Parkinsonism and Related Disorders 20 (2014) 351e352
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
GNAL deletion as a probable cause of dystonia in a patient with the 18p- syndrome Keywords: Dystonia 18p- syndrome Genetics GNAL Topiramate
The 18p- syndrome is a chromosomal disorder caused by the deletion of all or part of the short arm of chromosome 18 (18p) [1]. Clinical manifestations include post-natal growth retardation, short stature, mental retardation and dysmorphic features. Dystonia affects some 18p- patients, possibly related to the extent of the deletion; its frequency is probably underestimated given that in cases with severe neurological and skeletal malformations, dystonia may be overlooked. Only a subset of patients develop autoimmune disorders. Here we report a patient with the 18p- syndrome who developed generalized dystonia and immunological abnormalities. A 19-year-old female presented with progressive, leftpredominant dystonic movements of the head and upper limbs, rapidly extending to the lower limbs. Neither exposure to specific drugs nor fever or head trauma was reported. Family history for neurologic or psychiatric diseases was negative. The patient was the fourth child of healthy non-consanguineous parents. At birth, bilateral ptosis and microphthalmia were observed. The patient had speech and motor development delay and attended special schools. On examination, she presented with short stature, round face, bilateral ptosis and micrognathia. Neurological examination showed retrocollis and torticollis to the right with myoclonic jerks, upper limb dystonia increasing during walking, and mild dystonic gait disturbances. Brain MRI was normal. No response to levodopa, biperiden and clonazepam was observed. Symptoms worsened over the next 6 months, with the patient becoming disabled and displaying swallowing difficulties (Video-Segment 1). Blood tests revealed anti-cardiolipin and anti-beta2-glycoprotein I IgM antibodies, antinuclear and antinucleosome antibodies, and low complement levels. Urinalysis was negative for proteinuria. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2013.12.005. Initiation of Topiramate 25 mg t.i.d. led to a marked and rapid reduction of dystonic movements (Video-Segment 2) with the FahneMarsden dystonia rating scale score improving from 24 to 10 after treatment. Low-dose aspirin was introduced given the presence of prothrombotic immunological abnormalities. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2013.12.005. 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.12.005
Cytogenetics analysis (conventional karyotyping, G-banding) revealed that all cells lacked the short arm of chromosome 18 (monosomy 18p, deletion of 18p). Also, in 15% of cells there was an additional long arm of chromosome 18 instead of the lacking short arm, forming an isochromosome 18q (chromosomal mosaicism). The resulting genotype is an 18p monosomy in all observed cells and an additional 18q trisomy in a minority of cells. Comparative genomic hybridization (array-CGH, Agilent oligoNT arr cgh 180K) showed a 14.7 Mb deletion of the entire short arm of chromosome 18 (arr 18p11.32p11.21(118,760e14,796,024)1, GRCh37), but failed to detect the genomic imbalance involving the long arm of chromosome 18. This is likely due to the limitation of array-CGH for detecting low-level mosaicism. So far, 10 patients with the 18p- syndrome and dystonic symptoms have been described [2], with only one displaying both dystonia and autoimmune disorders (throiditis, vitiligo and brain demyelinating lesions). Of note, mosaicism has been reported in patients with 18p- syndrome [1]. In our patient, all cells displayed a deleted 18p, therefore the diagnosis of 18p- syndrome is supported by genetic findings. Clinical features observed in our patient are consistent with previous descriptions of the 18p- syndrome with dystonia. However, our patient has immunological abnormalities not previously observed in 18p- patients, with laboratory findings compatible with a “lupus-like immunological profile” not fulfilling diagnostic criteria for systemic lupus erythematosus. Most of the reports do not provide details about the size of the 18p deletion. However, in three of the ten cases with 18p- and dystonia, the same 49.6 cM region was observed to be deleted, possibly suggesting an area of particular instability. Moreover in two cases of 18p- syndrome with associated immunological deficits, a telomeric deletion of respectively 10.1 Mb and 2 Mb was described. Our observation supports the existence of dystonia and autoimmunity loci on 18p. Of note, two dystonia loci, DYT7 and DYT15, were mapped to this chromosomal region, even though recent evidence questions the existence of DYT7. Recently, a new dystonia locus, the GNAL gene (DYT25), was identified centromeric to DYT7 and DYT15 in two Caucasian families with primary torsion dystonia [3]. The same gene was also implicated in an African-American pedigree with cervical, laryngeal and hand-forearm dystonia and in three additional Caucasian families [4]. Age at onset of dystonia in patients with GNAL mutations is in adult life. Cervical or cranial predominance is observed and some patients also display evidence of hyposmia on formal testing. Unfortunately, our patient is too impaired to be reliably and accurately administered smell testing.
352
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 351e352
Table 1 Selection of genes affecting signalling pathways potentially involved in dystonia or autoimmunity and located on the short arm of chromosome 18. Symbol
Description
ADCYAP1
Involved in stimulating adenylate cyclase and can function as a neurotransmitter and neuromodulator Encodes a protein localized in mitochondria and closely related to paraplegin Encodes one of the major proteins involved in intracellular signal transduction via NMDA; it plays a role in the molecular organization of synapses and in neuronal signalling. Encodes the alpha subunit of the GTP-binding protein, which plays a role in coupling dopamine type 1 receptors (D1R) and adenosine A2A receptors (A2AR) in striatal neurons. It is highly expressed in the striatum and cerebellar Purkinje cells; it has been recently demonstrated to be associated to primary torsion dystonia, pointing to abnormalities in D1R and/or A2AR transmission as possibly leading causes for dystonia. Encodes the subunit alpha-1 of laminin, which is involved in neurite outgrowth Mutated in families with a rare autosomal recessive inflammatory disorder, Majeed syndrome Highly expressed in B and T lymphocytes and may play a role in immune regulation Encodes a subunit of the mitochondrial respiratory chain complex 1. Genetic variants were implicated in Parkinson’s disease, bipolar disorder, schizophrenia Expressed in the brain and involved in intracellular signal transduction pathways Associated with holoprosencephaly type 4; may participate in transmission of nuclear signals during development and in adult
AFG3L2 DLGAP1
GNAL
LAMA1 LPIN2 MC2R NDUFV2
PTPRM TGIF
GNAL encodes the stimulatory a subunit Gaolf, a G protein that is involved in dopamine transmission by coupling dopamine type 1 receptors (D1) and that mediates signal transduction within the olfactory neuroepithelium and the basal ganglia. Gaolf is highly expressed in the striatum, cerebellar Purkinje cells and olfactory epithelium [4]. So far 11 point mutations in the GNAL gene have been identified in patients with primary dystonia. Most of them are nonsense mutations, which may cause premature stop codons, thereby reducing protein production; the remaining are missense mutations. In patients with the 18p- syndrome there is a deletion of the GNAL gene, which may contribute to dystonia by a mechanism of haploinsufficiency [4]. Of note, a 15 Mb deletion of chromosome 18p that included the GNAL gene was previously identified in a mother and her child both affected with dystonia [5]. In our patient, haploinsufficiency of other candidate genes on 18p may also have contributed to the clinical manifestations (Table 1). Interestingly, the DLGAP1 gene plays a role in NMDA-mediated neurotransmission. Therefore, in our patient deficient for the DLGAP1 gene, it may be speculated that topiramate altered excitatory glutamatergic neurotransmission, thereby leading to clinical improvement. Based on recent discoveries deletion of GNAL is the most likely cause of dystonia in patients with the 18p- syndrome. Deletion of other genes such as DLGAP1 may participate in some phenotype characteristics including therapeutic response to topiramate. Although we cannot rule out that the 18q trisomy observed in a minority of cells participated in part of the phenotype this is unlikely given the low degree of mosaicism (w15% of cells displaying the 18q trisomy in addition to the 18p monosomy). The mechanisms involved in immunological abnormalities remain to be explored, however some genes on 18p appear to be plausible biological candidates. The MCR5 gene encoding the melanocortin receptor 5 is expressed in B and T lymphocytes, suggesting it may play a role in immune regulation. Additionally, the LPIN2 gene is mutated in families affected by a rare autosomal recessive autoinflammatory disorder, Majeed syndrome.
In conclusion, patients with the 18p- syndrome should be assessed for dystonia and autoimmune disease and carefully followed over time. Topiramate may be considered a therapeutic option in patients non-responsive to classic first-line dystonia therapies. The patient reported here further supports a role for GNAL in dystonia, possibly involving a mechanism of haploinsufficiency. Financial disclosure Nothing to report. Conflict of interest Nothing to report. Acknowledgements CW receives research support from the Leenaards Foundation. References [1] Turleau C. Monosomy 18p. Orphanet J Rare Dis 2008;3:4. [2] Kowarik AC, Langer S, Keri C, Hemmer B, Oexle K, Winkelmann J. Myoclonusdystonia in 18p deletion syndrome. Mov Disord 2011;26:560e1. [3] Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013;45:88e92. ska M, Frei KP, et al. Role of [4] Vemula SR, Puschmann A, Xiao J, Zhao Y, Rudzin Ga(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet 2013;22:2510e9. [5] Nasir J, Frima N, Pickard B, Malloy MP, Zhan L, Grünewald R. Unbalanced whole arm translocation resulting in loss of 18p in dystonia. Mov Disord 2006;21: 859e63.
Federica Esposito Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), Lausanne, Switzerland Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Marie-Claude Addor Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Andrea M. Humm Unit of Neurology, Department of Internal Medicine, Hôpital Cantonal HFR, Fribourg, Switzerland François Vingerhoets Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), Lausanne, Switzerland Christian Wider* Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), BH13, Rue du Bugnon 21, 1011 Lausanne, Switzerland * Corresponding
author. Tel.: þ41 79 556 8117; fax: þ41 21 314 1244. E-mail address: [email protected] (C. Wider). 28 August 2013
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
GNAL deletion as a probable cause of dystonia in a patient with the 18p- syndrome Keywords: Dystonia 18p- syndrome Genetics GNAL Topiramate
The 18p- syndrome is a chromosomal disorder caused by the deletion of all or part of the short arm of chromosome 18 (18p) [1]. Clinical manifestations include post-natal growth retardation, short stature, mental retardation and dysmorphic features. Dystonia affects some 18p- patients, possibly related to the extent of the deletion; its frequency is probably underestimated given that in cases with severe neurological and skeletal malformations, dystonia may be overlooked. Only a subset of patients develop autoimmune disorders. Here we report a patient with the 18p- syndrome who developed generalized dystonia and immunological abnormalities. A 19-year-old female presented with progressive, leftpredominant dystonic movements of the head and upper limbs, rapidly extending to the lower limbs. Neither exposure to specific drugs nor fever or head trauma was reported. Family history for neurologic or psychiatric diseases was negative. The patient was the fourth child of healthy non-consanguineous parents. At birth, bilateral ptosis and microphthalmia were observed. The patient had speech and motor development delay and attended special schools. On examination, she presented with short stature, round face, bilateral ptosis and micrognathia. Neurological examination showed retrocollis and torticollis to the right with myoclonic jerks, upper limb dystonia increasing during walking, and mild dystonic gait disturbances. Brain MRI was normal. No response to levodopa, biperiden and clonazepam was observed. Symptoms worsened over the next 6 months, with the patient becoming disabled and displaying swallowing difficulties (Video-Segment 1). Blood tests revealed anti-cardiolipin and anti-beta2-glycoprotein I IgM antibodies, antinuclear and antinucleosome antibodies, and low complement levels. Urinalysis was negative for proteinuria. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2013.12.005. Initiation of Topiramate 25 mg t.i.d. led to a marked and rapid reduction of dystonic movements (Video-Segment 2) with the FahneMarsden dystonia rating scale score improving from 24 to 10 after treatment. Low-dose aspirin was introduced given the presence of prothrombotic immunological abnormalities. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2013.12.005. 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.12.005
Cytogenetics analysis (conventional karyotyping, G-banding) revealed that all cells lacked the short arm of chromosome 18 (monosomy 18p, deletion of 18p). Also, in 15% of cells there was an additional long arm of chromosome 18 instead of the lacking short arm, forming an isochromosome 18q (chromosomal mosaicism). The resulting genotype is an 18p monosomy in all observed cells and an additional 18q trisomy in a minority of cells. Comparative genomic hybridization (array-CGH, Agilent oligoNT arr cgh 180K) showed a 14.7 Mb deletion of the entire short arm of chromosome 18 (arr 18p11.32p11.21(118,760e14,796,024)1, GRCh37), but failed to detect the genomic imbalance involving the long arm of chromosome 18. This is likely due to the limitation of array-CGH for detecting low-level mosaicism. So far, 10 patients with the 18p- syndrome and dystonic symptoms have been described [2], with only one displaying both dystonia and autoimmune disorders (throiditis, vitiligo and brain demyelinating lesions). Of note, mosaicism has been reported in patients with 18p- syndrome [1]. In our patient, all cells displayed a deleted 18p, therefore the diagnosis of 18p- syndrome is supported by genetic findings. Clinical features observed in our patient are consistent with previous descriptions of the 18p- syndrome with dystonia. However, our patient has immunological abnormalities not previously observed in 18p- patients, with laboratory findings compatible with a “lupus-like immunological profile” not fulfilling diagnostic criteria for systemic lupus erythematosus. Most of the reports do not provide details about the size of the 18p deletion. However, in three of the ten cases with 18p- and dystonia, the same 49.6 cM region was observed to be deleted, possibly suggesting an area of particular instability. Moreover in two cases of 18p- syndrome with associated immunological deficits, a telomeric deletion of respectively 10.1 Mb and 2 Mb was described. Our observation supports the existence of dystonia and autoimmunity loci on 18p. Of note, two dystonia loci, DYT7 and DYT15, were mapped to this chromosomal region, even though recent evidence questions the existence of DYT7. Recently, a new dystonia locus, the GNAL gene (DYT25), was identified centromeric to DYT7 and DYT15 in two Caucasian families with primary torsion dystonia [3]. The same gene was also implicated in an African-American pedigree with cervical, laryngeal and hand-forearm dystonia and in three additional Caucasian families [4]. Age at onset of dystonia in patients with GNAL mutations is in adult life. Cervical or cranial predominance is observed and some patients also display evidence of hyposmia on formal testing. Unfortunately, our patient is too impaired to be reliably and accurately administered smell testing.
352
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 351e352
Table 1 Selection of genes affecting signalling pathways potentially involved in dystonia or autoimmunity and located on the short arm of chromosome 18. Symbol
Description
ADCYAP1
Involved in stimulating adenylate cyclase and can function as a neurotransmitter and neuromodulator Encodes a protein localized in mitochondria and closely related to paraplegin Encodes one of the major proteins involved in intracellular signal transduction via NMDA; it plays a role in the molecular organization of synapses and in neuronal signalling. Encodes the alpha subunit of the GTP-binding protein, which plays a role in coupling dopamine type 1 receptors (D1R) and adenosine A2A receptors (A2AR) in striatal neurons. It is highly expressed in the striatum and cerebellar Purkinje cells; it has been recently demonstrated to be associated to primary torsion dystonia, pointing to abnormalities in D1R and/or A2AR transmission as possibly leading causes for dystonia. Encodes the subunit alpha-1 of laminin, which is involved in neurite outgrowth Mutated in families with a rare autosomal recessive inflammatory disorder, Majeed syndrome Highly expressed in B and T lymphocytes and may play a role in immune regulation Encodes a subunit of the mitochondrial respiratory chain complex 1. Genetic variants were implicated in Parkinson’s disease, bipolar disorder, schizophrenia Expressed in the brain and involved in intracellular signal transduction pathways Associated with holoprosencephaly type 4; may participate in transmission of nuclear signals during development and in adult
AFG3L2 DLGAP1
GNAL
LAMA1 LPIN2 MC2R NDUFV2
PTPRM TGIF
GNAL encodes the stimulatory a subunit Gaolf, a G protein that is involved in dopamine transmission by coupling dopamine type 1 receptors (D1) and that mediates signal transduction within the olfactory neuroepithelium and the basal ganglia. Gaolf is highly expressed in the striatum, cerebellar Purkinje cells and olfactory epithelium [4]. So far 11 point mutations in the GNAL gene have been identified in patients with primary dystonia. Most of them are nonsense mutations, which may cause premature stop codons, thereby reducing protein production; the remaining are missense mutations. In patients with the 18p- syndrome there is a deletion of the GNAL gene, which may contribute to dystonia by a mechanism of haploinsufficiency [4]. Of note, a 15 Mb deletion of chromosome 18p that included the GNAL gene was previously identified in a mother and her child both affected with dystonia [5]. In our patient, haploinsufficiency of other candidate genes on 18p may also have contributed to the clinical manifestations (Table 1). Interestingly, the DLGAP1 gene plays a role in NMDA-mediated neurotransmission. Therefore, in our patient deficient for the DLGAP1 gene, it may be speculated that topiramate altered excitatory glutamatergic neurotransmission, thereby leading to clinical improvement. Based on recent discoveries deletion of GNAL is the most likely cause of dystonia in patients with the 18p- syndrome. Deletion of other genes such as DLGAP1 may participate in some phenotype characteristics including therapeutic response to topiramate. Although we cannot rule out that the 18q trisomy observed in a minority of cells participated in part of the phenotype this is unlikely given the low degree of mosaicism (w15% of cells displaying the 18q trisomy in addition to the 18p monosomy). The mechanisms involved in immunological abnormalities remain to be explored, however some genes on 18p appear to be plausible biological candidates. The MCR5 gene encoding the melanocortin receptor 5 is expressed in B and T lymphocytes, suggesting it may play a role in immune regulation. Additionally, the LPIN2 gene is mutated in families affected by a rare autosomal recessive autoinflammatory disorder, Majeed syndrome.
In conclusion, patients with the 18p- syndrome should be assessed for dystonia and autoimmune disease and carefully followed over time. Topiramate may be considered a therapeutic option in patients non-responsive to classic first-line dystonia therapies. The patient reported here further supports a role for GNAL in dystonia, possibly involving a mechanism of haploinsufficiency. Financial disclosure Nothing to report. Conflict of interest Nothing to report. Acknowledgements CW receives research support from the Leenaards Foundation. References [1] Turleau C. Monosomy 18p. Orphanet J Rare Dis 2008;3:4. [2] Kowarik AC, Langer S, Keri C, Hemmer B, Oexle K, Winkelmann J. Myoclonusdystonia in 18p deletion syndrome. Mov Disord 2011;26:560e1. [3] Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013;45:88e92. ska M, Frei KP, et al. Role of [4] Vemula SR, Puschmann A, Xiao J, Zhao Y, Rudzin Ga(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet 2013;22:2510e9. [5] Nasir J, Frima N, Pickard B, Malloy MP, Zhan L, Grünewald R. Unbalanced whole arm translocation resulting in loss of 18p in dystonia. Mov Disord 2006;21: 859e63.
Federica Esposito Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), Lausanne, Switzerland Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Marie-Claude Addor Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Andrea M. Humm Unit of Neurology, Department of Internal Medicine, Hôpital Cantonal HFR, Fribourg, Switzerland François Vingerhoets Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), Lausanne, Switzerland Christian Wider* Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), BH13, Rue du Bugnon 21, 1011 Lausanne, Switzerland * Corresponding
author. Tel.: þ41 79 556 8117; fax: þ41 21 314 1244. E-mail address: [email protected] (C. Wider). 28 August 2013
