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A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis
Journal of the Neurological Sciences 334 (2013) 192–195
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis Toshio Inui a,1, Toshitaka Kawarai b,⁎,1, Koji Fujita b, Kazuyuki Kawamura a, Takao Mitsui a, Antonio Orlacchio c,d, Masaki Kamada e, Takashi Abe f, Yuishin Izumi b, Ryuji Kaji b a
Department of Neurology, Tokushima Hospital, National Hospital Organization, Tokushima, Japan Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy d Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy e Department of Neurological Intractable Disease Research, Faculty of Medicine, Kagawa University, Kagawa, Japan f Department of Radiology, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan b c
a r t i c l e
i n f o
Article history: Received 19 April 2013 Received in revised form 15 July 2013 Accepted 14 August 2013 Available online 29 August 2013 Keywords: Hereditary diffuse leukoencephalopathy with spheroids Colony stimulating factor 1 receptor gene White matter lesions Primary progressive form of multiple sclerosis Differential diagnosis Genotype–phenotype correlations
a b s t r a c t HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. Genetic defects in the colony-stimulating factor 1 receptor (CSF1R) gene have been reported in many HDLS cases. The present report describes a new missense mutation Arg777Gln involving exon 18 of the CSF1R gene in a sporadic patient presenting with tumor-like lesions mimicking primary progressive multiple sclerosis. The patient was initially diagnosed with a progressive variant of multiple sclerosis and received inadequate treatments. Although most HDLS cases have a positive family history, this disease should also be suspected in sporadic patients showing unusual white matter lesions at MRI. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Hereditary diffuse leukoencephalopathy with spheroids (HLDS; OMIM 221820) is a central nervous system white matter disease with a broad spectrum of clinical manifestations including dementia, parkinsonism, seizures and several other symptoms. HDLS is caused by mutations of the colony-stimulating factor 1 receptor (CSF1R) gene, mainly consisting of missense substitutions of a single base within the protein tyrosine kinase domain, leading to a loss of autophosphorylation [1]. To date, more than 20 mutations have been detected in familial cases. Age of onset varies from late teens to early seventies, and the most common age at onset is the fourth decade
⁎ Correspondence to: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan, 3-18-15, Kuramoto-cho, Tokushima City, 770–0042, Japan. Tel.: +81 88 633 7207; fax: +81 88 633 7208. E-mail addresses: [email protected] (T. Inui), [email protected] (T. Kawarai), [email protected] (K. Fujita), [email protected] (K. Kawamura), [email protected] (T. Mitsui), [email protected] (A. Orlacchio), [email protected] (M. Kamada), [email protected] (T. Abe), [email protected] (Y. Izumi), [email protected] (R. Kaji). 1 These authors contributed equally. 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.08.020
of life. Increasing white matter lesions along with the disease progression detected by magnetic resonance imaging (MRI) might be a diagnostic clue for HDLS [2]. However, lack of specific findings in clinical features and neuroimages may make the diagnosis difficult, especially in patients without family history. 2. Case report At the end of January 1995, a 24-year-old man with an unremarkable medical history presented with difficulties in swallowing and speech. His dysphagia became severe and an enteral feeding tube was placed at the age of 30. He became bedridden and required occasional respiratory support from the age of 32. Repeated laboratory examinations, including lumbar puncture and biochemical blood tests, provided little supportive evidence for neuroinflammation and demyelination. Oligoclonal bands were never detected in the cerebrospinal fluid (CSF) and electromyography and nerve conduction studies revealed no involvement of the peripheral nervous system. However, somatosensory evoked potentials showed prolonged central conduction times from the median nerve, bilaterally. The visual evoked potentials showed no delayed latency. Possible diagnoses, including adrenoleukodystrophy and metachromatic leukodystrophy, were excluded by measurement of very long-chain fatty acids and arylsulfatase A activity, respectively. All currently living
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195
family members, the patient's mother aged 67, and two brothers aged 45 and 39, were examined by certified neurologists (T.I., K.K., and T.M.), and proved to be healthy, with no cognitive impairment. Furthermore, the mother's brain MRI showed normal findings without leukodystrophy (data available upon request). His father died of stroke at the age of 60,
193
but a detailed clinical record was not available. The patient's paternal and maternal grandparents died after the age of 80, and were considered healthy in their 70s. The patient's initial brain MRI revealed tumor-like lesions in the bilateral cerebral white matter (Fig. 1, A–C). A tentative diagnosis of multiple sclerosis was made in 1995. The patient received
C A
B
E D
F
G
H
Fig. 1. Magnetic Resonance Images. (A, B, C) Brain MRI at the age of 24. Coronal and sagittal T2-weighted images show tumor-like lesions in the bilateral cerebral white matter (solid arrowheads). Lesions show no contrast enhancement (data not shown). Consolidated white matter lesions show high intensity on diffusion-weighted imaging. (D) Involvement of the bilateral corticospinal tract is shown in MRI at 1-year follow-up, possibly reflecting Wallerian degeneration (white arrows). (E) T1-weighted MRI shows high intensity spots in the low intensity lesions in the deep cerebral white matter around the anterior horn of the lateral ventricle, suggesting subcortical calcifications (white arrows). (F) Marked central atrophy is observed at MRI at 10-year follow-up. The thickness of the cortex is relatively preserved. Cerebellar pathology is minimal. (G, H) Periventricular hyperintensity is observed at T2-weighted MRI, which is also observed on diffusion-weighted imaging, reflecting T2 shine-through.
194
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195
several immunotherapies, including methylprednisolone and cyclophosphamide, with no benefits. Follow-up brain MRI showed extensive white matter lesions, findings of corticospinal tract degeneration and subcortical calcifications, as well as a marked loss of neuronal tissue in the central part of the brain (Fig. 1, D–H). Leukodystrophies, including autosomal dominant or autosomal recessive arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL or CARASIL) and hereditary diffuse leukoencephalopathy with spheroids (HDLS), were later suspected. 3. Gene analysis After informed consent was given, genomic DNA was extracted from peripheral blood leukocytes according to standard methods. Genomic DNA was amplified by PCR with sets of specific primers in order to investigate coding sequences and intron/exon boundaries of CSF1R, NOTCH3 and HTRA1 genes, as described elsewhere [1,3,4]. PCR products were sequenced in forward and reverse directions using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit and ABI 3500xL autosequencer (Applied Biosystems, Foster City, CA) according to standard procedures. No mutation was detected in NOTCH3 and HTRA1 genes; however, a novel mutation c.2330G N A in exon 18 was revealed in CSF1R gene, which leads to an amino acid substitution (p.Arg777Gln) (Supplemental Fig. S1). This amino acid is located within the protein tyrosine kinase domain of the CSF1R gene. According to the Human Gene Mutation Database, the p.Arg777Gln mutation has not been reported previously. The missense mutation was not identified in 200 chromosomes of normal Japanese individuals, indicating that this is a novel variant, irrespective of ethnicity. The patient's healthy mother did not carry the mutation. Informed consent was not obtained from the two brothers. 4. In silico analysis of amino acid substitutions Missense variants were analyzed with PolyPhen-2, SIFT, and MutationTaster to predict the pathological character of single amino acid mutations [5–7]. p.Arg777Gln mutation was predicted to be “Probably damaging” by Polyphen-2, “Damaging” by SIFT, and “Disease-causing” by MutationTaster. Protein sequence alignment was performed with ClustalW2, demonstrating that the amino acid is highly conserved in evolution, including Rattus norvegicus, Mus musculus, Gallus gallus, Bos taurus, Zebrafish and Xenopustropicalis (Supplemental Fig. S1).
progressive multiple sclerosis [9]. Clinical features, including early onset, rapid progression and extensive white matter lesions are similar to those of the present case. This indicates that genotype is not strongly correlated with age-at-onset and progression. Sporadic cases may tend to show more severe features than familial cases. The high intensity lesions reveled in T1-weighted images might reflect white matter calcifications (Fig. 1, E). Calcifications were demonstrated by means of von Kossa staining in an autopsied brain from a genetically confirmed CSF1R-HDLS case (T.K. personal communication). A diagnostic algorithm has been proposed for the differentiation of leukodystrophies in the early stage of multiple sclerosis, in which “red flags” are described, including symmetric involvement of long spinal tracts and peripheral nerves, and lack of oligoclonal bands in CSF [10]. Some of the clinical features in the present case met the diagnostic criteria for suspecting leukodystrophy rather than multiple sclerosis. However, the diagnosis was not determined until the causative gene was identified. Absent or insufficient information on the family history might be explained by the possibilities of reduced penetrance or de novo mutations in CSF1R. The latter has been demonstrated in a sporadic case carrying the p.Lys793Thr or the p.Ile794Thr mutation, which was genetically proven [9,11]. In conclusion, this report suggests that the diagnosis of HDLS or a de novo mutation in CSF1R must be considered in patients with bilateral symmetric changes in leukodystrophies, also in the absence of family history of neurodegenerative disorders, if white matter lesions are unusual and have a tumor-like appearance. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2013.08.020. Funding agencies This work was supported by grants from the Japanese Ministry of Health, Labor and Welfare (Grant-in-Aid for Exploratory Research to R.K.), the Italian Ministry of Health (grant no. GR09.109 to A.O.), and the Comitato Telethon Fondazione Onlus, Italy (grant no. GGP10121 to A.O.). Relevant conflicts of interest/financial disclosures Nothing to report.
5. Discussion
Author contribution
Neither the missense mutation p.Arg777Gln, nor the nucleotide substitution was listed in public databases. The amino acid 777Arg is located in the highly conserved protein tyrosine kinase domain of CSF1R and is highly conserved amongst CSF1R homologous proteins. Taking into account both the strong conservation of the affected amino acid across species and the in silico prediction of functional impairment associated with the mutations, the mutation identified in this study is considered to be pathogenic. It remains unknown whether the mutation has occurred de novo in the patient or has been inherited from the father who died at the age of 60. An amino acid substitution at the same position, p.Arg777Trp, was previously reported in a familial HDLS case [8]. The patient carrying the mutation was an alcoholic at the age of 38, and then presented cognitive impairment and gait disturbance. His brain MRI at the age of 41 showed mild atrophy of frontal, parietal and temporal lobes, with confluent hyperintensities in periventricular regions, including the corpus callosum [8]. These clinical features are different from those of the present case, indicating that phenotypes can vary amongst patients carrying the missense mutation at the codon 777. Recently, a sporadic patient carrying a de novo mutation (p.Ile794Thr) has been reported, who showed clinical symptoms and brain MRI findings mimicking primary
Toshio Inui, Kazuyuki Kawamura and Takao Mitsui: patient review and medical writing for content. Koji Fujita, Antonio Orlacchio, Masaki Kamada,Yuishin Izumi and Ryuji Kaji: study supervision and coordination. Toshitaka Kawarai: genetic testing, sequencing of mutation, manuscript preparation. Takashi Abe: analysis and interpretation of the brain MRI findings. Acknowledgments We thank the patient and family members involved in this study. We thank Michela Renna (MA) for her language advice and assistance, as well as the Support Center for Advanced Medical Sciences, Tokushima University School of Medicine, for the use of their facilities to prepare the manuscript. References [1] Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2012;44:200–5. [2] Sundal C, Van Gerpen JA, Nicholson AM, Wider C, Shuster EA, Aasly J, et al. MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology 2012;79:566–74.
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195 [3] Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–10. [4] Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729–39. [5] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9. [6] Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res May 2001;11(5):863–74. [7] Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates diseasecausing potential of sequence alterations. Nat Methods Aug 2010;7(8):575–6.
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[8] Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, et al. CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. Am J Med Genet B Neuropsychiatr Genet Dec. 2012;159B(8):951–7. [9] Saitoh BY, Yamasaki R, Hayashi S, Yoshimura S, Tateishi T, Ohyagi Y, et al. A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis. Mult Scler 2013;10:1367–70. [10] Kohler W. Diagnostic algorithm for the differentiation of leukodystrophies in early MS. J Neurol 2008;255(Suppl. 6):123–6. [11] Kondo Y, Kinoshita M, Fukushima K, Yoshida K, Ikeda S. Early involvement of the corpus callosum in a patient with hereditary diffuse leukoencephalopathy with spheroids carrying the de novo K793T mutation of CSF1R. Intern Med 2013;52:503–6.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis Toshio Inui a,1, Toshitaka Kawarai b,⁎,1, Koji Fujita b, Kazuyuki Kawamura a, Takao Mitsui a, Antonio Orlacchio c,d, Masaki Kamada e, Takashi Abe f, Yuishin Izumi b, Ryuji Kaji b a
Department of Neurology, Tokushima Hospital, National Hospital Organization, Tokushima, Japan Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy d Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy e Department of Neurological Intractable Disease Research, Faculty of Medicine, Kagawa University, Kagawa, Japan f Department of Radiology, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan b c
a r t i c l e
i n f o
Article history: Received 19 April 2013 Received in revised form 15 July 2013 Accepted 14 August 2013 Available online 29 August 2013 Keywords: Hereditary diffuse leukoencephalopathy with spheroids Colony stimulating factor 1 receptor gene White matter lesions Primary progressive form of multiple sclerosis Differential diagnosis Genotype–phenotype correlations
a b s t r a c t HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. Genetic defects in the colony-stimulating factor 1 receptor (CSF1R) gene have been reported in many HDLS cases. The present report describes a new missense mutation Arg777Gln involving exon 18 of the CSF1R gene in a sporadic patient presenting with tumor-like lesions mimicking primary progressive multiple sclerosis. The patient was initially diagnosed with a progressive variant of multiple sclerosis and received inadequate treatments. Although most HDLS cases have a positive family history, this disease should also be suspected in sporadic patients showing unusual white matter lesions at MRI. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Hereditary diffuse leukoencephalopathy with spheroids (HLDS; OMIM 221820) is a central nervous system white matter disease with a broad spectrum of clinical manifestations including dementia, parkinsonism, seizures and several other symptoms. HDLS is caused by mutations of the colony-stimulating factor 1 receptor (CSF1R) gene, mainly consisting of missense substitutions of a single base within the protein tyrosine kinase domain, leading to a loss of autophosphorylation [1]. To date, more than 20 mutations have been detected in familial cases. Age of onset varies from late teens to early seventies, and the most common age at onset is the fourth decade
⁎ Correspondence to: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan, 3-18-15, Kuramoto-cho, Tokushima City, 770–0042, Japan. Tel.: +81 88 633 7207; fax: +81 88 633 7208. E-mail addresses: [email protected] (T. Inui), [email protected] (T. Kawarai), [email protected] (K. Fujita), [email protected] (K. Kawamura), [email protected] (T. Mitsui), [email protected] (A. Orlacchio), [email protected] (M. Kamada), [email protected] (T. Abe), [email protected] (Y. Izumi), [email protected] (R. Kaji). 1 These authors contributed equally. 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.08.020
of life. Increasing white matter lesions along with the disease progression detected by magnetic resonance imaging (MRI) might be a diagnostic clue for HDLS [2]. However, lack of specific findings in clinical features and neuroimages may make the diagnosis difficult, especially in patients without family history. 2. Case report At the end of January 1995, a 24-year-old man with an unremarkable medical history presented with difficulties in swallowing and speech. His dysphagia became severe and an enteral feeding tube was placed at the age of 30. He became bedridden and required occasional respiratory support from the age of 32. Repeated laboratory examinations, including lumbar puncture and biochemical blood tests, provided little supportive evidence for neuroinflammation and demyelination. Oligoclonal bands were never detected in the cerebrospinal fluid (CSF) and electromyography and nerve conduction studies revealed no involvement of the peripheral nervous system. However, somatosensory evoked potentials showed prolonged central conduction times from the median nerve, bilaterally. The visual evoked potentials showed no delayed latency. Possible diagnoses, including adrenoleukodystrophy and metachromatic leukodystrophy, were excluded by measurement of very long-chain fatty acids and arylsulfatase A activity, respectively. All currently living
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195
family members, the patient's mother aged 67, and two brothers aged 45 and 39, were examined by certified neurologists (T.I., K.K., and T.M.), and proved to be healthy, with no cognitive impairment. Furthermore, the mother's brain MRI showed normal findings without leukodystrophy (data available upon request). His father died of stroke at the age of 60,
193
but a detailed clinical record was not available. The patient's paternal and maternal grandparents died after the age of 80, and were considered healthy in their 70s. The patient's initial brain MRI revealed tumor-like lesions in the bilateral cerebral white matter (Fig. 1, A–C). A tentative diagnosis of multiple sclerosis was made in 1995. The patient received
C A
B
E D
F
G
H
Fig. 1. Magnetic Resonance Images. (A, B, C) Brain MRI at the age of 24. Coronal and sagittal T2-weighted images show tumor-like lesions in the bilateral cerebral white matter (solid arrowheads). Lesions show no contrast enhancement (data not shown). Consolidated white matter lesions show high intensity on diffusion-weighted imaging. (D) Involvement of the bilateral corticospinal tract is shown in MRI at 1-year follow-up, possibly reflecting Wallerian degeneration (white arrows). (E) T1-weighted MRI shows high intensity spots in the low intensity lesions in the deep cerebral white matter around the anterior horn of the lateral ventricle, suggesting subcortical calcifications (white arrows). (F) Marked central atrophy is observed at MRI at 10-year follow-up. The thickness of the cortex is relatively preserved. Cerebellar pathology is minimal. (G, H) Periventricular hyperintensity is observed at T2-weighted MRI, which is also observed on diffusion-weighted imaging, reflecting T2 shine-through.
194
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195
several immunotherapies, including methylprednisolone and cyclophosphamide, with no benefits. Follow-up brain MRI showed extensive white matter lesions, findings of corticospinal tract degeneration and subcortical calcifications, as well as a marked loss of neuronal tissue in the central part of the brain (Fig. 1, D–H). Leukodystrophies, including autosomal dominant or autosomal recessive arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL or CARASIL) and hereditary diffuse leukoencephalopathy with spheroids (HDLS), were later suspected. 3. Gene analysis After informed consent was given, genomic DNA was extracted from peripheral blood leukocytes according to standard methods. Genomic DNA was amplified by PCR with sets of specific primers in order to investigate coding sequences and intron/exon boundaries of CSF1R, NOTCH3 and HTRA1 genes, as described elsewhere [1,3,4]. PCR products were sequenced in forward and reverse directions using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit and ABI 3500xL autosequencer (Applied Biosystems, Foster City, CA) according to standard procedures. No mutation was detected in NOTCH3 and HTRA1 genes; however, a novel mutation c.2330G N A in exon 18 was revealed in CSF1R gene, which leads to an amino acid substitution (p.Arg777Gln) (Supplemental Fig. S1). This amino acid is located within the protein tyrosine kinase domain of the CSF1R gene. According to the Human Gene Mutation Database, the p.Arg777Gln mutation has not been reported previously. The missense mutation was not identified in 200 chromosomes of normal Japanese individuals, indicating that this is a novel variant, irrespective of ethnicity. The patient's healthy mother did not carry the mutation. Informed consent was not obtained from the two brothers. 4. In silico analysis of amino acid substitutions Missense variants were analyzed with PolyPhen-2, SIFT, and MutationTaster to predict the pathological character of single amino acid mutations [5–7]. p.Arg777Gln mutation was predicted to be “Probably damaging” by Polyphen-2, “Damaging” by SIFT, and “Disease-causing” by MutationTaster. Protein sequence alignment was performed with ClustalW2, demonstrating that the amino acid is highly conserved in evolution, including Rattus norvegicus, Mus musculus, Gallus gallus, Bos taurus, Zebrafish and Xenopustropicalis (Supplemental Fig. S1).
progressive multiple sclerosis [9]. Clinical features, including early onset, rapid progression and extensive white matter lesions are similar to those of the present case. This indicates that genotype is not strongly correlated with age-at-onset and progression. Sporadic cases may tend to show more severe features than familial cases. The high intensity lesions reveled in T1-weighted images might reflect white matter calcifications (Fig. 1, E). Calcifications were demonstrated by means of von Kossa staining in an autopsied brain from a genetically confirmed CSF1R-HDLS case (T.K. personal communication). A diagnostic algorithm has been proposed for the differentiation of leukodystrophies in the early stage of multiple sclerosis, in which “red flags” are described, including symmetric involvement of long spinal tracts and peripheral nerves, and lack of oligoclonal bands in CSF [10]. Some of the clinical features in the present case met the diagnostic criteria for suspecting leukodystrophy rather than multiple sclerosis. However, the diagnosis was not determined until the causative gene was identified. Absent or insufficient information on the family history might be explained by the possibilities of reduced penetrance or de novo mutations in CSF1R. The latter has been demonstrated in a sporadic case carrying the p.Lys793Thr or the p.Ile794Thr mutation, which was genetically proven [9,11]. In conclusion, this report suggests that the diagnosis of HDLS or a de novo mutation in CSF1R must be considered in patients with bilateral symmetric changes in leukodystrophies, also in the absence of family history of neurodegenerative disorders, if white matter lesions are unusual and have a tumor-like appearance. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2013.08.020. Funding agencies This work was supported by grants from the Japanese Ministry of Health, Labor and Welfare (Grant-in-Aid for Exploratory Research to R.K.), the Italian Ministry of Health (grant no. GR09.109 to A.O.), and the Comitato Telethon Fondazione Onlus, Italy (grant no. GGP10121 to A.O.). Relevant conflicts of interest/financial disclosures Nothing to report.
5. Discussion
Author contribution
Neither the missense mutation p.Arg777Gln, nor the nucleotide substitution was listed in public databases. The amino acid 777Arg is located in the highly conserved protein tyrosine kinase domain of CSF1R and is highly conserved amongst CSF1R homologous proteins. Taking into account both the strong conservation of the affected amino acid across species and the in silico prediction of functional impairment associated with the mutations, the mutation identified in this study is considered to be pathogenic. It remains unknown whether the mutation has occurred de novo in the patient or has been inherited from the father who died at the age of 60. An amino acid substitution at the same position, p.Arg777Trp, was previously reported in a familial HDLS case [8]. The patient carrying the mutation was an alcoholic at the age of 38, and then presented cognitive impairment and gait disturbance. His brain MRI at the age of 41 showed mild atrophy of frontal, parietal and temporal lobes, with confluent hyperintensities in periventricular regions, including the corpus callosum [8]. These clinical features are different from those of the present case, indicating that phenotypes can vary amongst patients carrying the missense mutation at the codon 777. Recently, a sporadic patient carrying a de novo mutation (p.Ile794Thr) has been reported, who showed clinical symptoms and brain MRI findings mimicking primary
Toshio Inui, Kazuyuki Kawamura and Takao Mitsui: patient review and medical writing for content. Koji Fujita, Antonio Orlacchio, Masaki Kamada,Yuishin Izumi and Ryuji Kaji: study supervision and coordination. Toshitaka Kawarai: genetic testing, sequencing of mutation, manuscript preparation. Takashi Abe: analysis and interpretation of the brain MRI findings. Acknowledgments We thank the patient and family members involved in this study. We thank Michela Renna (MA) for her language advice and assistance, as well as the Support Center for Advanced Medical Sciences, Tokushima University School of Medicine, for the use of their facilities to prepare the manuscript. References [1] Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2012;44:200–5. [2] Sundal C, Van Gerpen JA, Nicholson AM, Wider C, Shuster EA, Aasly J, et al. MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology 2012;79:566–74.
T. Inui et al. / Journal of the Neurological Sciences 334 (2013) 192–195 [3] Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–10. [4] Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729–39. [5] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9. [6] Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res May 2001;11(5):863–74. [7] Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates diseasecausing potential of sequence alterations. Nat Methods Aug 2010;7(8):575–6.
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[8] Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, et al. CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. Am J Med Genet B Neuropsychiatr Genet Dec. 2012;159B(8):951–7. [9] Saitoh BY, Yamasaki R, Hayashi S, Yoshimura S, Tateishi T, Ohyagi Y, et al. A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis. Mult Scler 2013;10:1367–70. [10] Kohler W. Diagnostic algorithm for the differentiation of leukodystrophies in early MS. J Neurol 2008;255(Suppl. 6):123–6. [11] Kondo Y, Kinoshita M, Fukushima K, Yoshida K, Ikeda S. Early involvement of the corpus callosum in a patient with hereditary diffuse leukoencephalopathy with spheroids carrying the de novo K793T mutation of CSF1R. Intern Med 2013;52:503–6.