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Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report Koichi Maruyama a,⇑, Shunsuke Ogaya a, Naoko Kurahashi a, Ayako Umemura a, Keitaro Yamada a, Akihiro Hashiguchi b, Hiroshi Takashima b, Rosa J. Torres c,d, Kosaburo Aso a b
a Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Kasugai, Japan Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan c Department of Biochemistry, La Paz University Hospital, IdiPaz, Madrid, Spain d Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
Received 29 March 2015; received in revised form 11 May 2016; accepted 16 May 2016
Abstract Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections. Arts syndrome is an X-linked disorder caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase 1. Only three families have been reported. Here, we report another family with Arts syndrome. The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss. Both central nervous system involvement and peripheral neuropathy were demonstrated. His three maternal uncles had died before the age of 3 years. A genetic analysis of PRPS1 revealed a novel missense mutation, c.367C>G (p.His123Asp). PRPS enzymatic activity was markedly reduced in the patient. His mother was supposed to be an asymptomatic carrier. Arts syndrome should be included in the differential diagnosis of infantile hypotonia and weakness aggravated by recurrent infection with a family history of X-linked inheritance. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Hypotonia; Ataxia; Hearing impairment; Recurrent infection; X-linked
1. Introduction Arts syndrome (MIM 301835) is an X-linked recessive disorder characterized by early-onset hypotonia, ataxia, delayed motor development, intellectual
⇑ Corresponding author at: Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan. Tel.: +81 568 88 0811; fax: +81 568 88 0828. E-mail address: [email protected] (K. Maruyama).
disability, sensorineural hearing loss, progressive optic atrophy, and a tendency to develop infections [1,2]. Peripheral neuropathy may develop during early childhood. It is caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase (PRPS) 1 [3]. PRPS catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP), which is a substrate for de novo purine and pyrimidine synthesis. Only three families with Arts syndrome have been reported [1,2,4], and the initial neurological symptoms
http://dx.doi.org/10.1016/j.braindev.2016.05.003 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: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
2
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
Ophthalmoplegia and ptosis were absent. He spoke no meaningful words. Responses to auditory stimuli were unremarkable. Visual acuity seemed to be normal. Fundoscopy showed no abnormalities. Serum creatine kinase and uric acid levels were 18 IU/L and 3.3 mg/dL, respectively. Other routine biochemical tests were normal. Brain magnetic resonance imaging revealed mild diffuse cortical atrophy (Fig. 1B). A tibial nerve conduction velocity study revealed slow motor conduction velocity (35.2 m/s) [5]. Electromyography showed a reduced interference pattern. Auditory brainstem responses were not elicited bilaterally up to a 100-dB sound pressure level. A muscle biopsy revealed variations in fiber size, group atrophy, fiber type grouping, and an increased number of type IIc fibers, reflecting an active reinnervation process. Written informed consent was obtained from the parents for genetic analysis. The patient’s karyotype was 46, XY. A fluorescence in situ hybridization analysis of the SMN, NAIP, and PMP22 genes detected no deletions or duplications. Exome sequencing of PRPS1 revealed a novel hemizygous missense c.367C>G mutation, changing a highly conserved amino acid
are not fully understood. Here, we report another family with Arts syndrome involving a novel PRPS1 mutation. 2. Case report A 19-month-old boy was referred to our hospital because of hypotonia and motor regression. He was the first son of healthy non-consanguineous JapaneseBrazilian parents. His three maternal uncles had died before the age of 3 years (Fig. 1A). He was born uneventfully at term with a birth weight of 2960 g. Gross motor development was delayed; he could stand with support at 11 months, but could not walk because of ataxia. He developed respiratory syncytial virus bronchiolitis at 18 months of age and required mechanical ventilation for 10 days. He subsequently lost control of his head due to hypotonia. He was 85.5 cm tall (75th–90th percentile), and weighed 10 kg (25th–50th percentile). Head circumference was within normal limits. He could not raise his arm against gravity, although voluntary movements of the distal limbs were preserved. Deep tendon reflexes could not be elicited except for the brachioradialis.
A
B 1
2
3
4
I 1
2
3
4
5
6
7
8
II
1
2
3
4
III
C
D patient
father
mother
PRPS activity (nmol AMP/h/mg protein)
140 120 100 80 60 40 20 0 II-3; father
II-8; III-1; mother proband
III-2; sister
Fig. 1. (A) Family tree; the proband is III-1. Three maternal uncles died in infancy: II-4 died at 31 months due to pneumonia; II-5 died at 15 days due to tetanus; he was born prematurely; and II-6 died at 19 months due to pneumonia. (B) Brain magnetic resonance images (Axial T2-weighted). Mild diffuse cerebral atrophy was noted, whereas cerebellar atrophy was absent. No abnormal intensity was found. (C) Sanger sequencing electropherogram indicates the single nucleotide alteration c.367C>G (p.His123Asp) found in the patient and his mother. (D) PRPS enzymatic activity in haemolysate (normal range: 70–126 nmol AMP/h/mg protein) was markedly decreased in the patient (1.3), slightly reduced in his mother (75.4), and normal in his father (91.9) and his sister (118.6).
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
residue (p.His123Asp), confirmed by conventional Sanger sequencing (Fig. 1C). His mother had the heterozygous form of this mutation. In silico, this mutation was predicted to be damaging (PolyPhen-2 score [6], 0.725; SIFT score [7], 0.003; Mutation Taster [8], disease causing). PRPS activity determined in haemolysate [9] was markedly decreased in the patient, slightly reduced in his mother, and normal in his father and his sister (Fig. 1D). His weakness recovered gradually. He was able to stand with support at the age of 24 months, but could never walk. Recurrent infections temporarily exacerbated his weakness. At 4 years of age, he needed intermittent mechanical ventilation support, showed marked ataxia, expressed some sign language, and had normal visual acuity. A nerve conduction velocity study
3
revealed decreased conduction velocities and action potential amplitudes for motor nerves (Table 1). 3. Discussion We have described a boy with early-onset hypotonia and ataxia, delayed motor and intellectual development, congenital sensorineural hearing loss, peripheral neuropathy, and transient deterioration of muscle strength due to infections. The family history suggested X-linked recessive inheritance. He and his mother had a novel missense mutation, c.367C>T (p.His123Asp) in PRPS1. PRPS enzymatic activity in the patient was markedly decreased. PRPS activity was slightly reduced in his mother, which supposed that she was an
Table 1 Electrophysiological studies at 4 years of age. Items examined
Normal values*
Determined values Right
Left
Motor nerve conduction velocity Median nerve TL (ms) CV (m/s) CMAP (mV)
4.3 38.9 0.6
4.8 33.4 4.1
2.2 ± 0.3 52.7 ± 4.7 5.9 ± 2.5
Ulnar nerve TL CV CMAP
(ms) (m/s) (mV)
3.5 32.8 4.2
4.0 38.8 2.7
1.8 ± 0.2 56.9 ± 4.3 8.8 ± 2.4
Peroneal nerve TL CV CMAP
(ms) (m/s) (mV)
12.1 55.7 0.5
6.1 38.1 1.8
2.6 ± 0.4 49.6 ± 5.0 7.1 ± 1.2
Tibial nerve TL CV CMAP
(ms) (m/s) (mV)
5.4 37.5 3.8
5.8 30.5 2.0
2.8 ± 0.4 48.6 ± 4.3 15.8 ± 2.2
Sensory nerve conduction velocity Median nerve (finger–wrist) CV (m/s) SNAP (lV)
45.7 45.2
42.3 59.1
41.0 ± 4.9
Median nerve (finger–elbow) CV SNAP
(m/s) (lV)
ND ND
50.4 23.6
51.2 ± 5.1 19.8 ± 4.2
(m/s) (lV)
38.5 15.7
40.0 8.8
42.9 ± 4.6
(m/s) (lV)
ND ND
ND ND
51.6 ± 4.5 13.2 ± 3.6
(m/s) (lV)
39.8 11.5
44.1 24.6
39.4 ± 4.6 18.5 ± 3.9
Ulnar nerve (finger–wrist) CV SNAP Ulnar nerve (finger–elbow) CV SNAP Sural nerve CV SNAP
Abbreviations: TL, terminal latency; CV, conduction velocity; CMAP, compound muscle action potentials; SNAP, sensory nerve action potentials; ND, not detected. * Adopted from Ref. [5].
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
4
Category
Items
Growth
Poor growth Early death
Head & neck
Sensorineural hearing loss Optic atrophy
PRPS superactivity (Early onset)
Early onset
Genitourinary
Urolithiasis Recurrent respiratory tract infections
Gastrointestinal
Dysphagia
Skeletal
Gouty arthritis Pes cavus
+
Intellectual disability Lack of speech Early-onset hypotonia Ataxia Delayed motor development
+
Peripheral nervous system
Susceptibility to infections
Laboratory abnormality
Hyperuricemia PRPS activity
PRPS1 mutation
Congenital +
DFN2
Current patient
Early onset +
Congenital
Congenital
+ (Family history)
+ +
+ + (During infection)
+ +
+ + +
Muscle weakness Areflexia Delayed motor nerve conduction velocity
Immunology
CMTX5
+ +
Respiratory
Central nervous system
(Adult onset)
Arts syndrome
+ + + + +
+ +
+ + + + +
+ + +
+(distal limb) +(lower limb) +
+ + +
+ + Increased Asp51His Asn113Ser Leu128Ile Val142Leu* Asp182His Ala189Val His192Gln
+ Increased
+
Decreased
Decreased
Decreased
Decreased
Gln133Pro Val142Leu* Leu152Pro
Glu43Asp Met115Thr Ala121Gly
Asp65Asn Ala87Thr Ile290Thr Gly306Arg
His123Asp
Modified from: Phosphoribosylpyrophosphate synthetase I; PRPS1. Online Mendelian Inheritance in Man. http://omim.org/entry/311850#2, accessed on August 22, 2015. ‘‘+” Indicates presence, and ‘‘ ” indicates absence. * The Val142Leu mutation produces both PRPS supersensitivity and Arts syndrome [10]. Abbreviations: PRPS, phosphoribosylpyrophosphate synthetase; CMTX5, X-linked Charcot–Marie–Tooth disease type 5; DFN2, X-linked nonsyndromic sensorineural deafness.
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
Table 2 Comparison of the clinical findings in PRPS1-related disorders.
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
asymptomatic carrier. These findings are compatible with the clinical description of Arts syndrome (Table 2). The spectrum of PRPS1-related disorders includes four syndromes: PRPS superactivity, Arts syndrome, X-linked Charcot–Marie–Tooth disease type 5 (CMTX5), and X-linked nonsyndromic sensorineural deafness (DFN2) (Table 2) [3]. PRPS superactivity is characterized by hyperuricemia and gouty arthritis. The early-onset phenotype is accompanied by intellectual disability, hypotonia, ataxia, and sensorineural hearing loss. Our patient had similar neurological symptoms, but did not have hyperuricemia or arthritis. The three other syndromes are caused by a reduction in PRPS activity. They have a continuum of manifestations, and the severity is determined by the residual PRPS activity [4]. CMTX5 is characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. Contrasting Arts syndrome, however, intelligence is normal, and neurological symptoms start at about 10 years of age. Interestingly, a complex phenotype comprising both PRPS superactivity and Arts syndrome with the PRPS1 c.424G>C (p.Val142Leu) mutation has been reported [10]. Both the central and peripheral nervous systems are thought to be involved in Arts syndrome, but few neuropathological data are available. Arts et al. reported that a sural nerve biopsy showed mild paranodal demyelination [1]. In our patient, the motor nerve conduction velocities were decreased, but the sensory nerve conduction velocities were not. This suggests that the peripheral nerve demyelination occurs in motor nerves, but not sensory nerves. Arts reported the complete absence of myelin in the posterior columns of the spinal cord at autopsy [1]. We could not evaluate the sensory impairment in our case. However, the ataxia may have been due to a disturbance in proprioceptive sensation. Atrophy of the parietal lobe and cerebellar hemisphere were observed in an adult patient with a CMTX5/Arts intermediate phenotype and his sibling presenting with DFN2 [4]. We observed diffuse cortical atrophy and a normal cerebellum in our case. No abnormal signal intensity suggestive of demyelination was detected in the cerebral white matter. Arts syndrome should be included in the differential diagnosis of acute motor deterioration triggered by recurrent infections in an infant. Hypotonia, ataxia, neurogenic muscular atrophy, developmental delay, hearing impairment, and X-linked recessive inheritance are the key features of Arts syndrome.
5
Acknowledgments The authors are grateful to the patient and his family. They also acknowledge Dr. Ichizo Nishino of the National Center for Neurology and Psychiatry for diagnosing the muscle biopsy. Exome sequencing and conventional Sanger sequencing were performed by the authors A.H. and H.T. at Kagoshima University Graduate School of Medical and Dental Sciences, supported by grants from the Nervous and Mental Disorders and Research Committee for Charcot–Marie–Tooth disease, Neuropathy, Ataxic Disease, and Research on Applying Health Technology at the Japanese Ministry of Health, Welfare, and Labor and by the Research for Conquering Intractable Disease from Japan Agency for Medical Research and Development, AMED. References [1] Arts WF, Loonen MC, Sengers RC, Slooff JL. X-linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course. Ann Neurol 1993;33:535–9. [2] de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, et al. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet 2007;81:507–18. [3] de Brouwer AP, van Bokhoven H, Nabuurs SB, Arts WF, Christodoulou J, Duley J. PRPS1 mutations: four distinct syndromes and potential treatment. Am J Hum Genet 2010;86:506–18. [4] Synofzik M, Muller vom Hagen J, Haack TB, Wilhelm C, Lindig T, Beck-Wodl S, et al. X-linked Charcot-Marie-Tooth disease, arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation. Orphanet J Rare Dis 2014;9:24. [5] Cai F, Zhang J. Study of nerve conduction and late responses in normal Chinese infants, children, and adults. J Child Neurol 1997;12:13–8. [6] 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. [7] Kumar P, Henikoff S, Ng PC. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–81. [8] Schwarz JM, Ro¨delsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575–6. [9] Torres RJ, Mateos FA, Puig JG, Becker MA. A simplified method for the determination of phosphoribosylpyrophosphate synthetase activity in hemolysates. Clin Chim Acta 1994;224:55–63. [10] Moran R, Kuilenburg AB, Duley J, Nabuurs SB, Retno-Fitri A, Christodoulou J, et al. Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. Am J Med Genet A 2012;158A:455–60.
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
Case Report
Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report Koichi Maruyama a,⇑, Shunsuke Ogaya a, Naoko Kurahashi a, Ayako Umemura a, Keitaro Yamada a, Akihiro Hashiguchi b, Hiroshi Takashima b, Rosa J. Torres c,d, Kosaburo Aso a b
a Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Kasugai, Japan Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan c Department of Biochemistry, La Paz University Hospital, IdiPaz, Madrid, Spain d Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
Received 29 March 2015; received in revised form 11 May 2016; accepted 16 May 2016
Abstract Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections. Arts syndrome is an X-linked disorder caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase 1. Only three families have been reported. Here, we report another family with Arts syndrome. The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss. Both central nervous system involvement and peripheral neuropathy were demonstrated. His three maternal uncles had died before the age of 3 years. A genetic analysis of PRPS1 revealed a novel missense mutation, c.367C>G (p.His123Asp). PRPS enzymatic activity was markedly reduced in the patient. His mother was supposed to be an asymptomatic carrier. Arts syndrome should be included in the differential diagnosis of infantile hypotonia and weakness aggravated by recurrent infection with a family history of X-linked inheritance. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Hypotonia; Ataxia; Hearing impairment; Recurrent infection; X-linked
1. Introduction Arts syndrome (MIM 301835) is an X-linked recessive disorder characterized by early-onset hypotonia, ataxia, delayed motor development, intellectual
⇑ Corresponding author at: Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan. Tel.: +81 568 88 0811; fax: +81 568 88 0828. E-mail address: [email protected] (K. Maruyama).
disability, sensorineural hearing loss, progressive optic atrophy, and a tendency to develop infections [1,2]. Peripheral neuropathy may develop during early childhood. It is caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase (PRPS) 1 [3]. PRPS catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP), which is a substrate for de novo purine and pyrimidine synthesis. Only three families with Arts syndrome have been reported [1,2,4], and the initial neurological symptoms
http://dx.doi.org/10.1016/j.braindev.2016.05.003 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: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
2
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
Ophthalmoplegia and ptosis were absent. He spoke no meaningful words. Responses to auditory stimuli were unremarkable. Visual acuity seemed to be normal. Fundoscopy showed no abnormalities. Serum creatine kinase and uric acid levels were 18 IU/L and 3.3 mg/dL, respectively. Other routine biochemical tests were normal. Brain magnetic resonance imaging revealed mild diffuse cortical atrophy (Fig. 1B). A tibial nerve conduction velocity study revealed slow motor conduction velocity (35.2 m/s) [5]. Electromyography showed a reduced interference pattern. Auditory brainstem responses were not elicited bilaterally up to a 100-dB sound pressure level. A muscle biopsy revealed variations in fiber size, group atrophy, fiber type grouping, and an increased number of type IIc fibers, reflecting an active reinnervation process. Written informed consent was obtained from the parents for genetic analysis. The patient’s karyotype was 46, XY. A fluorescence in situ hybridization analysis of the SMN, NAIP, and PMP22 genes detected no deletions or duplications. Exome sequencing of PRPS1 revealed a novel hemizygous missense c.367C>G mutation, changing a highly conserved amino acid
are not fully understood. Here, we report another family with Arts syndrome involving a novel PRPS1 mutation. 2. Case report A 19-month-old boy was referred to our hospital because of hypotonia and motor regression. He was the first son of healthy non-consanguineous JapaneseBrazilian parents. His three maternal uncles had died before the age of 3 years (Fig. 1A). He was born uneventfully at term with a birth weight of 2960 g. Gross motor development was delayed; he could stand with support at 11 months, but could not walk because of ataxia. He developed respiratory syncytial virus bronchiolitis at 18 months of age and required mechanical ventilation for 10 days. He subsequently lost control of his head due to hypotonia. He was 85.5 cm tall (75th–90th percentile), and weighed 10 kg (25th–50th percentile). Head circumference was within normal limits. He could not raise his arm against gravity, although voluntary movements of the distal limbs were preserved. Deep tendon reflexes could not be elicited except for the brachioradialis.
A
B 1
2
3
4
I 1
2
3
4
5
6
7
8
II
1
2
3
4
III
C
D patient
father
mother
PRPS activity (nmol AMP/h/mg protein)
140 120 100 80 60 40 20 0 II-3; father
II-8; III-1; mother proband
III-2; sister
Fig. 1. (A) Family tree; the proband is III-1. Three maternal uncles died in infancy: II-4 died at 31 months due to pneumonia; II-5 died at 15 days due to tetanus; he was born prematurely; and II-6 died at 19 months due to pneumonia. (B) Brain magnetic resonance images (Axial T2-weighted). Mild diffuse cerebral atrophy was noted, whereas cerebellar atrophy was absent. No abnormal intensity was found. (C) Sanger sequencing electropherogram indicates the single nucleotide alteration c.367C>G (p.His123Asp) found in the patient and his mother. (D) PRPS enzymatic activity in haemolysate (normal range: 70–126 nmol AMP/h/mg protein) was markedly decreased in the patient (1.3), slightly reduced in his mother (75.4), and normal in his father (91.9) and his sister (118.6).
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
residue (p.His123Asp), confirmed by conventional Sanger sequencing (Fig. 1C). His mother had the heterozygous form of this mutation. In silico, this mutation was predicted to be damaging (PolyPhen-2 score [6], 0.725; SIFT score [7], 0.003; Mutation Taster [8], disease causing). PRPS activity determined in haemolysate [9] was markedly decreased in the patient, slightly reduced in his mother, and normal in his father and his sister (Fig. 1D). His weakness recovered gradually. He was able to stand with support at the age of 24 months, but could never walk. Recurrent infections temporarily exacerbated his weakness. At 4 years of age, he needed intermittent mechanical ventilation support, showed marked ataxia, expressed some sign language, and had normal visual acuity. A nerve conduction velocity study
3
revealed decreased conduction velocities and action potential amplitudes for motor nerves (Table 1). 3. Discussion We have described a boy with early-onset hypotonia and ataxia, delayed motor and intellectual development, congenital sensorineural hearing loss, peripheral neuropathy, and transient deterioration of muscle strength due to infections. The family history suggested X-linked recessive inheritance. He and his mother had a novel missense mutation, c.367C>T (p.His123Asp) in PRPS1. PRPS enzymatic activity in the patient was markedly decreased. PRPS activity was slightly reduced in his mother, which supposed that she was an
Table 1 Electrophysiological studies at 4 years of age. Items examined
Normal values*
Determined values Right
Left
Motor nerve conduction velocity Median nerve TL (ms) CV (m/s) CMAP (mV)
4.3 38.9 0.6
4.8 33.4 4.1
2.2 ± 0.3 52.7 ± 4.7 5.9 ± 2.5
Ulnar nerve TL CV CMAP
(ms) (m/s) (mV)
3.5 32.8 4.2
4.0 38.8 2.7
1.8 ± 0.2 56.9 ± 4.3 8.8 ± 2.4
Peroneal nerve TL CV CMAP
(ms) (m/s) (mV)
12.1 55.7 0.5
6.1 38.1 1.8
2.6 ± 0.4 49.6 ± 5.0 7.1 ± 1.2
Tibial nerve TL CV CMAP
(ms) (m/s) (mV)
5.4 37.5 3.8
5.8 30.5 2.0
2.8 ± 0.4 48.6 ± 4.3 15.8 ± 2.2
Sensory nerve conduction velocity Median nerve (finger–wrist) CV (m/s) SNAP (lV)
45.7 45.2
42.3 59.1
41.0 ± 4.9
Median nerve (finger–elbow) CV SNAP
(m/s) (lV)
ND ND
50.4 23.6
51.2 ± 5.1 19.8 ± 4.2
(m/s) (lV)
38.5 15.7
40.0 8.8
42.9 ± 4.6
(m/s) (lV)
ND ND
ND ND
51.6 ± 4.5 13.2 ± 3.6
(m/s) (lV)
39.8 11.5
44.1 24.6
39.4 ± 4.6 18.5 ± 3.9
Ulnar nerve (finger–wrist) CV SNAP Ulnar nerve (finger–elbow) CV SNAP Sural nerve CV SNAP
Abbreviations: TL, terminal latency; CV, conduction velocity; CMAP, compound muscle action potentials; SNAP, sensory nerve action potentials; ND, not detected. * Adopted from Ref. [5].
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
4
Category
Items
Growth
Poor growth Early death
Head & neck
Sensorineural hearing loss Optic atrophy
PRPS superactivity (Early onset)
Early onset
Genitourinary
Urolithiasis Recurrent respiratory tract infections
Gastrointestinal
Dysphagia
Skeletal
Gouty arthritis Pes cavus
+
Intellectual disability Lack of speech Early-onset hypotonia Ataxia Delayed motor development
+
Peripheral nervous system
Susceptibility to infections
Laboratory abnormality
Hyperuricemia PRPS activity
PRPS1 mutation
Congenital +
DFN2
Current patient
Early onset +
Congenital
Congenital
+ (Family history)
+ +
+ + (During infection)
+ +
+ + +
Muscle weakness Areflexia Delayed motor nerve conduction velocity
Immunology
CMTX5
+ +
Respiratory
Central nervous system
(Adult onset)
Arts syndrome
+ + + + +
+ +
+ + + + +
+ + +
+(distal limb) +(lower limb) +
+ + +
+ + Increased Asp51His Asn113Ser Leu128Ile Val142Leu* Asp182His Ala189Val His192Gln
+ Increased
+
Decreased
Decreased
Decreased
Decreased
Gln133Pro Val142Leu* Leu152Pro
Glu43Asp Met115Thr Ala121Gly
Asp65Asn Ala87Thr Ile290Thr Gly306Arg
His123Asp
Modified from: Phosphoribosylpyrophosphate synthetase I; PRPS1. Online Mendelian Inheritance in Man. http://omim.org/entry/311850#2, accessed on August 22, 2015. ‘‘+” Indicates presence, and ‘‘ ” indicates absence. * The Val142Leu mutation produces both PRPS supersensitivity and Arts syndrome [10]. Abbreviations: PRPS, phosphoribosylpyrophosphate synthetase; CMTX5, X-linked Charcot–Marie–Tooth disease type 5; DFN2, X-linked nonsyndromic sensorineural deafness.
K. Maruyama et al. / Brain & Development xxx (2016) xxx–xxx
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003
Table 2 Comparison of the clinical findings in PRPS1-related disorders.
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asymptomatic carrier. These findings are compatible with the clinical description of Arts syndrome (Table 2). The spectrum of PRPS1-related disorders includes four syndromes: PRPS superactivity, Arts syndrome, X-linked Charcot–Marie–Tooth disease type 5 (CMTX5), and X-linked nonsyndromic sensorineural deafness (DFN2) (Table 2) [3]. PRPS superactivity is characterized by hyperuricemia and gouty arthritis. The early-onset phenotype is accompanied by intellectual disability, hypotonia, ataxia, and sensorineural hearing loss. Our patient had similar neurological symptoms, but did not have hyperuricemia or arthritis. The three other syndromes are caused by a reduction in PRPS activity. They have a continuum of manifestations, and the severity is determined by the residual PRPS activity [4]. CMTX5 is characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. Contrasting Arts syndrome, however, intelligence is normal, and neurological symptoms start at about 10 years of age. Interestingly, a complex phenotype comprising both PRPS superactivity and Arts syndrome with the PRPS1 c.424G>C (p.Val142Leu) mutation has been reported [10]. Both the central and peripheral nervous systems are thought to be involved in Arts syndrome, but few neuropathological data are available. Arts et al. reported that a sural nerve biopsy showed mild paranodal demyelination [1]. In our patient, the motor nerve conduction velocities were decreased, but the sensory nerve conduction velocities were not. This suggests that the peripheral nerve demyelination occurs in motor nerves, but not sensory nerves. Arts reported the complete absence of myelin in the posterior columns of the spinal cord at autopsy [1]. We could not evaluate the sensory impairment in our case. However, the ataxia may have been due to a disturbance in proprioceptive sensation. Atrophy of the parietal lobe and cerebellar hemisphere were observed in an adult patient with a CMTX5/Arts intermediate phenotype and his sibling presenting with DFN2 [4]. We observed diffuse cortical atrophy and a normal cerebellum in our case. No abnormal signal intensity suggestive of demyelination was detected in the cerebral white matter. Arts syndrome should be included in the differential diagnosis of acute motor deterioration triggered by recurrent infections in an infant. Hypotonia, ataxia, neurogenic muscular atrophy, developmental delay, hearing impairment, and X-linked recessive inheritance are the key features of Arts syndrome.
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Acknowledgments The authors are grateful to the patient and his family. They also acknowledge Dr. Ichizo Nishino of the National Center for Neurology and Psychiatry for diagnosing the muscle biopsy. Exome sequencing and conventional Sanger sequencing were performed by the authors A.H. and H.T. at Kagoshima University Graduate School of Medical and Dental Sciences, supported by grants from the Nervous and Mental Disorders and Research Committee for Charcot–Marie–Tooth disease, Neuropathy, Ataxic Disease, and Research on Applying Health Technology at the Japanese Ministry of Health, Welfare, and Labor and by the Research for Conquering Intractable Disease from Japan Agency for Medical Research and Development, AMED. References [1] Arts WF, Loonen MC, Sengers RC, Slooff JL. X-linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course. Ann Neurol 1993;33:535–9. [2] de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, et al. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet 2007;81:507–18. [3] de Brouwer AP, van Bokhoven H, Nabuurs SB, Arts WF, Christodoulou J, Duley J. PRPS1 mutations: four distinct syndromes and potential treatment. Am J Hum Genet 2010;86:506–18. [4] Synofzik M, Muller vom Hagen J, Haack TB, Wilhelm C, Lindig T, Beck-Wodl S, et al. X-linked Charcot-Marie-Tooth disease, arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation. Orphanet J Rare Dis 2014;9:24. [5] Cai F, Zhang J. Study of nerve conduction and late responses in normal Chinese infants, children, and adults. J Child Neurol 1997;12:13–8. [6] 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. [7] Kumar P, Henikoff S, Ng PC. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–81. [8] Schwarz JM, Ro¨delsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575–6. [9] Torres RJ, Mateos FA, Puig JG, Becker MA. A simplified method for the determination of phosphoribosylpyrophosphate synthetase activity in hemolysates. Clin Chim Acta 1994;224:55–63. [10] Moran R, Kuilenburg AB, Duley J, Nabuurs SB, Retno-Fitri A, Christodoulou J, et al. Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. Am J Med Genet A 2012;158A:455–60.
Please cite this article in press as: Maruyama K et al. Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.05.003