- Email: [email protected]
Benign hereditary chorea: Clinical features and long-term follow-up in a Spanish family
Parkinsonism and Related Disorders 19 (2013) 394–396
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Benign hereditary chorea: Clinical features and long-term follow-up in a Spanish family Keywords: Benign hereditary chorea Chorea Thyroid transcription factor NKX2-1
Benign hereditary chorea (MIM 118700) is an infrequent autosomal dominant disorder characterized by childhood-onset chorea and occasionally associated with hypothyroidism and respiratory disease [1]. Mutations in the NKX2-1 gene (also known as TITF1 or TTF1 gene) on chromosome 14q13 encoding the thyroid transcription factor-1 (TITF-1) have been identified in several families with benign hereditary chorea (BHC) [2]. In addition to this locus, there has been a report of genetic heterogeneity for this disease [3]. NKX2-1 is a regulatory gene involved in brain morphogenesis with a role in directing striatal and cortical interneurons. TITF-1 is only expressed during embryological brain development and not in mature brain. Gross and microscopic pathology was unremarkable, supporting the hypothesis that BHC is a developmental disorder although immunohistochemical staining of striatal tissue demonstrated a loss of most TITF-1-mediated striatal interneurons [4]. From a clinical perspective, the phenotype can be very variable even within the same family. Studies have not determined the factors that predict the clinical phenotype and severity. Due to its rarity, there is little information on the natural course of the disease and treatment experience is based only on a few patients. In this paper, we report the clinical features and long-term follow-up of a Spanish family with a novel NKX2-1 mutation. Fig. 1 shows the genealogical tree of the family being studied. The medical history of patients 2001, 2002 and 2003 is very similar (Table 1). Choreic movements of the face, trunk and limbs appeared few days after birth. Their motor development was markedly delayed. Cranial CT scan was normal and laboratory tests including thyroid hormones were unrevealing. Gait was greatly impaired through childhood and adolescence, requiring wheeling chairs. School performances were poor due to both cognitive and motor problems, without completing primary education. The three brothers were in the 1 percentile for height, with normal head size. Growth retardation affected mainly the legs. In adulthood, choreic movements declined but were still present in the face, trunk and limbs, along with axial and leg dystonia, and walking was difficult (video 1). No improvement 1353-8020/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.08.006
of the choreic movements was observed with alcohol consumption. On neurological examination, eye movements were normal and hearing was preserved, muscle tone was normal, deeptendon reflexes were 2 þ bilateral, plantar reflexes were flexor and there was no major sensory deficit. Brain MRI showed no abnormalities. Neuropsychological evaluation showed slight attentional deficit, moderate deficit in episodic, semantic and working memory, and constructive apraxia. In childhood, clonazepam and haloperidol were tried without success. Levodopa therapy was tried at a dose of 750 mg/day during one month without any improvement. Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2012.08.006. Patients 1001 and 2004 showed different clinical phenotypes (Table 1). Choreic movements were mild, gait was not impaired and motor development was not delayed. School performance was normal. Brain MRI revealed no abnormalities. Neuro psychological evaluation showed only slight deficit in working memory. After obtaining ethical approval and informed consent from participants, DNA was isolated from peripheral blood samples. For the molecular analysis of NKX2-1 coding exons, primers were taken from Breedveld et al. [2] and all three coding exons were subjected to amplification. After purification of the amplicons, direct sequencing was performed on both strands using Sanger sequencing on an ABIPrism 3100 automated DNA sequencer and compared against the reference (Acc. No. NM_001079668). In this family we found a C to T transition that produced a non-sense mutation, p.Q107Amber. The identified variant was found absent in 300 chromosomes from an ethnicity matched population, to segregate with the disease and to affect a conserved residue among vertebrates. BHC shows great heterogeneity of the clinical presentation within and among the families [1]. Chorea is the most typical presenting symptom but other presentations have been reported: developmental delay, dysarthria, pyramidal signs, hypotonia, ataxia, intention tremor, cognitive dysfunction and psychosis. In the present family the clinical features in 3 of the 4 brothers were similar and severe while the neurological features of the remaining brother and the affected father were mild. Considering the sometimes strikingly severe and disabling presentation, the term “benign” in the name of the disease may be misleading. Concerning extra-neurologic features, no member of the pedigree suffered from hypothyroidism or neonatal respiratory distress; short stature was observed in the most affected brothers. Short
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 394–396
9991
2001
0004
0001
1001
1002
2002
2003
395
9992
0002
1003
0003
1004
2004
Fig. 1. Pedigree of the family. -/C affected individuals.
stature has been reported in patients from two different families [1]. One characteristic feature of BHC is the lack of progression of symptoms and even improvement through adulthood. Treatment experience in BHC is scarce. Levodopa improved chorea and gait in two siblings [5]. In our family, levodopa was tried in adulthood without improvement. The mutation found in this pedigree results, if translated, in a truncated protein. To date, a few mutations have been described in NKX2.1 causing BHC of which those introducing a premature stop codon usually affected the second half of the protein. The mutation found in this pedigree locates in the first half of the protein,
Table 1 Clinical features in Spanish family with a NKX2-1 mutation causing BHC.
Acknowledgments
Pedigree no.
Actual age (years) Chorea Age at onset Pulmonary alteration Hypothyroidism Developmental delay Gait disorder Progression Short stature Cognitive deficits Brain MRI Improvement on LD
a location usually affected in Choreoathetosis, congenital hypothyroidism and respiratory distress (CCHRD, OMIM: 610978). This finding supports the notion that BHC and CCHRD are part of the same disease spectrum. The possibility that the mutation in the pedigree is related to the severity of the disease should be confirmed in additional families. Molecular and genetic characterization of BHC has been limited by the rarity, phenotypic heterogeneity and lack of recognition of this disorder. To overcome this problem, an international database from well characterized BHC cases will be a major asset. This will lead to a better understanding of genotype–phenotype relationship and provide insight into the molecular mechanisms underlying the development of BHC, eventually leading to novel therapeutic interventions [1].
1001
2004
2003
2002
2001
64 Yes Infancy No No No No No No NT NA NT
36 Yes Infancy No No No No No No Noa Normal NT
39 Yes Infancy No No Yes Yes No Yes Yes Normal No
41 Yes Infancy No No Yes Yes No Yes Yes Normal No
42 Yes Infancy No No Yes Yes No Yes Yes Normal No
BHC ¼ benign hereditary chorea; NA ¼ not available; NT ¼ not tested. a Slight deficit in working memory.
This project was supported in part by Generalitat Valenciana (ACOMP/2012/024) and MICINN (SAF2009-10434) References [1] Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: an update. Parkinsonism Relat Disord 2011;17:301–7. [2] Breedveld GJ, van Dongen JWF, Danesino C, Guala A, Percy AK, Dure LS, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 2002;11:971–9. [3] Breedveld GJ, Percy AK, MacDonald ME, de Vries BBA, Yapijakis C, Dure LS, et al. Clinical and genetic heterogeneity in benign hereditary chorea. Neurology 2002;59:579–84. [4] Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF, Lang AE. Alterations of striatal neurons in benign hereditary chorea. Mov Disord 2005;20:1353–7.
396
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 394–396
[5] Asmus F, Horber V, Pohlenz J, Schwabe D, Zimprich A, Munz M, et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 2005;64:1952–4.
Angel P. Sempere* Neurology Department, Hospital General Universitario de Alicante, Calle Pintor Baeza 12, Alicante 03010, Spain Silvia Aparicio Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC i Ciberned, Valencia, Spain
Santiago Mola Neurology Service, Hospital Vega Baja, Orihuela, Spain Jordi Pérez-Tur Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC i Ciberned, Valencia, Spain * Corresponding author. E-mail address: [email protected] (A.P. Sempere) 13 July 2012
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Benign hereditary chorea: Clinical features and long-term follow-up in a Spanish family Keywords: Benign hereditary chorea Chorea Thyroid transcription factor NKX2-1
Benign hereditary chorea (MIM 118700) is an infrequent autosomal dominant disorder characterized by childhood-onset chorea and occasionally associated with hypothyroidism and respiratory disease [1]. Mutations in the NKX2-1 gene (also known as TITF1 or TTF1 gene) on chromosome 14q13 encoding the thyroid transcription factor-1 (TITF-1) have been identified in several families with benign hereditary chorea (BHC) [2]. In addition to this locus, there has been a report of genetic heterogeneity for this disease [3]. NKX2-1 is a regulatory gene involved in brain morphogenesis with a role in directing striatal and cortical interneurons. TITF-1 is only expressed during embryological brain development and not in mature brain. Gross and microscopic pathology was unremarkable, supporting the hypothesis that BHC is a developmental disorder although immunohistochemical staining of striatal tissue demonstrated a loss of most TITF-1-mediated striatal interneurons [4]. From a clinical perspective, the phenotype can be very variable even within the same family. Studies have not determined the factors that predict the clinical phenotype and severity. Due to its rarity, there is little information on the natural course of the disease and treatment experience is based only on a few patients. In this paper, we report the clinical features and long-term follow-up of a Spanish family with a novel NKX2-1 mutation. Fig. 1 shows the genealogical tree of the family being studied. The medical history of patients 2001, 2002 and 2003 is very similar (Table 1). Choreic movements of the face, trunk and limbs appeared few days after birth. Their motor development was markedly delayed. Cranial CT scan was normal and laboratory tests including thyroid hormones were unrevealing. Gait was greatly impaired through childhood and adolescence, requiring wheeling chairs. School performances were poor due to both cognitive and motor problems, without completing primary education. The three brothers were in the 1 percentile for height, with normal head size. Growth retardation affected mainly the legs. In adulthood, choreic movements declined but were still present in the face, trunk and limbs, along with axial and leg dystonia, and walking was difficult (video 1). No improvement 1353-8020/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.08.006
of the choreic movements was observed with alcohol consumption. On neurological examination, eye movements were normal and hearing was preserved, muscle tone was normal, deeptendon reflexes were 2 þ bilateral, plantar reflexes were flexor and there was no major sensory deficit. Brain MRI showed no abnormalities. Neuropsychological evaluation showed slight attentional deficit, moderate deficit in episodic, semantic and working memory, and constructive apraxia. In childhood, clonazepam and haloperidol were tried without success. Levodopa therapy was tried at a dose of 750 mg/day during one month without any improvement. Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2012.08.006. Patients 1001 and 2004 showed different clinical phenotypes (Table 1). Choreic movements were mild, gait was not impaired and motor development was not delayed. School performance was normal. Brain MRI revealed no abnormalities. Neuro psychological evaluation showed only slight deficit in working memory. After obtaining ethical approval and informed consent from participants, DNA was isolated from peripheral blood samples. For the molecular analysis of NKX2-1 coding exons, primers were taken from Breedveld et al. [2] and all three coding exons were subjected to amplification. After purification of the amplicons, direct sequencing was performed on both strands using Sanger sequencing on an ABIPrism 3100 automated DNA sequencer and compared against the reference (Acc. No. NM_001079668). In this family we found a C to T transition that produced a non-sense mutation, p.Q107Amber. The identified variant was found absent in 300 chromosomes from an ethnicity matched population, to segregate with the disease and to affect a conserved residue among vertebrates. BHC shows great heterogeneity of the clinical presentation within and among the families [1]. Chorea is the most typical presenting symptom but other presentations have been reported: developmental delay, dysarthria, pyramidal signs, hypotonia, ataxia, intention tremor, cognitive dysfunction and psychosis. In the present family the clinical features in 3 of the 4 brothers were similar and severe while the neurological features of the remaining brother and the affected father were mild. Considering the sometimes strikingly severe and disabling presentation, the term “benign” in the name of the disease may be misleading. Concerning extra-neurologic features, no member of the pedigree suffered from hypothyroidism or neonatal respiratory distress; short stature was observed in the most affected brothers. Short
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 394–396
9991
2001
0004
0001
1001
1002
2002
2003
395
9992
0002
1003
0003
1004
2004
Fig. 1. Pedigree of the family. -/C affected individuals.
stature has been reported in patients from two different families [1]. One characteristic feature of BHC is the lack of progression of symptoms and even improvement through adulthood. Treatment experience in BHC is scarce. Levodopa improved chorea and gait in two siblings [5]. In our family, levodopa was tried in adulthood without improvement. The mutation found in this pedigree results, if translated, in a truncated protein. To date, a few mutations have been described in NKX2.1 causing BHC of which those introducing a premature stop codon usually affected the second half of the protein. The mutation found in this pedigree locates in the first half of the protein,
Table 1 Clinical features in Spanish family with a NKX2-1 mutation causing BHC.
Acknowledgments
Pedigree no.
Actual age (years) Chorea Age at onset Pulmonary alteration Hypothyroidism Developmental delay Gait disorder Progression Short stature Cognitive deficits Brain MRI Improvement on LD
a location usually affected in Choreoathetosis, congenital hypothyroidism and respiratory distress (CCHRD, OMIM: 610978). This finding supports the notion that BHC and CCHRD are part of the same disease spectrum. The possibility that the mutation in the pedigree is related to the severity of the disease should be confirmed in additional families. Molecular and genetic characterization of BHC has been limited by the rarity, phenotypic heterogeneity and lack of recognition of this disorder. To overcome this problem, an international database from well characterized BHC cases will be a major asset. This will lead to a better understanding of genotype–phenotype relationship and provide insight into the molecular mechanisms underlying the development of BHC, eventually leading to novel therapeutic interventions [1].
1001
2004
2003
2002
2001
64 Yes Infancy No No No No No No NT NA NT
36 Yes Infancy No No No No No No Noa Normal NT
39 Yes Infancy No No Yes Yes No Yes Yes Normal No
41 Yes Infancy No No Yes Yes No Yes Yes Normal No
42 Yes Infancy No No Yes Yes No Yes Yes Normal No
BHC ¼ benign hereditary chorea; NA ¼ not available; NT ¼ not tested. a Slight deficit in working memory.
This project was supported in part by Generalitat Valenciana (ACOMP/2012/024) and MICINN (SAF2009-10434) References [1] Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: an update. Parkinsonism Relat Disord 2011;17:301–7. [2] Breedveld GJ, van Dongen JWF, Danesino C, Guala A, Percy AK, Dure LS, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 2002;11:971–9. [3] Breedveld GJ, Percy AK, MacDonald ME, de Vries BBA, Yapijakis C, Dure LS, et al. Clinical and genetic heterogeneity in benign hereditary chorea. Neurology 2002;59:579–84. [4] Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF, Lang AE. Alterations of striatal neurons in benign hereditary chorea. Mov Disord 2005;20:1353–7.
396
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 394–396
[5] Asmus F, Horber V, Pohlenz J, Schwabe D, Zimprich A, Munz M, et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 2005;64:1952–4.
Angel P. Sempere* Neurology Department, Hospital General Universitario de Alicante, Calle Pintor Baeza 12, Alicante 03010, Spain Silvia Aparicio Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC i Ciberned, Valencia, Spain
Santiago Mola Neurology Service, Hospital Vega Baja, Orihuela, Spain Jordi Pérez-Tur Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC i Ciberned, Valencia, Spain * Corresponding author. E-mail address: [email protected] (A.P. Sempere) 13 July 2012