Delayed diagnosis of oculopharyngeal muscular dystrophy in Scotland
- Pankaj Kumar Agarwal1,
- David C Mansfield1,
- Dorothy Mechan2,
- Rustam Al-Shahi Salman3,
- Richard J Davenport3,
- Myles Connor4,
- Richard Metcalfe5,
- Richard Petty5
- 1Department of Ophthalmology, Inverclyde Royal Hospital, Greenock, UK
- 2East of Scotland Regional Genetic Service, Ninewells Hospital, Dundee, UK
- 3Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK
- 4Department of Neurology, Queen Margaret Hospital, Dunfermline, UK
- 5Department of Neurology, Institute of Neurological Sciences, Glasgow, UK
- Correspondence to Dr Pankaj Kumar Agarwal, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh EH3 9HA, UK;
- Accepted 15 April 2011
- Published Online First 20 May 2011
Introduction Oculopharyngeal muscular dystrophy (OPMD) presents with progressive ptosis, dysphagia and limb girdle weakness, and is caused by expansion of a trinucleotide tandem repeat within the gene encoding poly-(A) binding protein 2.
Aim To review the clinical manifestations of all genetically confirmed patients with OPMD in Scotland identified since 2002, and to estimate the delay between symptom onset and diagnosis.
Method Retrospective case note review.
Results The authors identified 17 patients. The commonest first symptom was ptosis at about the age of 60 years. Three to 20 years elapsed from the onset of ptosis to OPMD diagnosis. In 14 (82%) patients, dysphagia had developed by the time of diagnosis, and four (24%) out of these 14 patients with dysphagia had undergone a decade of investigation and treatment for pharyngeal problems. Thirteen patients (77%) also had symptoms of limb girdle muscle weakness. Every patient had a first-degree relative with ptosis.
Conclusions OPMD could have been diagnosed earlier in every patient in this case series. Greater awareness of OPMD among ophthalmologists, gastroenterologists and otolaryngologists may lead to earlier diagnosis, improved management and avoidance of unnecessary investigations.
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder (OPMD; MIM no 164300) caused by expansion of a trinucleotide repeat within the gene encoding poly-(A) binding protein 2(PABP2).1
The highest known prevalence of OPMD is among French Canadians.2 The phenotype has been documented in 144 families occurring in that population. The next largest clusters of cases are Bukhara Jew immigrants in Israel3 and Hispanic New Mexicans.4 Smaller series with a similar clinical spectrum have been reported in Caucasians in the South of England.5 Inheritance of OPMD is almost always autosomal dominant.6
In 1998, Brais and colleague identified the repeat expansion in French Canadian population,2 and over 99% of patients carry the pathogenic PABP2 triplet repeat expansion.7 Thus, a single blood test provides a quick and simple diagnostic test for almost all with OPMD.
The features of OPMD include progressive ptosis, dysphagia and weakness of proximal limb muscles. The ptosis is symmetrical and sometimes severe, and may be associated with variable generalised restriction of ocular movements. Dysphagia may cause weight loss, malnutrition or aspiration pneumonia. Weakness of the limb girdle muscles may cause further disability.
Clinical onset is usually in the fifth to sixth decade of life. Earlier onset appears to be characteristic of the genotypes (GCG)7, (GCG)8 and (GCG)6, (GCG)13.8
The probability of the clinical diagnosis being made on the basis of a patient's symptoms has been estimated to be about 15% at age 65, 35% at age 75 and 80% at age 85.9
A delay in the diagnosis may occur because of the insidious onset and very slow progression of symptoms, coupled with a lack of familiarity among doctors. Because ptosis is the first symptom in two-thirds of cases,5 many will present initially to ophthalmologists.
We undertook this retrospective audit to identify all genetically confirmed cases in Scotland, to estimate the delay between symptom onset and diagnosis, and to record the clinical features of the cases.
This was a retrospective case audit. The East of Scotland Regional Genetic Service at Ninewells Hospital in Dundee is the only centre in Scotland performing genetic testing for OPMD. Mutation detection was carried out by electrophoresis of PCR-amplified alleles of the PABP2 gene as described by standard protocol as Brais and Colleagues.2 The Centre provided data regarding the patients and the clinicians who had referred all genetically confirmed cases since testing began in 2002. The relevant clinician was then contacted and invited to contribute data on the patients' symptoms, signs, family history and investigations for a retrospective review using a standardised proforma. All the clinicians (100%) provided the data. The study was registered with the Clinical Effectiveness Office of NHS Greater Glasgow and Clyde Health Board, and deemed not to require consideration by the research ethics committee.
We identified seventeen patients with genetically confirmed OPMD. All but one patient had a pathological (GCG) expansion in the PABP2 gene. The commonest was (GCG)9 in 10 patients. (GCG)11 was detected in three patients, and the alleles (GCG)10, (GCG)12 and (GCG)13 were each detected once. One patient had a different point mutation, which also has the effect of coding for a run of 13 alanine residues.10
Seven (41%) patients were male. The age at diagnosis ranged from 56 to 87 years with a mean of 66 years. All of the patients were Caucasian, and none was known to have French Canadian ancestry.
The first symptom was ptosis in 14 (82%), dysphagia in two patients and proximal muscle weakness in one patient. These symptoms had been documented by a hospital specialist in ophthalmology or gastroenterology between 3 and 20 years before the correct diagnosis (figure 1A). In most cases, the hospital notes recorded patients' recollections that the onset of the first symptom (ptosis) had been approximately 3–20 years before the first hospital appointment (figure 1B).
Ptosis was present at the time of molecular diagnosis in 16 (94%), and had been symptomatic for 3 to 20 years with a median of 7 years. An external ophthalmoplegia occurred in 10 (60%) patients. The number of ophthalmic consultations prior to diagnosis varied from 1 to 11, with a mean of 6. All (100%) the patients had a first-degree relative with ptosis. Six (35%) patients had undergone ptosis correction surgery prior to diagnosis. Five of these six underwent further surgery, usually bilateral brow suspension. Two out of six patients chose non-surgical treatment with ptosis props or Lundi loops.
Four patients (24%) had dysphagia at the time of first consultation. Fourteen (82%) had dysphagia at the time of diagnosis. The number of years of hospital consultations for dysphagia varied from 1 to 25 with a mean of 5 years. Nine (53%) patients had a first-degree relative with dysphagia. Thirteen (93%) out of fourteen patients required some intervention for dysphagia: five (35%) required percutaneous endoscopic gastrostomy tube insertion, and two (14%) underwent cricopharyngeal myotomy.
Nine patients (52%) had dysarthria at diagnosis, but this was reported at onset by only three (17%). None of the patients received treatment prior to diagnosis, but six (35%) received speech therapy subsequently. Only two patients (11%) had a first-degree relative with dysarthria.
Fourteen patients (82%) had proximal limb weakness at the time of diagnosis: this was generally mild and was not severe or disabling for any patient. In seven out of 17 patients for whom further details about proximal muscle weakness were retrieved, arm weakness preceded leg weakness in all seven cases. Nine (53%) out of 17 patients had a first-degree relative with proximal limb weakness. Details about the treatment received could not be retrieved from the notes, but the notes of these seven patients suggest they all had physiotherapy after the diagnosis was confirmed.
This retrospective review of the presentation and progression of OPMD in 17 Scottish patients serves as a reminder to consider the diagnosis when patients present with ptosis or dysphagia. Two clinical aspects of OPMD can assist in making the diagnosis. First, as it has an autosomal dominant pattern of inheritance, patients are often aware of similar symptoms within the family, and thus a family history should always be sought. In several of our cases, the family history was not recognised. Second, the combination of ptosis, dysphagia and proximal weakness differentiates OPMD from isolated ptosis; Specialists must therefore be prepared to ask questions outside their own field (eg, ophthalmologists must ask about swallowing difficulties or weakness, gastroenterologists about ptosis).
Genetic testing for OPMD costs approximately £100 (€145.12), so early testing in suspected cases may avoid the need for further expensive or invasive tests; for example, nine of our cases had investigation and treatment of their dysphagia prior to the correct diagnosis of OPMD. Confirmation also allows for improved management, including genetic counselling.
Surgical correction of ptosis can involve diverse techniques, selected according to factors including obstruction of the sight, maximal voluntary vertical excursion of the lid margin, possible impairment of corneal sensation, anticipated difficulty in lid closure after surgery, preservation of upward rotation of the globe in sleep (‘Bell's phenomenon’) and future progression of the underlying cause. For example, in chronic progressive external ophthalmoplegia, it has been argued that bilateral brow suspension may be preferable to advancement of the aponeurosis of the levator palpebrae superioris,11 and in progressive supranuclear palsy, surgery may be contraindicated. Likewise in OPMD, aponeurosis surgery may be suboptimal. We noted that six patients in this series did have that form of ptosis surgery prior to diagnosis, and five of them needed brow suspension later. We concur with other authors11 that there is scope for a specialist review of surgical outcomes for ptosis in OPMD.
Although not designed as an epidemiological study, these data provide a crude prevalence of OPMD of 3.22 per 100 000 for the Scottish population aged 60–80 years. It is highly likely this underestimates the true prevalence.
Careful history-taking including family history and associated symptoms in older patients with gradually progressive ptosis may help speed up diagnosis and appropriate management.
Presented as a poster at the Annual Conference of The Royal College of Ophthalmologists, 2010.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.