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Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation
Clinical Neurology and Neurosurgery 150 (2016) 194–196
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation Ayumi Nishiyama (MD) a , Hitoshi Warita (MD PhD) a , Toshiaki Takahashi (MD PhD) b , Naoki Suzuki (MD PhD) a , Shuhei Nishiyama (MD PhD) a , Ohito Tano (MD) a , Tetsuya Akiyama (MD) a , Yasuaki Watanabe (MD) a , Kenta Takahashi (MD) a , Hiroshi Kuroda (MD PhD) a , Masaaki Kato (MD PhD) a , Maki Tateyama (MD PhD) a , Tetsuya Niihori (MD PhD) c , Yoko Aoki (MD PhD) (Prof.) c , Masashi Aoki (MD PhD) (Prof.) a,∗ a b c
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Neurology and Division of Clinical Research, Sendai Nishitaga National Hospital, Sendai, Japan Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
a r t i c l e
i n f o
Article history: Received 25 February 2016 Received in revised form 3 August 2016 Accepted 5 August 2016 Available online 6 August 2016 Keywords: Familial ALS SOD1 Sensory involvement Peripheral neuropathy Neurodegeneration
1. Introduction Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease characterized by loss of motor neurons. Approximately 10% of ALS cases are classified as familial (FALS) and the remaining are considered to be sporadic (SALS). To date, more than 20 causative FALS genes were identified, and 20% of FALS cases are reported to be caused by mutations in the superoxide dismutase (SOD1) gene. In SOD1-linked FALS cases, the median age of onset is about 50 years, and the disease duration is 3 years [1]. A part of SOD1-mutated patients has atypical ALS phenotypes. The H46R, G41D, and G93S mutations in SOD1 are generally associated with later onset and slower progression without bulbar involvement, when compared with the remaining SOD1-linked cases. [2] How-
∗ Corresponding author at: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail address: [email protected] (M. Aoki). http://dx.doi.org/10.1016/j.clineuro.2016.08.008 0303-8467/© 2016 Elsevier B.V. All rights reserved.
ever, atypical extramotor symptoms, particularly those involving the sensory nervous system, have been quite rare. Here, we report novel clinical findings in an FALS patient with L8V SOD1 mutation. The proband presented prominent sensory involvement followed by motor neuron disease, while other family members showed typical ALS. The present case may broaden clinical phenotypes of SOD1-linked FALS and suggest intra-familial heterogeneity. 2. Case report At 51 years, a proband female patient noticed cold paresthesia in the sole of her right foot. She developed ascending numbness in her right leg. The initial neurological examination revealed distal dominant sensory impairment in the leg. Reflexes were normal except for hyporeflexia in the right Achilles. Nerve conduction study revealed normal compound muscle action potentials and motor conduction velocity in median, ulnar and tibial nerves, whereas
A. Nishiyama et al. / Clinical Neurology and Neurosurgery 150 (2016) 194–196
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Fig. 1. (A, B) A light microscopic image of a transverse section of Toluidine blue-stained sural nerve of the proband. Note diffuse loss of large myelinated fibers and very few clusters of small myelinated fibers. The black arrows show myelin ovoids. Bars = 50 m (A), 10 m (B). (C, D) Magnetic resonance imaging of the proband. Note moderate thoracic spinal cord atrophy without abnormal intensity. (C) T2-weighted axial imaging at the level of 10th thoracic vertebra (Lt, left); (D) T1-weighted sagittal imaging.
sensory nerve action potentials (SNAPs) were not evoked in the right sural. By sural nerve biopsy, we confirmed diffuse loss of large myelinated fibers together with formation of myelin ovoids and very few clusters of small myelinated fibers without sufficient regeneration. Inflammatory or vasculitic findings and amyloid deposits were absent (Fig. 1A). Unmyelinated fibers were preserved at the light microscopic level (Fig. 1B). The needle electromyography (EMG) in the lumbosacral and cervical regions showed none of the findings of denervation. Two years after the onset of sensory impairment, the patient also developed slowly progressive muscle weakness in the right leg. In the following year, she developed same sensory symptoms in her left leg. She could not walk without a cane after age 55. However, she discontinued the hospital visit from 54 to 61 years. At 61 years, reexamination disclosed the progression of muscle weakness in both lower extremities. Moreover, the sensory impairment had expanded to lower body below umbilicus, and also emerged in the right hand. Tendon reflexes were increased in jaw and upper extremities, but were diminished in lower extremities. Extensive laboratory screening showed no potential causes of neuropathy, including hyperglycemia, thyroid dysfunction, uremia, deficient vitamins B1 , B6 , B12 and folates, and positive autoantibodies such as antinuclear, anti-SS-A/Ro or SS-B/La, and antineutrophil cytoplasmic antibodies. Virus screening and tumor markers were also negative. SNAPs in the left sural nerve were not evoked. We could not detect tibial nerve-stimulated sensory evoked potentials (SSEP) at the lumbosacral and the primary sensory cortex. Needle EMG showed acute denervation potentials and chronic neurogenic changes in the lumbosacral regions. Magnetic resonance imaging showed moderate spinal cord atrophy below the thoracic level without any abnormal intensity area (Fig. 1C, D). In the following years, the sensorimotor symptoms gradually progressed to the right upper extremities and, ultimately, to bulbar palsy. At 65 years, acute and chronic neurogenic EMG changes were evident in the cervical regions. The amplitude of SNAP in the right median nerve decreased. She was diagnosed as clinically probable-laboratory supported ALS according to the revised El Escorial criteria.
Fig. 2. (A) Pedigree of the presented family. An arrow indicates the proband (III2). The proband’s father (II-3) died of typical ALS with spinal onset at 62 years. The proband’s paternal uncle (II-2) had similar clinical symptoms in his 80s. The proband’s younger brother died of acute myelocytic leukemia at age of 60 years. (B) Sequencing SOD1 in the proband showed the heterozygous L8V mutation. (C) The position of the mutation in exon 1 of SOD1 is relatively conserved.
Her father was compatible with typical ALS, and died 3 years after the onset of limb muscle weakness at 62 years without sensory involvement (Fig. 2A, II-3). Her uncle also developed ALS in his 80s (Fig. 2A, II-2). However, their precise medical records were unavailable. DNA extraction from peripheral blood of the proband was performed using standard protocols. We sequenced all exons of SOD1 and SETX by Sanger analysis; SETX is known to be associated with autosomal dominant ALS with peripheral neuropathy in Japanese patients [3]. Polymerase chain reaction was performed with
196
A. Nishiyama et al. / Clinical Neurology and Neurosurgery 150 (2016) 194–196
appropriate primers. The patient had the heterozygous c.25C > G; p.Leu9Val (L8V) mutation in SOD1 (Fig. 2B). The L8V mutation was negative in the database from single nucleotide polymorphism (SNP), 1000 Genomes Project, exome sequencing project (ESP) and Human Genetic Variation Database (HGVD, http://www.genome. med.kyoto-u.ac.jp/SnpDB/). The resulting amino acid change was predicted to be deleterious by SIFT (http://sift.jcvi.org/), and to be possibly damaging by Polyphen2 (http://genetics.bwh.harvard. edu/pph2/). Furthermore, the position of the mutation in exon 1 of SOD1 is relatively conserved (Fig. 2C). No pathological mutation was detected in SETX. Samples from other affected/unaffected family members were not available. Because of the existence of peripheral neuropathy, we also screened for mutations associated with Charcot-Marie-Tooth disease (CMT)-linked 28 genes using the custom MyGeneChipTM CustomSeqTM Resequencing Array (Affymetrix, Inc., Santa Clara, CA, USA) as described previously, [4] and known CMT genes were excluded.
It is difficult to totally prove the linkage between the atypical phenotype and the SOD1 mutation in the presented case. ALS is primarily an elderly-onset and rapidly progressive disease, often resulting in limited clinical/genetic information from family members at the time of diagnosis. Thus, accumulating atypical FALS cases with neuropathological analyses are needed to establish possible genotype–phenotype correlations, and to confirm the multisystem degeneration caused by SOD1 mutations.
3. Discussion
Sources of support
The present case with the L8V SOD1 mutation was characterized by the preceding sensory involvement, which was based on pure sensory axonopathy confirmed both electrophysiologically and pathologically. In addition, the proband also showed an exceptionally slower progression than the majority of reported patients with SOD1-linked ALS [1]. Motor neuron disease followed the sensory dysfunction in same metameric regions, and ultimately fulfilled the ALS diagnostic criteria. The L8V mutation has been identified as the ALS-linked toxic mutation with common property of an association with Derlin-1 that is a component of endoplasmic reticulum-associated degradation like other pathogenic SOD1 mutants [5]. Based on the absence of laboratory data and genetic mutations related to peripheral neuropathies, together with the pathogenicity of L8V mutation including predicted damaging effects without registration in the aforementioned databases, we diagnosed the patient as an atypical FALS. The sensory axonopathy seemed to extend from the caudal to rostral spinal cord, and demonstrated the ascendingly expanding hypoesthesia. This manifestation suggests progressive degeneration of primary sensory neurons. Moreover, the loss of central responses in SSEP supports an involvement of the central sensory nervous system, which might result in the atrophy of the spinal cord. Although earlier research has not provided detailed extramotor findings associated with the L8V SOD1 mutation, an SALS patient with the identical mutation was reported to show urgency of micturition. Additionally, previous reports have rarely shown atypical phenotypes in SOD1-linked ALS: sensory and autonomic dysfunction with the D90A heterozygous mutation, and autonomic and sensory involvement with the V31A heterozygous mutation. Collectively, the ALS-linked L8V mutation can cause an atypical sensory phenotype in addition to motor neuron disease. Thus, specific SOD1 mutations may cause multisystem degeneration beyond loss of motor neurons.
This study was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan; and Grant-in-Aid for Research on Rare and Intractable Diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis, from Japan Agency for Medical Research and Development, AMED.
4. Conclusion This case presents novel clinical manifestation of L8V mutant SOD1-linked FALS. The mutation may cause multisystem degeneration such as sensory axonopathy followed by motor neuron disease. Conflicts of interest None.
Acknowledgements We wish to thank Prof. Hiroshi Takashima for the gene analyses associated with CMT, Ms. Naoko Shimakura for Sanger analyses, and Mr. Brent Bell for reading the manuscript. References [1] S. Millecamps, F. Salachas, C. Cazeneuve, P. Gordon, B. Bricka, A. Camuzat, L. Guillot-Noel, O. Russaouen, G. Bruneteau, P.F. Pradat, N. Le Forestier, N. Vandenberghe, V. Danel-Brunaud, N. Guy, C. Thauvin-Robinet, L. Lacomblez, P. Couratier, D. Hannequin, D. Seilhean, I. Le Ber, P. Corcia, W. Camu, A. Brice, G. Rouleau, E. LeGuern, V. Meininger, SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations, J. Med. Genet. 47 (2010) 554–560. [2] M. Aoki, M. Ogasawara, Y. Matsubara, K. Narisawa, S. Nakamura, Y. Itoyama, K. Abe, Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: a possible new subtype of familial ALS, J. Neurol. Sci. 126 (1994) 77–83. [3] T. Asaka, H. Yokoji, J. Ito, K. Yamaguchi, A. Matsushima, Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX, Neurology 66 (2006) 1580–1581. [4] K. Maeda, R. Idehara, A. Hashiguchi, H. Takashima, A family with distal hereditary motor neuropathy and a K141Q mutation of small heat shock protein HSPB1, Intern. Med. 53 (2014) 1655–1658. [5] T. Fujisawa, N. Yamaguchi, H. Kadowaki, Y. Tsukamoto, N. Tsuburaya, A. Tsubota, H. Takahashi, I. Naguro, Y. Takahashi, J. Goto, S. Tsuji, H. Nishitoh, K. Homma, H. Ichijo, A systematic immunoprecipitation approach reinforces the concept of common conformational alterations in amyotrophic lateral sclerosis-linked SOD1 mutants, Neurobiol. Dis. 82 (2015) 478–486.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation Ayumi Nishiyama (MD) a , Hitoshi Warita (MD PhD) a , Toshiaki Takahashi (MD PhD) b , Naoki Suzuki (MD PhD) a , Shuhei Nishiyama (MD PhD) a , Ohito Tano (MD) a , Tetsuya Akiyama (MD) a , Yasuaki Watanabe (MD) a , Kenta Takahashi (MD) a , Hiroshi Kuroda (MD PhD) a , Masaaki Kato (MD PhD) a , Maki Tateyama (MD PhD) a , Tetsuya Niihori (MD PhD) c , Yoko Aoki (MD PhD) (Prof.) c , Masashi Aoki (MD PhD) (Prof.) a,∗ a b c
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Neurology and Division of Clinical Research, Sendai Nishitaga National Hospital, Sendai, Japan Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
a r t i c l e
i n f o
Article history: Received 25 February 2016 Received in revised form 3 August 2016 Accepted 5 August 2016 Available online 6 August 2016 Keywords: Familial ALS SOD1 Sensory involvement Peripheral neuropathy Neurodegeneration
1. Introduction Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease characterized by loss of motor neurons. Approximately 10% of ALS cases are classified as familial (FALS) and the remaining are considered to be sporadic (SALS). To date, more than 20 causative FALS genes were identified, and 20% of FALS cases are reported to be caused by mutations in the superoxide dismutase (SOD1) gene. In SOD1-linked FALS cases, the median age of onset is about 50 years, and the disease duration is 3 years [1]. A part of SOD1-mutated patients has atypical ALS phenotypes. The H46R, G41D, and G93S mutations in SOD1 are generally associated with later onset and slower progression without bulbar involvement, when compared with the remaining SOD1-linked cases. [2] How-
∗ Corresponding author at: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail address: [email protected] (M. Aoki). http://dx.doi.org/10.1016/j.clineuro.2016.08.008 0303-8467/© 2016 Elsevier B.V. All rights reserved.
ever, atypical extramotor symptoms, particularly those involving the sensory nervous system, have been quite rare. Here, we report novel clinical findings in an FALS patient with L8V SOD1 mutation. The proband presented prominent sensory involvement followed by motor neuron disease, while other family members showed typical ALS. The present case may broaden clinical phenotypes of SOD1-linked FALS and suggest intra-familial heterogeneity. 2. Case report At 51 years, a proband female patient noticed cold paresthesia in the sole of her right foot. She developed ascending numbness in her right leg. The initial neurological examination revealed distal dominant sensory impairment in the leg. Reflexes were normal except for hyporeflexia in the right Achilles. Nerve conduction study revealed normal compound muscle action potentials and motor conduction velocity in median, ulnar and tibial nerves, whereas
A. Nishiyama et al. / Clinical Neurology and Neurosurgery 150 (2016) 194–196
195
Fig. 1. (A, B) A light microscopic image of a transverse section of Toluidine blue-stained sural nerve of the proband. Note diffuse loss of large myelinated fibers and very few clusters of small myelinated fibers. The black arrows show myelin ovoids. Bars = 50 m (A), 10 m (B). (C, D) Magnetic resonance imaging of the proband. Note moderate thoracic spinal cord atrophy without abnormal intensity. (C) T2-weighted axial imaging at the level of 10th thoracic vertebra (Lt, left); (D) T1-weighted sagittal imaging.
sensory nerve action potentials (SNAPs) were not evoked in the right sural. By sural nerve biopsy, we confirmed diffuse loss of large myelinated fibers together with formation of myelin ovoids and very few clusters of small myelinated fibers without sufficient regeneration. Inflammatory or vasculitic findings and amyloid deposits were absent (Fig. 1A). Unmyelinated fibers were preserved at the light microscopic level (Fig. 1B). The needle electromyography (EMG) in the lumbosacral and cervical regions showed none of the findings of denervation. Two years after the onset of sensory impairment, the patient also developed slowly progressive muscle weakness in the right leg. In the following year, she developed same sensory symptoms in her left leg. She could not walk without a cane after age 55. However, she discontinued the hospital visit from 54 to 61 years. At 61 years, reexamination disclosed the progression of muscle weakness in both lower extremities. Moreover, the sensory impairment had expanded to lower body below umbilicus, and also emerged in the right hand. Tendon reflexes were increased in jaw and upper extremities, but were diminished in lower extremities. Extensive laboratory screening showed no potential causes of neuropathy, including hyperglycemia, thyroid dysfunction, uremia, deficient vitamins B1 , B6 , B12 and folates, and positive autoantibodies such as antinuclear, anti-SS-A/Ro or SS-B/La, and antineutrophil cytoplasmic antibodies. Virus screening and tumor markers were also negative. SNAPs in the left sural nerve were not evoked. We could not detect tibial nerve-stimulated sensory evoked potentials (SSEP) at the lumbosacral and the primary sensory cortex. Needle EMG showed acute denervation potentials and chronic neurogenic changes in the lumbosacral regions. Magnetic resonance imaging showed moderate spinal cord atrophy below the thoracic level without any abnormal intensity area (Fig. 1C, D). In the following years, the sensorimotor symptoms gradually progressed to the right upper extremities and, ultimately, to bulbar palsy. At 65 years, acute and chronic neurogenic EMG changes were evident in the cervical regions. The amplitude of SNAP in the right median nerve decreased. She was diagnosed as clinically probable-laboratory supported ALS according to the revised El Escorial criteria.
Fig. 2. (A) Pedigree of the presented family. An arrow indicates the proband (III2). The proband’s father (II-3) died of typical ALS with spinal onset at 62 years. The proband’s paternal uncle (II-2) had similar clinical symptoms in his 80s. The proband’s younger brother died of acute myelocytic leukemia at age of 60 years. (B) Sequencing SOD1 in the proband showed the heterozygous L8V mutation. (C) The position of the mutation in exon 1 of SOD1 is relatively conserved.
Her father was compatible with typical ALS, and died 3 years after the onset of limb muscle weakness at 62 years without sensory involvement (Fig. 2A, II-3). Her uncle also developed ALS in his 80s (Fig. 2A, II-2). However, their precise medical records were unavailable. DNA extraction from peripheral blood of the proband was performed using standard protocols. We sequenced all exons of SOD1 and SETX by Sanger analysis; SETX is known to be associated with autosomal dominant ALS with peripheral neuropathy in Japanese patients [3]. Polymerase chain reaction was performed with
196
A. Nishiyama et al. / Clinical Neurology and Neurosurgery 150 (2016) 194–196
appropriate primers. The patient had the heterozygous c.25C > G; p.Leu9Val (L8V) mutation in SOD1 (Fig. 2B). The L8V mutation was negative in the database from single nucleotide polymorphism (SNP), 1000 Genomes Project, exome sequencing project (ESP) and Human Genetic Variation Database (HGVD, http://www.genome. med.kyoto-u.ac.jp/SnpDB/). The resulting amino acid change was predicted to be deleterious by SIFT (http://sift.jcvi.org/), and to be possibly damaging by Polyphen2 (http://genetics.bwh.harvard. edu/pph2/). Furthermore, the position of the mutation in exon 1 of SOD1 is relatively conserved (Fig. 2C). No pathological mutation was detected in SETX. Samples from other affected/unaffected family members were not available. Because of the existence of peripheral neuropathy, we also screened for mutations associated with Charcot-Marie-Tooth disease (CMT)-linked 28 genes using the custom MyGeneChipTM CustomSeqTM Resequencing Array (Affymetrix, Inc., Santa Clara, CA, USA) as described previously, [4] and known CMT genes were excluded.
It is difficult to totally prove the linkage between the atypical phenotype and the SOD1 mutation in the presented case. ALS is primarily an elderly-onset and rapidly progressive disease, often resulting in limited clinical/genetic information from family members at the time of diagnosis. Thus, accumulating atypical FALS cases with neuropathological analyses are needed to establish possible genotype–phenotype correlations, and to confirm the multisystem degeneration caused by SOD1 mutations.
3. Discussion
Sources of support
The present case with the L8V SOD1 mutation was characterized by the preceding sensory involvement, which was based on pure sensory axonopathy confirmed both electrophysiologically and pathologically. In addition, the proband also showed an exceptionally slower progression than the majority of reported patients with SOD1-linked ALS [1]. Motor neuron disease followed the sensory dysfunction in same metameric regions, and ultimately fulfilled the ALS diagnostic criteria. The L8V mutation has been identified as the ALS-linked toxic mutation with common property of an association with Derlin-1 that is a component of endoplasmic reticulum-associated degradation like other pathogenic SOD1 mutants [5]. Based on the absence of laboratory data and genetic mutations related to peripheral neuropathies, together with the pathogenicity of L8V mutation including predicted damaging effects without registration in the aforementioned databases, we diagnosed the patient as an atypical FALS. The sensory axonopathy seemed to extend from the caudal to rostral spinal cord, and demonstrated the ascendingly expanding hypoesthesia. This manifestation suggests progressive degeneration of primary sensory neurons. Moreover, the loss of central responses in SSEP supports an involvement of the central sensory nervous system, which might result in the atrophy of the spinal cord. Although earlier research has not provided detailed extramotor findings associated with the L8V SOD1 mutation, an SALS patient with the identical mutation was reported to show urgency of micturition. Additionally, previous reports have rarely shown atypical phenotypes in SOD1-linked ALS: sensory and autonomic dysfunction with the D90A heterozygous mutation, and autonomic and sensory involvement with the V31A heterozygous mutation. Collectively, the ALS-linked L8V mutation can cause an atypical sensory phenotype in addition to motor neuron disease. Thus, specific SOD1 mutations may cause multisystem degeneration beyond loss of motor neurons.
This study was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan; and Grant-in-Aid for Research on Rare and Intractable Diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis, from Japan Agency for Medical Research and Development, AMED.
4. Conclusion This case presents novel clinical manifestation of L8V mutant SOD1-linked FALS. The mutation may cause multisystem degeneration such as sensory axonopathy followed by motor neuron disease. Conflicts of interest None.
Acknowledgements We wish to thank Prof. Hiroshi Takashima for the gene analyses associated with CMT, Ms. Naoko Shimakura for Sanger analyses, and Mr. Brent Bell for reading the manuscript. References [1] S. Millecamps, F. Salachas, C. Cazeneuve, P. Gordon, B. Bricka, A. Camuzat, L. Guillot-Noel, O. Russaouen, G. Bruneteau, P.F. Pradat, N. Le Forestier, N. Vandenberghe, V. Danel-Brunaud, N. Guy, C. Thauvin-Robinet, L. Lacomblez, P. Couratier, D. Hannequin, D. Seilhean, I. Le Ber, P. Corcia, W. Camu, A. Brice, G. Rouleau, E. LeGuern, V. Meininger, SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations, J. Med. Genet. 47 (2010) 554–560. [2] M. Aoki, M. Ogasawara, Y. Matsubara, K. Narisawa, S. Nakamura, Y. Itoyama, K. Abe, Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: a possible new subtype of familial ALS, J. Neurol. Sci. 126 (1994) 77–83. [3] T. Asaka, H. Yokoji, J. Ito, K. Yamaguchi, A. Matsushima, Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX, Neurology 66 (2006) 1580–1581. [4] K. Maeda, R. Idehara, A. Hashiguchi, H. Takashima, A family with distal hereditary motor neuropathy and a K141Q mutation of small heat shock protein HSPB1, Intern. Med. 53 (2014) 1655–1658. [5] T. Fujisawa, N. Yamaguchi, H. Kadowaki, Y. Tsukamoto, N. Tsuburaya, A. Tsubota, H. Takahashi, I. Naguro, Y. Takahashi, J. Goto, S. Tsuji, H. Nishitoh, K. Homma, H. Ichijo, A systematic immunoprecipitation approach reinforces the concept of common conformational alterations in amyotrophic lateral sclerosis-linked SOD1 mutants, Neurobiol. Dis. 82 (2015) 478–486.