CASE OF THE MONTH ABSTRACT: Oculopharyngeal muscular dystrophy (OPMD) is usuallytransmitted as an autosomal-dominant trait and characterized by an expan-sion from 6 to 8 or more GCG/GCA repeats in the poly-(A) binding proteinnuclear 1 (PABPN1) gene on chromosome 14q11. Autosomal-recessiveOPMD with a homozygous (GCG)7 expansion of PABPN1 has only beendescribed in two Canadian patients, who showed a comparably mild phe-notype, suggesting that it is less severe than the dominant form. We clini-cally and genetically characterized the first two reported cases of autosomal-recessive OPMD in Europe. Remarkably, both patients revealed severe anddiverse phenotypes, with an unusual onset and atypical clinical course inone patient. Former studies found a 1%–2% frequency of the (GCG)7 allele,which theoretically produces an incidence of 1:10,000 of autosomal-reces-sive OPMD in the general population. We conclude that the apparent rarityof the autosomal-recessive form of OPMD may be due to the fact thatgenetic testing is generally administered only to patients with typical clinicalfeatures or a positive family history.

Muscle Nerve 35: 681–684, 2007

VARIABILITY OF THE RECESSIVE OCULOPHARYNGEALMUSCULAR DYSTROPHY PHENOTYPE

ALEXANDER SEMMLER, MD,1 WOLFRAM KRESS, PhD,2 STEFAN VIELHABER, MD,3

ROLF SCHRODER, MD,4 and CORNELIA KORNBLUM, MD1

1 Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany2 Department of Human Genetics, University Hospital Wuerzburg, Wuerzburg, Germany3 Department of Neurology II, University Hospital Magdeburg, Magdeburg, Germany4 Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany

Accepted 12 November 2006

Oculopharyngeal muscular dystrophy (OPMD,OMIM 164300) is a late-onset inherited polyalaninedisorder that usually begins in the fifth or sixthdecade with progressive ptosis and dysphagia. Occa-sionally, proximal limb-muscle weakness occurs inthe course of the disease. OPMD usually follows anautosomal-dominant mode of inheritance and iscaused by expansions of a GCG-trinucleotide repeatin the coding region of the poly-(A) binding proteinnuclear 1 gene (PABPN1) on chromosome 14q11.3

The presence of mutant poly-(A) binding proteinnuclear 1 (PABPN1)–containing intranuclear inclu-sions (INI) is unique in autosomal-dominant OPMDand is also observed in transgenic mouse and cellmodels.13 In unaffected individuals the wildtype

(GCG)6 repeat stretch encodes for the first six ala-nines in a homopolymeric stretch of 10 alanines. Inindividuals with OPMD the (GCG)6 repeat is ex-panded to (GCG/GCA)8–13 in the first exon of thegene and translated in a stretch of 12–17 alanines inthe N-terminal domain of mutant PABPN1.3,10 The(GCG)7 polymorphism in the PABPN1 gene has a1%–2% prevalence in North America, Europe, andJapan.4 This (GCG)7 allele has no effect on pheno-type in the heterozygous state.3 In compound het-erozygotes carrying one expanded dominant (GCG/GCA)8–13 allele and one (GCG)7 allele, (GCG)7 actsas a modifier and leads to a more severe phenotype.3

The only two genetically proven recessive OPMDcases to date were Canadians of French-Canadianand Anglo-Saxon descent and were homozygous car-riers of two (GCG)7 PABPN1 alleles. Both patientspresented with a mild late-onset phenotype as com-pared to the dominant form.3,12

CASE REPORTS

Patient 1. A 61-year-old German woman with a 10-year history of swallowing difficulties and a 1-yearhistory of progressive bilateral ptosis presented at

Abbreviations: INI, intranuclear inclusions; MRC, Medical Research Council;OPMD, oculopharyngeal muscular dystrophy; PCR, polymerase chain reac-tion; PABPN1, poly-(A) binding protein nuclear 1Key words: oculopharyngeal muscular dystrophy; phenotype; genotype;gene dosageCorrespondence to: A. Semmler; e-mail: alexander.semmler@ukb.uni-bonn.de

© 2007 Wiley Periodicals, Inc.Published online 5 January 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20726

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our neurological outpatient department for diagnos-tic evaluation. The patient also reported exercise-induced proximal limb weakness starting a fewmonths before presentation. There was no familyhistory of neuromuscular disorders (parents, foursiblings, six children, and six grandchildren). Physi-cal examination showed bilateral ptosis severely re-stricting the visual fields. There was no external oph-thalmoplegia. Evaluation of skeletal muscle strengthshowed mild head-flexion weakness, graded as 4�on the Medical Research Council scale (MRC)6 aswell as a symmetric weakness of shoulder and hip-girdle muscles (MRC 4� to 4), especially limitingthe patient when lifting heavy weights, climbingstairs, or standing up from a seated position. Therewas no weakness of distal muscle groups and nomuscle wasting. Deep tendon reflexes were normaland the plantar responses were flexor. Sensation wasnormal. Swallowing was lengthy, and the time re-quired to drink an 80-ml glass of ice-cold water ac-cording to the clinical diagnostic criteria and swal-lowing test proposed by Brais et al.2 was 45 s.

Patient 2. A 79-year-old man presented for diagnos-tic evaluation. He had a more than 20-year history ofprogressive limb-girdle muscle weakness and a 5-yearhistory of bilateral ptosis and dysphagia. Hip-girdlemuscles were affected first, followed by shoulder-girdle and lower-limb muscles. The patient was seri-ously handicapped at presentation and had beenwheelchair-bound for 4 years. There was no familyhistory of neuromuscular disorders (parents, onesibling, two children). Physical examination showedbilateral ptosis without restriction of visual fields.Upper gaze was limited without further signs of ex-ternal ophthalmoplegia. Evaluation of skeletal mus-cle strength excluded weakness of facial muscles orhead flexion weakness. He had symmetric weaknessof the shoulder- and hip-girdle muscles (MRC 2 to 3)together with distinct muscle wasting but no scapularwinging. Furthermore, there was a less pronouncedweakness of distal muscles of the upper and lowerextremities (MRC 3 to 4). The patient was able tostand for a short time with help and could walk threesteps. The arms could not be raised over the head.Deep tendon reflexes were diminished and the plan-tar responses were flexor. Sensation was intact. Thetime required to drink an 80-ml glass of ice-coldwater was 75 s.

With both patients physical examination was per-formed by two independent neurologists to ensurereliability of phenotype description. The history ofprogressive ptosis was confirmed by assessing serialpictures of both patients. The patients were of Ger-

man descent and had no known French-Canadian orother non-German ancestors. Laboratory testing, in-cluding serum creatine kinase levels, acetylcholinereceptor autoantibodies, and thyroid function tests,was normal. Electromyography in proximal muscles(one deltoid and one vastus lateralis muscle in eachpatient) showed fibrillation potentials and complexrepetitive discharges in both patients. The motorunit potentials were normal in patient 1, but of lowamplitude in patient 2. We additionally performednerve conduction studies (one median, ulnar, pero-neal, tibial, and sural nerve in each patient) andrepetitive nerve stimulation (accessory and facialnerve) as well as fiberoptic evaluation of swallowing(FEES) and videofluoroscopy in patient 1, whichwere unremarkable except for the finding of a mildcricopharyngeal achalasia.

Standard genetic testing using a polymerasechain reaction (PCR) method to size amplificationproducts suggested a homozygous (GCG)7 expan-sion in the first exon of PABPN1 (Fig. 1) in bothpatients. Sequencing of the first exon of PABPN1 ofpatient 1 showed a (GCG)7 expansion on one alleleand a (GCG)6/(GCA)1 expansion in the other copyof the PABPN1 gene (Fig. 2). Sequencing of the firstexon of PABPN1 of patient 2 showed a homozygous(GCG)7 expansion (sequence not shown). Openskeletal muscle biopsy of vastus lateralis in patient 1did not yield sufficient muscle tissue for further his-topathological or ultrastructural examination. Pa-tient 2 decided against open skeletal muscle biopsy.

DISCUSSION

We are not aware of previous phenotypic and ge-netic characterizations of autosomal-recessiveOPMD in Europe. Surprisingly, the symptoms of ourpatients were not as mild as expected from previousreports on autosomal-recessive OPMD, and the dis-eases did not manifest substantially late in life.3,12

Even more interesting, the phenotypes of the twopatients were remarkably different in comparison toone another and also in comparison to the typicalphenotype of autosomal-dominant OPMD in thecase of patient 2. In patient 1, major clinical symp-toms and age at disease onset did not discriminateagainst the phenotype of autosomal-dominantOPMD. However, swallowing difficulties were re-markable and the swallowing time needed to drinkan 80-ml glass of ice-cold water was 45 s, which issignificantly longer than the time required by mostof the age-matched carriers of only one (GCG)9 copyin a previous study on autosomal-dominant OPMD.3

In patient 2, age-related impairments might have

682 Recessive OPMD MUSCLE & NERVE May 2007

obscured phenotype severity grading. However, thephenotype differed substantially from the classicautosomal-dominant form. The patient presentedwith a long-standing history of proximal limb weak-ness without any oculopharyngeal symptoms, pri-marily suggesting limb-girdle muscular dystrophyand being unusual for autosomal-dominant OPMD.

The finding that the most severe phenotypes arereported for individuals homozygous for a dominant(GCG)8–13 expansion or for compound heterozy-gotes carrying one dominant and one recessive mu-

tation is compatible with a gene-dosage effect inautosomal-dominant OPMD.1,3,5,7 The (GCG)7 poly-morphism obviously either acts as a disease modifierin dominant OPMD or leads to autosomal-recessiveOMPD in the homozygous state. Disease severity andthe marked difference of clinical symptoms and dis-ease course of our patients suggest that other geneticor environmental factors may be modulators of dis-ease expression.

According to previously published data, autoso-mal-recessive OPMD seems to be extremely rare.3,4,8

This is surprising, as 2% of the French-Canadianpopulation carries a (GCG)7 allele,3 and a 1%–2%carrier prevalence has been estimated in NorthAmerica, Europe, and Japan.4 Theoretically, thisshould cause an incidence of 1:10,000 for the auto-somal-recessive form of the disorder in these popu-lations, and autosomal-recessive OPMD should bedetected easily by routine genetic testing if present.The discrepancy between observed and expectedpatient numbers suggests that autosomal-recessiveOPMD may be underdiagnosed. This may have dif-ferent reasons: the phenotype could differ signifi-cantly from autosomal-dominant OPMD or the phe-notype could be too mild and manifest too late in lifeto be clinically evident; either of these reasons wouldimpede genetic analysis. Interestingly, our autosomal-recessive OPMD patients both showed comparablysevere clinical symptoms. However, patient 2 pre-sented with a disease course that was not suggestive

FIGURE 1. After standard isolation of DNA from an EDTA bloodsample, fragments of the first exon of the PABPN1 gene wereamplified using radiolabeled P32-dCTP and separated beside aladder of fragments from patients with known expansions on asequencing gel. Allelic sizes are given below the lanes; the lanemarked with an arrow suggests a homozygous (GCG)7 expan-sion in the reported patients (data of patient 1 are shown).

FIGURE 2. Sequence of the GCG repeat stretch in the first exon of the PABPN1 gene of patient 1. The arrow depicts the single nucleotidepolymorphism in the seventh repeated triplet. Sequencing reaction was performed as described previously11 using a Beckman sequencerCEQ 8000.

Recessive OPMD MUSCLE & NERVE May 2007 683

of autosomal-dominant OPMD. We conclude thatindications for genetic analysis may be too rigorousin patients with “classic” symptoms but a negativefamily history or in patients with atypical symptoms,thus leading to substantial underdiagnosis of theautosomal-recessive form of the disorder. We suggestthat OPMD should be considered even in clinicallyatypical cases, and all patients with a combination ofdysphagia and ptosis past the age of 50 should begenetically tested despite the absence of a familyhistory.

Interestingly, sequencing of PABPN1 showed a(GCG)7 expansion on one allele and a (GCG)6/(GCA)1 expansion on the other allele in patient 1,whereas patient 2 showed a (GCG)7 expansion onboth alleles. Originally, the extra triplet repeats inOPMD were described as pure GCG. However, re-cent studies have identified various GCA intersper-sions within the expanded GCG sequence in autoso-mal-dominant OPMD.8–10 Genetic heterogeneity wasshown in German autosomal-dominant OPMD pa-tients, indicating that there is no single founder ofOPMD within the German population.8 Our findingshows that trinucleotide repeat expansions can beheterogeneous even in the autosomal-recessive formof the disorder. Moreover, like other non-GCG elon-gations the (GCG)6/(GCA)1 genotype of our patientmay be explained by unequal crossing-over duringgerm cell homologous recombination rather than byreplication slippage as probable mutational mecha-nism.3,8–10 Additionally, our finding of two differentalleles confirms that there was no consanguinity inthe genealogy of patient 1. The repeat heterogene-ity, however, should not contribute to phenotypicvariations in OPMD, as GCA and GCG repeats aretranslated into the same amino acid, alanine.

It would be of interest to study specimens ofautosomal-recessive OPMD for formation of intranu-clear inclusions (INIs) or to perform in vitro cellculture studies for a better understanding of geno-type–phenotype correlations in this polyalanine dis-ease. Unfortunately, further studies on skeletal mus-cle tissue could not be performed due to the above-mentioned reasons. In autosomal-dominant OPMD,different models of polyalanine toxic gain-of-func-tion pathogenesis were proposed comprising INI-dependent and -independent mechanisms.4 How-

ever, the precise pathophysiological mechanismsleading to skeletal muscle damage and to the phe-notype of OPMD in the autosomal-dominant andautosomal-recessive form remain to be clarified.

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11. Schober R, Kress W, Grahmann F, Kellermann S, Baum P,Gunzel S, et al. Unusual triplet expansion associated withneurogenic changes in a family with oculopharyngeal muscu-lar dystrophy. Neuropathology 2001;21:45–52.

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