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First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Case Report
First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations Ryo Sato a,b,⇑, Takehiko Inui a, Wakaba Endo a, Yukimune Okubo a,b, Yusuke Takezawa a,b, Mai Anzai a, Hiroyuki Morita c, Hirotomo Saitsu d, Naomichi Matsumoto d, Kazuhiro Haginoya a a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Departmetn of Pediatrics, Fukushima Rehabilitation Center for Children, Koriyama, Japan d Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan Received 1 December 2015; received in revised form 16 February 2016; accepted 12 April 2016
Abstract The clinical phenotypes of neuronal ceroid lipofuscinoses (NCLs) have been determined based on the age of onset and clinical symptoms. NCLs with onset between age 2 and 4 years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs). The clinical features of LINCLs include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. There have been reports of several genes associated with LINCLs, with mutations in the CLN6 gene reported to cause variant forms of LINCLs (vLINCLs). Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient diagnosed by whole-exome sequencing. Visual acuity in our patient was preserved until the early teens. It remains to be elucidated if preserved visual function is related to the novel mutations of CLN6. Our case reveals the efficacy of whole-exome sequencing for examination of PMEs and highlights the existence of the CLN6 mutation in the Japanese population. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Late infantile neuronal ceroid lipofudcinosis; CLN6; Whole-exome sequencing
1. Introduction Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and neurodegenerative diseases caused by an accumulation of autofluorescent lipopigments in various tissues. The clinical phenotypes of NCLs have been postulated based on the age of onset and clinical symp⇑ Corresponding author at: Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan. E-mail address: [email protected] (R. Sato).
toms [1]. NCLs appearing between age 2 and 4 years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs), and their clinical features include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. The causative genes of LINCLs have been identified, among which CLN2 (TPP1) is a major one. The other causative genes of different variants of LINCLs (vLINCLs) include CLN5, CLN6, CLN7 (MFSD8), and CLN8. Patients with vLINCLs caused by CLN6 mutations have been reported in the Czech Republic, Croatia,
http://dx.doi.org/10.1016/j.braindev.2016.04.007 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
2
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
Portugal, Central and South America, and more rarely, in Central and Northern Europe [2]. Visual impairments typically appear in early infancy and progress rapidly to blindness. Life expectancy often ranges to the mid-20 s in such cases [3]. Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient with preserved visual function until the early teens.
(a)
2. Case report A 13-year-old male, the sole child of nonconsanguineous parents, was born by spontaneous delivery after 39 weeks of uneventful pregnancy. His father had presented with hyperactivity disorder. The child’s birth weight, height, and occipitofrontal circumference were 2875 g ( 0.3 SD), 49 cm (0 SD), and 30 cm
(b)
Fp1-F7 F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 Fz-Cz Cz-Pz ECG
4 Hz PS
8 Hz PS
(c)
100 μV
1sec
(d)
Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Lt. SCM Rt. SCM Lt. triceps Rt. triceps Lt. biceps Rt. biceps Lt. TA Rt. TA
(e)
500 μV
1sec
Fig. 1. Results of neurophysiological studies. (a) Electroencephalogram (EEG) recorded at 8 years old. The 4 Hz photic stimuli evoked spike-wave bursts in the left posterior temporal area and the surroundings, which showed propagation to the bilateral frontal areas. (b) Shortly after the 8 Hz photic stimuli, irregular spikes bursts appeared in the bilateral frontal areas and gelastic seizure developed shortly thereafter. (c) EEGs and surface electromyogram (EMGs) recorded during supported standing at 8 years old. Rhythmic myoclonic discharges were noted in the bilateral triceps, biceps, and tibialis anterior muscles. No simultaneous epileptic activities were noted with myoclonus. (d) Somatosensory evoked potential (SEP) of the left median nerve at 8 years old. Giant SEPs were observed. (e) Electroretinogram (ERG) at 12 years old. Normal a and b waves and oscillatory potentials were observed.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
( 2.4 SD), respectively. He had been diagnosed with moderate mental retardation and hyperactivity disorder before 6 years of age. Facial and limb myoclonus developed after 6 years of age. He was diagnosed with epilepsy based on epileptic abnormalities in electroencephalograms (EEGs), and began therapy with antiepileptic drugs.
3
However, action myoclonus of the legs and muscle weakness as well as ataxia were increasingly recognized at the age of 7 years, when he was referred to our hospital for further tests. On examination, he had ataxia, intellectual deterioration, action myoclonus of the extremities, and photosensitive epilepsy. Brain magnetic resonance imaging (MRI) demonstrated both cerebral
Fig. 2. MRI findings and CLN6 mutations. (a) Brain MRI (T1-weighted imaging) at 8 (A–C) and 11 (D–F) years old. Atrophy of the cerebrum and cerebellum, decreased white matter volume, and thinning of the corpus callosum were observed. The patient showed progression of symptoms. (b) Genomic DNA sequence of our patient. He had compound heterozygous mutations in the CLN6 gene (c.917_918dup and c.348C>A). Each was inherited from his father and mother. Neither of these mutations has previously been reported. (c) Ser116 is highly conserved among vertebrates. Aligned homologous sequences are obtained from HomoloGene (http://www.ncbi.nlm.nih.gov/homologene/).
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
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R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
and cerebellar atrophy, decreased white matter volume, and thinning of the corpus callosum. Interictal EEG showed frequent, diffuse, spike-wave bursts and highvoltage slow waves dominant over both frontal regions. Photic stimuli produced continuous spike-waves in the bilateral occipital area, and evoked gelastic seizures (Fig. 1a and b). Surface electromyogram (EMG) with the patient in the supported standing position revealed action myoclonus of the extremities (Fig. 1c). The left median nerve showed giant somatosensory evoked potentials (SEPs) (Fig. 1d), and a diagnosis of PME of unknown cause was made. The seizures were well controlled with valproate, and myoclonus was ameliorated with clonazepam. However, he lost his ability to walk and speak at 8 and 10 years old, respectively. Progressive apraxia was also observed as a sign of intellectual regression. At 11 years old, he had generalized tonic– clonic seizures, after which choreoathetotic movement of the extremities became evident. Massive and prolonged myoclonus of the extremities was sometimes evoked by sunlight in the morning. Brain MRI demonstrated progression of atrophy at 11 years old (Fig. 2a). At 12 years old, the patient could not sit or stand by himself and pyramidal signs were evident. From 6 to 12 years old, his developmental quotient (Enjoji Scale of Infant Analytical Development [4]) decreased from 57 to 16. Notably, his visual activity was preserved, and he had no optic atrophy, degeneration of the retina, or cherry red spots in the optic fundus at that time. Electroretinogram (ERG) at the age of 12 years showed normal amplitudes of a and b waves with oscillatory potential (Fig. 1e). An extensive work-up for PME was performed, but all of which yielded unremarkable results. Whole-exome sequencing (WES) and Sanger sequencing revealed that he had compound heterozygous mutations in the CLN6 gene (NM_017882.2: c.917_918dup and c.348C>A) (Fig. 2b). These mutations have not been reported previously, and were not found in Human Genetic Variation Database (http://www.genome.med.kyoto-u.ac.jp/SnpDB/index. html), Exome Variant Server (http://evs.gs.washington. edu/EVS/), a dbSNP137 database, or our in-house 575 control exome data. The c.348C>A(p.Ser116Arg) mutation was conserved among vertebrates (Fig. 2c) and predicted to be damaging by PolyPhen-2 (score 0.986, http://genetics.bwh.harvard.edu/pph2/) and MutationTaster (score 0.999, http://www.mutationtaster.org/). 3. Discussion Mutations in CLN6, which maps to chromosome 15q21-q23, were originally identified in Costa Rican and Venezuelan patients [MIM 601780] [5,6]. Over 60 mutations are now known, including missense and
nonsense mutations, small deletions or insertions, and splice site mutations [3,6]. The age of onset of vLINCL caused by CLN6 mutations was reported to be between 3 and 8 years, which is slightly later than classic LINCL that generally begins between 2 and 4 years old [7]. Clinical symptoms of vLINCLs caused by CLN6 mutations are similar to classic LINCLs. Seizures and motor difficulties typically present early, followed by myoclonus, speech impairments, ataxia, and mental regression [7]. Patients lose all motor skills between 4 and 10 years old [8]. The ultrastructural appearance of skin biopsy consists of curvilinear profiles and fingerprint profiles [9]. T2-weighted brain MRI shows high signal intensity in the periventricular white matter and decreased signal intensity in the thalamus and putamen with some cerebellar atrophy [10]. Previous reports have indicated that visual impairments are seen in all cases of vLINCL caused by CLN6 mutations. Visual loss typically appears between 3 and 8 years old, and rapidly progresses to only light/dark awareness before 9 years old. All eight cases in a Portuguese study became blind between 4 and 9 years old [8]. Furthermore, the ERG changes to a flat pattern. In an Italian report, only two children aged 3.4 and 4.3 years old among 11 cases had normal ERG patterns, which later became flat in both cases [11]. It remains to be determined whether the preserved visual function in our patient is related to the new mutations in CLN6 discussed here. In conclusion, we report a case of vLINCL caused by novel CLN6 mutations with no visual loss. Our case demonstrates the efficacy of WES for examining PMEs and reveals the presence of CLN6 mutations in the Japanese population. References [1] Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, editors. GeneReviews(R). Seattle WA: University of Washington, Seattle; 1993. [2] Sharp JD, Wheeler RB, Parker KA, Gardiner RM, Williams RE, Mole SE. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 2003;22:35–42. [3] Warrier V, Vieira M, Mole SE. Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. Biochim Biophys Acta 2013;1832:1827–30. [4] Enjoji M, Yanai N. Analytic test for development in infancy and childhood. Pediatr Int 1961;4:2–6. [5] Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, et al. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002;70:324–35. [6] Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 2012;33:42–63.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx [7] Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 2005;6: 107–26. [8] Teixeira CA, Espinola J, Huo L, Kohlschutter J, Persaud Sawin DA, Minassian B, et al. Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 2003;21:502–8.
5
[9] Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta 2013;1832:1807–26. [10] Pena JA, Cardozo JJ, Montiel CM, Molina OM, Boustany R. Serial MRI findings in the Costa Rican variant of neuronal ceroid-lipofuscinosis. Pediatr Neurol 2001;25:78–80. [11] Nardocci N, Morbin M, Bugiani M, Lamantea E, Bugiani O. Neuronal ceroid lipofuscinosis: detection of atypical forms. Neurol Sci 2000;21:S57–61.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
Case Report
First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations Ryo Sato a,b,⇑, Takehiko Inui a, Wakaba Endo a, Yukimune Okubo a,b, Yusuke Takezawa a,b, Mai Anzai a, Hiroyuki Morita c, Hirotomo Saitsu d, Naomichi Matsumoto d, Kazuhiro Haginoya a a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Departmetn of Pediatrics, Fukushima Rehabilitation Center for Children, Koriyama, Japan d Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan Received 1 December 2015; received in revised form 16 February 2016; accepted 12 April 2016
Abstract The clinical phenotypes of neuronal ceroid lipofuscinoses (NCLs) have been determined based on the age of onset and clinical symptoms. NCLs with onset between age 2 and 4 years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs). The clinical features of LINCLs include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. There have been reports of several genes associated with LINCLs, with mutations in the CLN6 gene reported to cause variant forms of LINCLs (vLINCLs). Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient diagnosed by whole-exome sequencing. Visual acuity in our patient was preserved until the early teens. It remains to be elucidated if preserved visual function is related to the novel mutations of CLN6. Our case reveals the efficacy of whole-exome sequencing for examination of PMEs and highlights the existence of the CLN6 mutation in the Japanese population. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Late infantile neuronal ceroid lipofudcinosis; CLN6; Whole-exome sequencing
1. Introduction Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and neurodegenerative diseases caused by an accumulation of autofluorescent lipopigments in various tissues. The clinical phenotypes of NCLs have been postulated based on the age of onset and clinical symp⇑ Corresponding author at: Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan. E-mail address: [email protected] (R. Sato).
toms [1]. NCLs appearing between age 2 and 4 years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs), and their clinical features include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. The causative genes of LINCLs have been identified, among which CLN2 (TPP1) is a major one. The other causative genes of different variants of LINCLs (vLINCLs) include CLN5, CLN6, CLN7 (MFSD8), and CLN8. Patients with vLINCLs caused by CLN6 mutations have been reported in the Czech Republic, Croatia,
http://dx.doi.org/10.1016/j.braindev.2016.04.007 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
2
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
Portugal, Central and South America, and more rarely, in Central and Northern Europe [2]. Visual impairments typically appear in early infancy and progress rapidly to blindness. Life expectancy often ranges to the mid-20 s in such cases [3]. Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient with preserved visual function until the early teens.
(a)
2. Case report A 13-year-old male, the sole child of nonconsanguineous parents, was born by spontaneous delivery after 39 weeks of uneventful pregnancy. His father had presented with hyperactivity disorder. The child’s birth weight, height, and occipitofrontal circumference were 2875 g ( 0.3 SD), 49 cm (0 SD), and 30 cm
(b)
Fp1-F7 F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 Fz-Cz Cz-Pz ECG
4 Hz PS
8 Hz PS
(c)
100 μV
1sec
(d)
Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Lt. SCM Rt. SCM Lt. triceps Rt. triceps Lt. biceps Rt. biceps Lt. TA Rt. TA
(e)
500 μV
1sec
Fig. 1. Results of neurophysiological studies. (a) Electroencephalogram (EEG) recorded at 8 years old. The 4 Hz photic stimuli evoked spike-wave bursts in the left posterior temporal area and the surroundings, which showed propagation to the bilateral frontal areas. (b) Shortly after the 8 Hz photic stimuli, irregular spikes bursts appeared in the bilateral frontal areas and gelastic seizure developed shortly thereafter. (c) EEGs and surface electromyogram (EMGs) recorded during supported standing at 8 years old. Rhythmic myoclonic discharges were noted in the bilateral triceps, biceps, and tibialis anterior muscles. No simultaneous epileptic activities were noted with myoclonus. (d) Somatosensory evoked potential (SEP) of the left median nerve at 8 years old. Giant SEPs were observed. (e) Electroretinogram (ERG) at 12 years old. Normal a and b waves and oscillatory potentials were observed.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
( 2.4 SD), respectively. He had been diagnosed with moderate mental retardation and hyperactivity disorder before 6 years of age. Facial and limb myoclonus developed after 6 years of age. He was diagnosed with epilepsy based on epileptic abnormalities in electroencephalograms (EEGs), and began therapy with antiepileptic drugs.
3
However, action myoclonus of the legs and muscle weakness as well as ataxia were increasingly recognized at the age of 7 years, when he was referred to our hospital for further tests. On examination, he had ataxia, intellectual deterioration, action myoclonus of the extremities, and photosensitive epilepsy. Brain magnetic resonance imaging (MRI) demonstrated both cerebral
Fig. 2. MRI findings and CLN6 mutations. (a) Brain MRI (T1-weighted imaging) at 8 (A–C) and 11 (D–F) years old. Atrophy of the cerebrum and cerebellum, decreased white matter volume, and thinning of the corpus callosum were observed. The patient showed progression of symptoms. (b) Genomic DNA sequence of our patient. He had compound heterozygous mutations in the CLN6 gene (c.917_918dup and c.348C>A). Each was inherited from his father and mother. Neither of these mutations has previously been reported. (c) Ser116 is highly conserved among vertebrates. Aligned homologous sequences are obtained from HomoloGene (http://www.ncbi.nlm.nih.gov/homologene/).
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
4
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx
and cerebellar atrophy, decreased white matter volume, and thinning of the corpus callosum. Interictal EEG showed frequent, diffuse, spike-wave bursts and highvoltage slow waves dominant over both frontal regions. Photic stimuli produced continuous spike-waves in the bilateral occipital area, and evoked gelastic seizures (Fig. 1a and b). Surface electromyogram (EMG) with the patient in the supported standing position revealed action myoclonus of the extremities (Fig. 1c). The left median nerve showed giant somatosensory evoked potentials (SEPs) (Fig. 1d), and a diagnosis of PME of unknown cause was made. The seizures were well controlled with valproate, and myoclonus was ameliorated with clonazepam. However, he lost his ability to walk and speak at 8 and 10 years old, respectively. Progressive apraxia was also observed as a sign of intellectual regression. At 11 years old, he had generalized tonic– clonic seizures, after which choreoathetotic movement of the extremities became evident. Massive and prolonged myoclonus of the extremities was sometimes evoked by sunlight in the morning. Brain MRI demonstrated progression of atrophy at 11 years old (Fig. 2a). At 12 years old, the patient could not sit or stand by himself and pyramidal signs were evident. From 6 to 12 years old, his developmental quotient (Enjoji Scale of Infant Analytical Development [4]) decreased from 57 to 16. Notably, his visual activity was preserved, and he had no optic atrophy, degeneration of the retina, or cherry red spots in the optic fundus at that time. Electroretinogram (ERG) at the age of 12 years showed normal amplitudes of a and b waves with oscillatory potential (Fig. 1e). An extensive work-up for PME was performed, but all of which yielded unremarkable results. Whole-exome sequencing (WES) and Sanger sequencing revealed that he had compound heterozygous mutations in the CLN6 gene (NM_017882.2: c.917_918dup and c.348C>A) (Fig. 2b). These mutations have not been reported previously, and were not found in Human Genetic Variation Database (http://www.genome.med.kyoto-u.ac.jp/SnpDB/index. html), Exome Variant Server (http://evs.gs.washington. edu/EVS/), a dbSNP137 database, or our in-house 575 control exome data. The c.348C>A(p.Ser116Arg) mutation was conserved among vertebrates (Fig. 2c) and predicted to be damaging by PolyPhen-2 (score 0.986, http://genetics.bwh.harvard.edu/pph2/) and MutationTaster (score 0.999, http://www.mutationtaster.org/). 3. Discussion Mutations in CLN6, which maps to chromosome 15q21-q23, were originally identified in Costa Rican and Venezuelan patients [MIM 601780] [5,6]. Over 60 mutations are now known, including missense and
nonsense mutations, small deletions or insertions, and splice site mutations [3,6]. The age of onset of vLINCL caused by CLN6 mutations was reported to be between 3 and 8 years, which is slightly later than classic LINCL that generally begins between 2 and 4 years old [7]. Clinical symptoms of vLINCLs caused by CLN6 mutations are similar to classic LINCLs. Seizures and motor difficulties typically present early, followed by myoclonus, speech impairments, ataxia, and mental regression [7]. Patients lose all motor skills between 4 and 10 years old [8]. The ultrastructural appearance of skin biopsy consists of curvilinear profiles and fingerprint profiles [9]. T2-weighted brain MRI shows high signal intensity in the periventricular white matter and decreased signal intensity in the thalamus and putamen with some cerebellar atrophy [10]. Previous reports have indicated that visual impairments are seen in all cases of vLINCL caused by CLN6 mutations. Visual loss typically appears between 3 and 8 years old, and rapidly progresses to only light/dark awareness before 9 years old. All eight cases in a Portuguese study became blind between 4 and 9 years old [8]. Furthermore, the ERG changes to a flat pattern. In an Italian report, only two children aged 3.4 and 4.3 years old among 11 cases had normal ERG patterns, which later became flat in both cases [11]. It remains to be determined whether the preserved visual function in our patient is related to the new mutations in CLN6 discussed here. In conclusion, we report a case of vLINCL caused by novel CLN6 mutations with no visual loss. Our case demonstrates the efficacy of WES for examining PMEs and reveals the presence of CLN6 mutations in the Japanese population. References [1] Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, editors. GeneReviews(R). Seattle WA: University of Washington, Seattle; 1993. [2] Sharp JD, Wheeler RB, Parker KA, Gardiner RM, Williams RE, Mole SE. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 2003;22:35–42. [3] Warrier V, Vieira M, Mole SE. Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. Biochim Biophys Acta 2013;1832:1827–30. [4] Enjoji M, Yanai N. Analytic test for development in infancy and childhood. Pediatr Int 1961;4:2–6. [5] Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, et al. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002;70:324–35. [6] Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 2012;33:42–63.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007
R. Sato et al. / Brain & Development xxx (2016) xxx–xxx [7] Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 2005;6: 107–26. [8] Teixeira CA, Espinola J, Huo L, Kohlschutter J, Persaud Sawin DA, Minassian B, et al. Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 2003;21:502–8.
5
[9] Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta 2013;1832:1807–26. [10] Pena JA, Cardozo JJ, Montiel CM, Molina OM, Boustany R. Serial MRI findings in the Costa Rican variant of neuronal ceroid-lipofuscinosis. Pediatr Neurol 2001;25:78–80. [11] Nardocci N, Morbin M, Bugiani M, Lamantea E, Bugiani O. Neuronal ceroid lipofuscinosis: detection of atypical forms. Neurol Sci 2000;21:S57–61.
Please cite this article in press as: Sato R et al. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.04.007