Parkinsonism and Related Disorders 20 (2014) 353e354
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Familial IBGC caused by SLC20A2 mutation presenting as paroxysmal kinesigenic dyskinesia Keywords: Movement disorders Basal ganglia Dystonia Genetics
Familial idiopathic basal ganglia calcification (IBGC) is a rare autosomal dominant inherited disorder with metabolic dysfunction of calcium and phosphorus [1]. Defects of solute carrier family 20 phosphate transporter member 2 (SLC20A2) gene have been considered to be the major cause of familial IBCG [1,2]. Recent evidence suggests that sporadic IBGC might be associated with paroxysmal kinesigenic dyskinesia (PKD) [3]. However, the etiology and pathophysiology of such a relationship have not been elucidated. We describe an IBGC family, in which all patients presented with juvenile-onset PKD, caused by a novel deletion mutation in the SLC20A2 gene. 1. Case report A 15-year-old boy (III1) was admitted to our hospital complaining of paroxysmal limb stiffness and abnormal episodic movements for 5 years. At age 10, he suddenly felt stiffness of the right lower limb for several seconds when he stood up from a seated position after sitting for a prolonged time. Initially, the episodes occurred approximately once every 10 days. However, four months earlier the episodes became more frequent and severe. He complained of stiffening of his legs, inversion and dystonia of both feet, flexion of his left hand into a clawed position, and stiffness around his mouth. The episodes lasted for 3e10 s, and occurred 10e35 times a day. During an episode, he was unable to stand, had difficulty walking, and would sometimes fall. However, there was no pain or loss of consciousness during the attacks. Neurological examination was normal between the attacks. His school performance and intelligence were normal (Montreal cognitive assessment, MoCA was 29). The episodic attacks were completely controlled by carbamazepine (200 mg/day). Laboratory investigations revealed normal levels of serum calcium and phosphorus, 24 h urine calcium and phosphorus, and parathyroid hormone. Other laboratory investigations were within normal limits, including routine, blood biochemistry, thyroid hormone, serum ceruloplasmin, and antinuclear antibody profiles. An electroencephalogram recording was normal. CT showed bilateral calcification in the basal ganglia, thalamus, dentate nucleus, and subcortex of frontal lobe (Fig. 1). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.12.006
In the autosomal dominant inherited family, 6 members had similar symptoms (Fig. 1). Case descriptions were provided (Online Supplementary Table S1). Four affected members (II2, II7, III5, and III6) presented with episodic limb stiffness and abnormal movements stimulated by sudden action in their youth. Another member (II6) had intermittent headache, but no paroxysmal dyskinesia. No patients had evidence of parkinsonism, psychiatric disorders, cognitive impairment, or other neurological symptoms. CT scan showed all of them had widespread calcifications in several encephalic areas (Fig. 1). A novel heterozygous deletion mutation c.1086delC (p.His362Glnfs*54) was detected in exon 8 of the SLC20A2 gene in family members with intracranial calcification (see Online Supplementary Fig. S1) through direct sequencing, but not in unaffected family members. No patients had mutations in proline-rich transmembrane protein 2 (PRRT2) gene. All subjects signed informed consent for genetic testing, and the study was approved by the ethics committee of our hospital. Mutations of the SLC20A2 gene can cause type 3 of IBGC (IBGC3), which manifests as a movement disorder, most often as a parkinsonism phenotype, and less frequently as a hyperkinetic movement disorder (e.g., chorea, tremor, dystonia, athetosis, and orofacial dyskinesia) [2,4]. The typical age at onset is between 30 and 50 years [1,4], however, our patients showed neurological symptoms in their adolescence, and then gradually disappeared in their 30’s. The main symptoms in our patients were transient action-induced dystonia with involuntary movements, absence of cognitive impairment, psychiatric symptoms, and other neurological signs. Furthermore, the symptoms were effectively improved with a low dose of carbamazepine. These clinical characteristics are consistent for the diagnostic criteria of paroxysmal kinesigenic dyskinesia (PKD) [3]. The PKD is a movement disorder characterized by painless dystonia and choreiform movements. Most patients with PKD have an autosomal dominant inherited family history, but sporadic symptomatic cases also exist, usually secondary to a variety of identifiable pathologies [5]. Until now, only 2 sporadic IBGC cases coexisting with PKD have been reported in the literature [3]. The age of onset and clinical pictures in the 2 cases were similar to those in our patients, while the SLC20A2 and PRRT2 gene were not screened in the 2 cases [3]. The pathophysiology of PKD remains unknown. Impairment of indirect pathway of thalamo-corticobasal circuit due to dysfunctions of basal ganglia was proposed as one of mechanisms of the origin of PKD [5]. Therefore, the abnormal depositions of calcium phosphates in thalamo-corticobasal regions might be responsible for paroxysmal dyskinesias in our patients according to no mutation in the PRRT2 gene.
354
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 353e354
Acknowledgments Authors gratefully acknowledged the contribution of patient and his family. This work was supported by grants from the National Natural Science Foundation of China (81260194).
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2013.12.006. References
Fig. 1. The pedigree chart and cerebral CT features of the family patients. Square: male; circle: female; black filled symbol: affected patient; gray filled symbol: carrier; line through symbol: deceased; oblique vertical arrow: the index patient. Dotted lines respectively connect with the CT images of different patients, which showed widespread calcifications in bilateral basal ganglia, thalamus, and subcortical areas.
The protein encoded by the SLC20A2 gene is a transmembrane protein called sodium-dependent phosphate transporter 2, which plays a housekeeping role in the phosphorus balance [4]. A total of 30 mutations have been reported in the SLC20A2 gene, of which 8 mutations existed in the hotspot exon 8 [1,4]. The novel frameshift variation also locates in exon 8, which can cause the disturbance of process capturing phosphates in cytoplasm, and then haploinsufficiency plays a role in the pathogenic mechanism [4].
[1] Hsu SC, Sears RL, Lemos RR, Quintáns B, Huang A, Spiteri E, et al. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 2013;14:11e22. [2] Nicolas G, Pottier C, Charbonnier C, Guyant-Maréchal L, Le Ber I, Pariente J, et al. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 2013;136(Pt 11):3395e407. [3] Chung EJ, Cho GN, Kim SJ. A case of paroxysmal kinesigenic dyskinesia in idiopathic bilateral striopallidodentate calcinosis. Seizure 2012;21:802e4. [4] Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 2012;44:254e6. [5] Bonazza S, La Morgia C, Martinelli P, Capellari S. Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients. Neurol Sci 2011;32: 537e45.
Min Zhu, Xuan Zhu, Hui Wan, Daojun Hong* Department of Neurology, The First Affiliated Hospital of Nanchang University, Yong Wai Zheng Street 17#, Nanchang 330006, PR China * Corresponding
author. Tel./fax: þ86 791 8869 2511. E-mail addresses: [email protected], [email protected] (D. Hong). 3 September 2013
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Familial IBGC caused by SLC20A2 mutation presenting as paroxysmal kinesigenic dyskinesia Keywords: Movement disorders Basal ganglia Dystonia Genetics
Familial idiopathic basal ganglia calcification (IBGC) is a rare autosomal dominant inherited disorder with metabolic dysfunction of calcium and phosphorus [1]. Defects of solute carrier family 20 phosphate transporter member 2 (SLC20A2) gene have been considered to be the major cause of familial IBCG [1,2]. Recent evidence suggests that sporadic IBGC might be associated with paroxysmal kinesigenic dyskinesia (PKD) [3]. However, the etiology and pathophysiology of such a relationship have not been elucidated. We describe an IBGC family, in which all patients presented with juvenile-onset PKD, caused by a novel deletion mutation in the SLC20A2 gene. 1. Case report A 15-year-old boy (III1) was admitted to our hospital complaining of paroxysmal limb stiffness and abnormal episodic movements for 5 years. At age 10, he suddenly felt stiffness of the right lower limb for several seconds when he stood up from a seated position after sitting for a prolonged time. Initially, the episodes occurred approximately once every 10 days. However, four months earlier the episodes became more frequent and severe. He complained of stiffening of his legs, inversion and dystonia of both feet, flexion of his left hand into a clawed position, and stiffness around his mouth. The episodes lasted for 3e10 s, and occurred 10e35 times a day. During an episode, he was unable to stand, had difficulty walking, and would sometimes fall. However, there was no pain or loss of consciousness during the attacks. Neurological examination was normal between the attacks. His school performance and intelligence were normal (Montreal cognitive assessment, MoCA was 29). The episodic attacks were completely controlled by carbamazepine (200 mg/day). Laboratory investigations revealed normal levels of serum calcium and phosphorus, 24 h urine calcium and phosphorus, and parathyroid hormone. Other laboratory investigations were within normal limits, including routine, blood biochemistry, thyroid hormone, serum ceruloplasmin, and antinuclear antibody profiles. An electroencephalogram recording was normal. CT showed bilateral calcification in the basal ganglia, thalamus, dentate nucleus, and subcortex of frontal lobe (Fig. 1). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.12.006
In the autosomal dominant inherited family, 6 members had similar symptoms (Fig. 1). Case descriptions were provided (Online Supplementary Table S1). Four affected members (II2, II7, III5, and III6) presented with episodic limb stiffness and abnormal movements stimulated by sudden action in their youth. Another member (II6) had intermittent headache, but no paroxysmal dyskinesia. No patients had evidence of parkinsonism, psychiatric disorders, cognitive impairment, or other neurological symptoms. CT scan showed all of them had widespread calcifications in several encephalic areas (Fig. 1). A novel heterozygous deletion mutation c.1086delC (p.His362Glnfs*54) was detected in exon 8 of the SLC20A2 gene in family members with intracranial calcification (see Online Supplementary Fig. S1) through direct sequencing, but not in unaffected family members. No patients had mutations in proline-rich transmembrane protein 2 (PRRT2) gene. All subjects signed informed consent for genetic testing, and the study was approved by the ethics committee of our hospital. Mutations of the SLC20A2 gene can cause type 3 of IBGC (IBGC3), which manifests as a movement disorder, most often as a parkinsonism phenotype, and less frequently as a hyperkinetic movement disorder (e.g., chorea, tremor, dystonia, athetosis, and orofacial dyskinesia) [2,4]. The typical age at onset is between 30 and 50 years [1,4], however, our patients showed neurological symptoms in their adolescence, and then gradually disappeared in their 30’s. The main symptoms in our patients were transient action-induced dystonia with involuntary movements, absence of cognitive impairment, psychiatric symptoms, and other neurological signs. Furthermore, the symptoms were effectively improved with a low dose of carbamazepine. These clinical characteristics are consistent for the diagnostic criteria of paroxysmal kinesigenic dyskinesia (PKD) [3]. The PKD is a movement disorder characterized by painless dystonia and choreiform movements. Most patients with PKD have an autosomal dominant inherited family history, but sporadic symptomatic cases also exist, usually secondary to a variety of identifiable pathologies [5]. Until now, only 2 sporadic IBGC cases coexisting with PKD have been reported in the literature [3]. The age of onset and clinical pictures in the 2 cases were similar to those in our patients, while the SLC20A2 and PRRT2 gene were not screened in the 2 cases [3]. The pathophysiology of PKD remains unknown. Impairment of indirect pathway of thalamo-corticobasal circuit due to dysfunctions of basal ganglia was proposed as one of mechanisms of the origin of PKD [5]. Therefore, the abnormal depositions of calcium phosphates in thalamo-corticobasal regions might be responsible for paroxysmal dyskinesias in our patients according to no mutation in the PRRT2 gene.
354
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 353e354
Acknowledgments Authors gratefully acknowledged the contribution of patient and his family. This work was supported by grants from the National Natural Science Foundation of China (81260194).
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2013.12.006. References
Fig. 1. The pedigree chart and cerebral CT features of the family patients. Square: male; circle: female; black filled symbol: affected patient; gray filled symbol: carrier; line through symbol: deceased; oblique vertical arrow: the index patient. Dotted lines respectively connect with the CT images of different patients, which showed widespread calcifications in bilateral basal ganglia, thalamus, and subcortical areas.
The protein encoded by the SLC20A2 gene is a transmembrane protein called sodium-dependent phosphate transporter 2, which plays a housekeeping role in the phosphorus balance [4]. A total of 30 mutations have been reported in the SLC20A2 gene, of which 8 mutations existed in the hotspot exon 8 [1,4]. The novel frameshift variation also locates in exon 8, which can cause the disturbance of process capturing phosphates in cytoplasm, and then haploinsufficiency plays a role in the pathogenic mechanism [4].
[1] Hsu SC, Sears RL, Lemos RR, Quintáns B, Huang A, Spiteri E, et al. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 2013;14:11e22. [2] Nicolas G, Pottier C, Charbonnier C, Guyant-Maréchal L, Le Ber I, Pariente J, et al. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 2013;136(Pt 11):3395e407. [3] Chung EJ, Cho GN, Kim SJ. A case of paroxysmal kinesigenic dyskinesia in idiopathic bilateral striopallidodentate calcinosis. Seizure 2012;21:802e4. [4] Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 2012;44:254e6. [5] Bonazza S, La Morgia C, Martinelli P, Capellari S. Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients. Neurol Sci 2011;32: 537e45.
Min Zhu, Xuan Zhu, Hui Wan, Daojun Hong* Department of Neurology, The First Affiliated Hospital of Nanchang University, Yong Wai Zheng Street 17#, Nanchang 330006, PR China * Corresponding
author. Tel./fax: þ86 791 8869 2511. E-mail addresses: [email protected], [email protected] (D. Hong). 3 September 2013
