K, Mori K, Namekawa M, Shimazaki H, et al. Identification of a SACS gene missense mutation in ARSACS. Neurology 2004;62:107 – 9. [8] Hara K, Onodera O, Endo M, Kondo H, Shiota H, Miki K, et al. Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan. Mov Disord 2004;20:380 – 2. [9] Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I. A phenotype without spasticity in sacsin-related ataxia. Neurology 2005;64:2129 – 31. [10] Vasudevan S, Peltz SW. Nuclear mRNA surveillance. Curr Opin Cell Biol 2003;15:332 – 7. [11] Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia. The aprataxin gene mutations. Neurology 2002;59:590 – 5. [12] Izatt L, Neme´th HA, Meesaq A, Mills KR, Taylor AMR, Shaw CE. Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised a-fetoprotein. J Neurol 2004;251:805 – 12. [13] Nikali K, Suomalainen A, Terwilliger J, Koskinen T, Weissenbach J, Peltonen L. Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus. Am J Hum Genet 1995;56:1088 – 95.