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Siblings with recessive oculopharyngeal muscular dystrophy
Neuromuscular Disorders 17 (2007) 254–257 www.elsevier.com/locate/nmd
Case report
Siblings with recessive oculopharyngeal muscular dystrophy Srisha Hebbar
a,*
, Michael J. Webberley a, Peter Lunt b, David O. Robinson
c,d
a
d
Department of Gastroenterology, Aconbury East, Worcester Royal Hospital, Worcester WR5 1EP, UK b Clinical Genetics Service, St. Michael’s Hospital, Bristol BS2 8EG, UK c Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts. SP2 8BJ, UK Human Genetics Division, Southampton University School of Medicine, Southampton, Hants SO16 6YD, UK Received 10 May 2006; received in revised form 20 November 2006; accepted 29 November 2006
Abstract Oculopharyngeal muscular dystrophy (OPMD) is a late onset myopathy usually presenting in the 5th or 6th decade of life with progressive ptosis, dysphagia and proximal muscle weakness. It is usually dominantly inherited; however, a rare recessive form has also been described although documentation of such cases in the literature is very sparse. Here we report two siblings with recessive OPMD, in one of whom the clinical picture is complicated by ankylosing spondilitis and pneumonia. They exhibit later onset and milder symptoms than is typical for patients with dominantly inherited OPMD. This and the possibility that OPMD may be masked by symptoms of other diseases of the elderly may account for the paucity of cases of recessive OPMD reported in the literature. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Oculopharyngeal muscular dystrophy; Homozygosity; Recessive allele; Late onset ptosis
1. Introduction Oculopharyngeal muscular dystrophy (OPMD) is a late onset dominantly inherited condition that usually presents in the 5th or 6th decade of life with ptosis, dysphagia and progressive proximal limb weakness. Associated ophthalmoplegia is unusual, and if present is usually mild and predominantly for upward gaze. The underlying cause of OPMD is expansion of a repeat sequence normally encoding 10 contiguous alanine codons in exon 1 of the polyadenine binding protein nuclear 1 gene (PABPN1) [1,2]. Expansion mutations (2–7 additional alanine codons in dominantly inherited OPMD) cause an increase in the number of alanine residues in the PABPN1 protein and are associated with the deposition of characteristic nuclear inclusions in skeletal muscle fibres. A recessive allele has also been described consisting of a single additional alanine codon *
Corresponding author. E-mail address: [email protected] (S. Hebbar).
0960-8966/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.11.009
and a rare case of homozygosity for this mutation, although a detailed clinical description was not given [1]. Here we describe two siblings with recessive OPMD, one of whom has a clinical picture complicated with recurrent pneumonia and ankylosing spondylitis. 2. Case reports Patient A (Fig. 1) was a 76-year-old gentleman who had been admitted recurrently with right sided pneumonia over the last five years. He had worked in the iron and asbestos industry and was known to suffer from ankylosing spondylitis. He was an ex-smoker, had stopped smoking 20 years ago, and had been extensively investigated by the respiratory physicians two years ago. Restrictive lung defect secondary to ankylosing spondylitis, bronchiectasis and widespread centrilobar emphysema were thought to be implicated in the recurrent chest infections. He was admitted in February 2005 with progressive dysphagia for both solids and liquids and weight loss
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
(nearly 10 kg over 2–3 months). He had also had intermittent episodes of choking following meals for the last 2–3 years and had noted his voice had become husky over the past 2 months. On examination, speech was nasal. Bilateral partial ptosis was noted. Pupils were bilaterally equal in size and reactive to light. Cranial nerve examination was normal. There was no ophthalmoplegia. There was no obvious proximal myopathy. Fatigability was not demonstrated. There was no motor weakness and sensory examination was normal. Fundoscopy was normal. Decreased intensity of breath sounds and dullness on percussion in the right lower zone was noted on chest auscultation. Cardiovascular and abdominal examinations were normal. The patient‘s old photographs were reviewed and he was noted to have had bilateral ptosis for the last 5 years. Routine blood tests and chest X-ray were normal. Upper GI endoscopy was normal but barium swallow showed increased aspiration of barium into the trachea and right main bronchus. Antiacetylcholinesterase receptor antibodies and electromyography with repetitive stimulation, to rule out Myasthenia Gravis, were normal. CT scan of the chest was requested to rule out associated thymoma but right lower lobe collapse and consolidation was noted similar to the CT carried out in 2003. Patient B (Fig. 2) was the sister of patient A. At age 67 she had a 5 month history of bilateral progressive ptosis but no visual disturbances, diplopia, dysphagia or muscle weakness. No fatigability on sustained upward gaze was demonstrated and systemic examination including the nervous system was normal. Myasthenia gravis was suspected but tensilon test and anticholinesterase antibodies were negative. A diagnosis of bilateral tarsal plate dehiscence was made and tarsorrhaphy was carried out. The siblings reported a strong family history of ptosis (Fig. 3), including in their mother who had died aged 84 years, in a living maternal aunt aged 99 years and in both her daughters (cousins to patients A and B), but in none of these was there any known dysphagia. A diagnosis of OPMD was suspected because of the ptosis and dysphagia in patient A, ptosis in patient B and the family history. Genetic analysis for a mutation in the PABPN1 gene was requested. DNA was extracted from blood and analysed by PCR amplification of the PABPN1 gene as described previously [1,3,4]. Both patients were found to be homozygous for a single GCG triplet expansion, confirmed to be GCG by sequence analysis, in the polyalanine repeat codon region of the PABPN1 gene, consistent with a diagnosis of recessive OPMD. Analysis of the 14q11.2 region using the polymorphic marker D14S49 showed both patients to be heterozygous. Although this marker is 10 Mb distal to PABPN1 it indicates that the mutations are unlikely to have been inherited by recent common
255
Fig. 1. Patient A.
descent, although SNPs closer to PAPBN1 would need to be analysed to confirm this. Patient A was referred to ENT surgeons for myotomy, which was not considered due to operative risk, a PEG tube was inserted and the patient is currently doing well. Subsequent clinical assessment of the aunt and cousins revealed relatively narrow palpebral fissures in the 99-year-old aunt and in one of her daughters, and a history of surgery for unilateral (right) ptosis in the
Fig. 2. Patient B.
256
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
99y.
Died at 84y. Bilateral ptosis
76y Patient A Ptosis and dysphagia Homozygous for GCG expansion
Narrow palpebral fissures. Heterozygous for GCG expansion
69y Patient B Bilateral ptosis Homozygous for GCG expansion
69y Unaffected. Not tested for GCG expansion
76y. Narrow palpebral fissures. No GCG expansion
67y. Unilateral left ptosis. No GCG expansion
Fig. 3. Family pedigree.
aunt, but with the ptosis only developing following surgery for cataract, performed on one eye at age 85 years and on the other eye at 95 years. The aunt also now had right abducens palsy, giving double vision on right lateral gaze. There was no associated swallowing difficulty, although palatal movement seemed poor. The elder cousin, aged 73 years, also had narrow palpebral fissures, but no definite ptosis. The younger cousin, aged 67 years, did have a 5-year history of unilateral (left) ptosis, but associated with unequal pupils; that of the left eye being relatively dilated and hypo-reactive, and with a history of injury to the left orbital region at age 17 years. DNA testing showed the aunt to be heterozygous for the single GCG trinucleotide expansion, but both the cousins showed only normal sized alleles. 3. Discussion Both patients A and B were found to have the rare recessive form of OPMD caused by homozygosity for a small expansion of one repeat in the polyalanine codon repeat sequence in the PABPN1 gene [1]. For patient A the clinical picture was complicated by the presence of ankylosing spondilitis and pneumonia and in retrospect it is likely that he had recurrent aspiration pneumonia secondary to his oropharyngeal incoordination. However, both patient A and B reported onset of OPMD symptoms in the 7th decade of life, and therefore appear to have a later onset than is the case for typical dominant OPMD which usually becomes apparent
in the 5th or 6th decade of life [1,2]. The only other published case of recessive OPMD of which we are aware is that of Brais et al. [1] which specified that the disease was of later onset but gave no clinical details. Symptoms also appear to be milder for the two cases presented here with patient A exhibiting only ptosis and dysphagia, but no muscle weakness, and patient B only having ptosis. There is a paucity of cases of recessive OPMD in the literature; however, Brais et al. [1] estimated that relatively high proportions (2%) of the normal French Canadian population are heterozygous for the recessive allele. We would therefore expect a incidence of 1 in 10,000 and expect some cases to be reported from this population. However, the estimate of 2% was made from analysis of a cohort of only 86 normal control individuals and therefore has a high margin of error [1], although a 1–2% carrier rate has also been quoted for France, North America and Japan [2]. The paucity may also be because of the milder expression and later onset of the disease, such that cases only present in old age and the diagnosis may be masked or confounded by symptoms of other diseases of the elderly, as is the case in patient A. Furthermore, we estimate that the incidence of the recessive allele in the UK is lower than that of the French Canadian population as we have found no cases of heterozygosity for the recessive allele in 200 control samples. Heterozygotes in the Canadian study were asymptomatic, but the upper age limit of these is not available [1]. The reported history of ptosis in the mother of A and B, and the occurrence of this in the 99-year-old
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
aunt, raises the question of whether carriers of a single triplet repeat expansion in the PABPN1 gene may manifest an extreme late onset of symptoms and that this mutation is not truly recessive as suggested by Brais et al. [1]. Unfortunately this remains uncertain, as the ptosis in the aunt here developed only following cataract surgery, and is associated with external rectus palsy, which would not commonly be a feature in OPMD. The coincidence of possible post-traumatic ptosis in one of her daughters, and of narrow palpebral fissures in the other, neither of whom inherited the expanded PABPN1 allele, only serves to urge caution in the interpretation of unverified family history, emphasizing also that ptosis in later life is probably not particularly rare. In conclusion, not only does case A illustrate the importance of considering a neurological cause for recurrent right sided pneumonia, but both cases A and B add to the very sparse literature on recessive OPMD and are consistent with the finding of Brais et al. [1] that symptoms are milder and of later onset than is the case for typical dominantly inherited OPMD.
257
Acknowledgements The authors thank the clinicians who contributed to the clinical analysis of these patients and the patients themselves.
References [1] Brais B, Bouchard JP, Xie YG, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998;18:164–7. [2] Brais B. Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 2003;100:252–60. [3] Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, Hammans SR. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 2001;124(3):522–6. [4] Robinson DO, Hammans SR, Read SP, Sillibourne J. Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet 2005;116(4):267–71.
Case report
Siblings with recessive oculopharyngeal muscular dystrophy Srisha Hebbar
a,*
, Michael J. Webberley a, Peter Lunt b, David O. Robinson
c,d
a
d
Department of Gastroenterology, Aconbury East, Worcester Royal Hospital, Worcester WR5 1EP, UK b Clinical Genetics Service, St. Michael’s Hospital, Bristol BS2 8EG, UK c Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts. SP2 8BJ, UK Human Genetics Division, Southampton University School of Medicine, Southampton, Hants SO16 6YD, UK Received 10 May 2006; received in revised form 20 November 2006; accepted 29 November 2006
Abstract Oculopharyngeal muscular dystrophy (OPMD) is a late onset myopathy usually presenting in the 5th or 6th decade of life with progressive ptosis, dysphagia and proximal muscle weakness. It is usually dominantly inherited; however, a rare recessive form has also been described although documentation of such cases in the literature is very sparse. Here we report two siblings with recessive OPMD, in one of whom the clinical picture is complicated by ankylosing spondilitis and pneumonia. They exhibit later onset and milder symptoms than is typical for patients with dominantly inherited OPMD. This and the possibility that OPMD may be masked by symptoms of other diseases of the elderly may account for the paucity of cases of recessive OPMD reported in the literature. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Oculopharyngeal muscular dystrophy; Homozygosity; Recessive allele; Late onset ptosis
1. Introduction Oculopharyngeal muscular dystrophy (OPMD) is a late onset dominantly inherited condition that usually presents in the 5th or 6th decade of life with ptosis, dysphagia and progressive proximal limb weakness. Associated ophthalmoplegia is unusual, and if present is usually mild and predominantly for upward gaze. The underlying cause of OPMD is expansion of a repeat sequence normally encoding 10 contiguous alanine codons in exon 1 of the polyadenine binding protein nuclear 1 gene (PABPN1) [1,2]. Expansion mutations (2–7 additional alanine codons in dominantly inherited OPMD) cause an increase in the number of alanine residues in the PABPN1 protein and are associated with the deposition of characteristic nuclear inclusions in skeletal muscle fibres. A recessive allele has also been described consisting of a single additional alanine codon *
Corresponding author. E-mail address: [email protected] (S. Hebbar).
0960-8966/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.11.009
and a rare case of homozygosity for this mutation, although a detailed clinical description was not given [1]. Here we describe two siblings with recessive OPMD, one of whom has a clinical picture complicated with recurrent pneumonia and ankylosing spondylitis. 2. Case reports Patient A (Fig. 1) was a 76-year-old gentleman who had been admitted recurrently with right sided pneumonia over the last five years. He had worked in the iron and asbestos industry and was known to suffer from ankylosing spondylitis. He was an ex-smoker, had stopped smoking 20 years ago, and had been extensively investigated by the respiratory physicians two years ago. Restrictive lung defect secondary to ankylosing spondylitis, bronchiectasis and widespread centrilobar emphysema were thought to be implicated in the recurrent chest infections. He was admitted in February 2005 with progressive dysphagia for both solids and liquids and weight loss
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
(nearly 10 kg over 2–3 months). He had also had intermittent episodes of choking following meals for the last 2–3 years and had noted his voice had become husky over the past 2 months. On examination, speech was nasal. Bilateral partial ptosis was noted. Pupils were bilaterally equal in size and reactive to light. Cranial nerve examination was normal. There was no ophthalmoplegia. There was no obvious proximal myopathy. Fatigability was not demonstrated. There was no motor weakness and sensory examination was normal. Fundoscopy was normal. Decreased intensity of breath sounds and dullness on percussion in the right lower zone was noted on chest auscultation. Cardiovascular and abdominal examinations were normal. The patient‘s old photographs were reviewed and he was noted to have had bilateral ptosis for the last 5 years. Routine blood tests and chest X-ray were normal. Upper GI endoscopy was normal but barium swallow showed increased aspiration of barium into the trachea and right main bronchus. Antiacetylcholinesterase receptor antibodies and electromyography with repetitive stimulation, to rule out Myasthenia Gravis, were normal. CT scan of the chest was requested to rule out associated thymoma but right lower lobe collapse and consolidation was noted similar to the CT carried out in 2003. Patient B (Fig. 2) was the sister of patient A. At age 67 she had a 5 month history of bilateral progressive ptosis but no visual disturbances, diplopia, dysphagia or muscle weakness. No fatigability on sustained upward gaze was demonstrated and systemic examination including the nervous system was normal. Myasthenia gravis was suspected but tensilon test and anticholinesterase antibodies were negative. A diagnosis of bilateral tarsal plate dehiscence was made and tarsorrhaphy was carried out. The siblings reported a strong family history of ptosis (Fig. 3), including in their mother who had died aged 84 years, in a living maternal aunt aged 99 years and in both her daughters (cousins to patients A and B), but in none of these was there any known dysphagia. A diagnosis of OPMD was suspected because of the ptosis and dysphagia in patient A, ptosis in patient B and the family history. Genetic analysis for a mutation in the PABPN1 gene was requested. DNA was extracted from blood and analysed by PCR amplification of the PABPN1 gene as described previously [1,3,4]. Both patients were found to be homozygous for a single GCG triplet expansion, confirmed to be GCG by sequence analysis, in the polyalanine repeat codon region of the PABPN1 gene, consistent with a diagnosis of recessive OPMD. Analysis of the 14q11.2 region using the polymorphic marker D14S49 showed both patients to be heterozygous. Although this marker is 10 Mb distal to PABPN1 it indicates that the mutations are unlikely to have been inherited by recent common
255
Fig. 1. Patient A.
descent, although SNPs closer to PAPBN1 would need to be analysed to confirm this. Patient A was referred to ENT surgeons for myotomy, which was not considered due to operative risk, a PEG tube was inserted and the patient is currently doing well. Subsequent clinical assessment of the aunt and cousins revealed relatively narrow palpebral fissures in the 99-year-old aunt and in one of her daughters, and a history of surgery for unilateral (right) ptosis in the
Fig. 2. Patient B.
256
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
99y.
Died at 84y. Bilateral ptosis
76y Patient A Ptosis and dysphagia Homozygous for GCG expansion
Narrow palpebral fissures. Heterozygous for GCG expansion
69y Patient B Bilateral ptosis Homozygous for GCG expansion
69y Unaffected. Not tested for GCG expansion
76y. Narrow palpebral fissures. No GCG expansion
67y. Unilateral left ptosis. No GCG expansion
Fig. 3. Family pedigree.
aunt, but with the ptosis only developing following surgery for cataract, performed on one eye at age 85 years and on the other eye at 95 years. The aunt also now had right abducens palsy, giving double vision on right lateral gaze. There was no associated swallowing difficulty, although palatal movement seemed poor. The elder cousin, aged 73 years, also had narrow palpebral fissures, but no definite ptosis. The younger cousin, aged 67 years, did have a 5-year history of unilateral (left) ptosis, but associated with unequal pupils; that of the left eye being relatively dilated and hypo-reactive, and with a history of injury to the left orbital region at age 17 years. DNA testing showed the aunt to be heterozygous for the single GCG trinucleotide expansion, but both the cousins showed only normal sized alleles. 3. Discussion Both patients A and B were found to have the rare recessive form of OPMD caused by homozygosity for a small expansion of one repeat in the polyalanine codon repeat sequence in the PABPN1 gene [1]. For patient A the clinical picture was complicated by the presence of ankylosing spondilitis and pneumonia and in retrospect it is likely that he had recurrent aspiration pneumonia secondary to his oropharyngeal incoordination. However, both patient A and B reported onset of OPMD symptoms in the 7th decade of life, and therefore appear to have a later onset than is the case for typical dominant OPMD which usually becomes apparent
in the 5th or 6th decade of life [1,2]. The only other published case of recessive OPMD of which we are aware is that of Brais et al. [1] which specified that the disease was of later onset but gave no clinical details. Symptoms also appear to be milder for the two cases presented here with patient A exhibiting only ptosis and dysphagia, but no muscle weakness, and patient B only having ptosis. There is a paucity of cases of recessive OPMD in the literature; however, Brais et al. [1] estimated that relatively high proportions (2%) of the normal French Canadian population are heterozygous for the recessive allele. We would therefore expect a incidence of 1 in 10,000 and expect some cases to be reported from this population. However, the estimate of 2% was made from analysis of a cohort of only 86 normal control individuals and therefore has a high margin of error [1], although a 1–2% carrier rate has also been quoted for France, North America and Japan [2]. The paucity may also be because of the milder expression and later onset of the disease, such that cases only present in old age and the diagnosis may be masked or confounded by symptoms of other diseases of the elderly, as is the case in patient A. Furthermore, we estimate that the incidence of the recessive allele in the UK is lower than that of the French Canadian population as we have found no cases of heterozygosity for the recessive allele in 200 control samples. Heterozygotes in the Canadian study were asymptomatic, but the upper age limit of these is not available [1]. The reported history of ptosis in the mother of A and B, and the occurrence of this in the 99-year-old
S. Hebbar et al. / Neuromuscular Disorders 17 (2007) 254–257
aunt, raises the question of whether carriers of a single triplet repeat expansion in the PABPN1 gene may manifest an extreme late onset of symptoms and that this mutation is not truly recessive as suggested by Brais et al. [1]. Unfortunately this remains uncertain, as the ptosis in the aunt here developed only following cataract surgery, and is associated with external rectus palsy, which would not commonly be a feature in OPMD. The coincidence of possible post-traumatic ptosis in one of her daughters, and of narrow palpebral fissures in the other, neither of whom inherited the expanded PABPN1 allele, only serves to urge caution in the interpretation of unverified family history, emphasizing also that ptosis in later life is probably not particularly rare. In conclusion, not only does case A illustrate the importance of considering a neurological cause for recurrent right sided pneumonia, but both cases A and B add to the very sparse literature on recessive OPMD and are consistent with the finding of Brais et al. [1] that symptoms are milder and of later onset than is the case for typical dominantly inherited OPMD.
257
Acknowledgements The authors thank the clinicians who contributed to the clinical analysis of these patients and the patients themselves.
References [1] Brais B, Bouchard JP, Xie YG, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998;18:164–7. [2] Brais B. Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 2003;100:252–60. [3] Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, Hammans SR. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 2001;124(3):522–6. [4] Robinson DO, Hammans SR, Read SP, Sillibourne J. Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet 2005;116(4):267–71.