Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.310067
Source of Support: None, Conflict of Interest: None
Keywords: Blepharoptosis, congenital, mitochondrial, myopathy, myotonic dystrophy, oculopharyngeal
Blepharoptosis (abbreviated ptosis) describes the drop of the upper eyelid, partly or entirely covering pupil. Based on etiology, ptosis is classified into mechanical, cerebral, neurogenic, neuromuscular, myogenic and due to miscellaneous causes.,In our neuromuscular unit, we encounter patients with ptosis suffering from a muscular disorder extensively investigated to exclude various causes of ptosis.
As many physicians are not familiar with the fact that ptosis may be a sign of a myopathy, we present four illustrative cases with different genetically confirmed muscle diseases that can be associated with ptosis and discussthe relevant diagnosis.
We present four patients diagnosed with a primary muscular disorder who showed ptosis in their initial clinical picture. Patients were clinically examined upon admission and had undergone electrophysiological assessment, laboratory tests, muscle biopsy if appropriate, and genetic studies. All patients presented in this study had given their written, informed consent.
A 39-year-old woman presented with a history of bilateral asymmetric ptosis and permanent left and up gaze diplopia, aggravated by fatigue, for the last year. Family history was unremarkable for ptosis or any neuromuscular disease. Imaging studies, including cerebral MRI and MRA, and AchR antibody status, were normal. She reported that a short course of cholinesterase inhibitors yielded no improvement. Examination revealed asymmetric ptosis more severe on the right, increasing upon sustained up gaze [Figure 1]a and [Figure 1]b, and ophthalmoparesis in all fields of gaze. Laboratory evaluation only showed increased lactate levels (38.5 pg/mL, normal <19.8 pg/mL). Electrophysiological testing, including single fiber EMG and repetitive nerve stimulation, revealed short amplitude potentials in examined muscles. Left biceps muscle biopsy showed numerous ragged-red and cytochrome oxidase negative fibers [Figure 1]c. Genetic testing in muscle revealed a single large-scale deletion of mtDNA confirming the diagnosis of mitochondrial myopathy.
A muscle biopsy from a 52-year-old man was addressed for evaluation. According to the referring letter the patient presented slowly progressive, non-fluctuating, ptosis for the last year with no other symptoms or family history of neuromuscular disease. He had elevated creatine phosphokinase (CPK) levels (1000 U/L, normal <200 U/L), electromyography showed a myopathic pattern and the biopsy revealed myopathic changes with few rimmed vacuoles [Figure 1]d. The patient was addressed for further evaluation. Examination showed asymmetric ptosis [Figure 1]e and mild proximal weakness (4/5 according to the Medical Research Council (MRC) scale) involving psoas and deltoid muscles. A thorough review of the patient's personal and family history revealed mild dysphagia over the last 5 years, which was also present in his mother and maternal grandmother at an advanced age. The association of ptosis with mild dysphagia, the presence of rimmed vacuoles in the muscle biopsy, and the positive dominant family history, prompteda search for a GCG expansion in exon 1 of the PABPN1 gene. The patient carried an allele with 11 repeats confirming the diagnosis of oculopharyngeal muscular dystrophy (OPMD).
A 46-year-old man presented with bilateral, non-fluctuating, slowly progressive ptosis since his early twenties. Examination revealed bilateral ptosis, right eye exotropia [Figure 1]f and mild weakness of neck flexion, and ankle dorsiflexion. Frontal balding, temporal wasting, and percussion myotonia were also evident. He reported that his sister and father presented walking difficulties. Electromyography revealed myopathic potentials and myotonic runs in distal muscles. Genetic testing showed an expansion of 150 CTG trinucleotide repeats in the non coding region of the DMPK gene, confirming the diagnosis of myotonic dystrophy type 1 (DM1).
A 42-year-old man presented with ptosis since childhood, progressively aggravated over the last few years. He had no family history of neuromuscular disease and he reported delayed motor milestones, with autonomous walking achieved at 30 months of age, difficulties in running, climbing stairs, and getting up from the floor since childhood. On examination, he presented bilateral, symmetrical, eyelid ptosis, and limitation of horizontal eye movements a long narrow face and high arched palate. He showed mild proximal weakness, involving deltoid, pectoralis muscles, and psoas muscles (graded 4, 3+/5and 3+/5 at the MRC scale, respectively). Adeltoid muscle biopsy showed type 1 muscle fiber atrophy and central nuclei in approximately 80% of fibers, raising the suspicion of centronuclear myopathy. Genetic testing revealed two heterozygous RYR1 gene mutations: c.1250T>C (p.Leu417Pro) within exon 13 and c.5815-16G>A within intron 1.
All patients' characteristics are summarized in [Table 1].
Myopathies are rare causes of ptosis and patients sometimes reach the correct diagnosis after a diagnostic Odyssey. Ptosis is often the manifestation leading to medical consultation and additional symptoms and signs of an underlying myopathy are frequently overlooked by physicians and not reported by patients unless specifically asked for. Nevertheless, a muscular disorder could have been suspected if the family history, clinical, and laboratory examination were appropriately evaluated.
The first case illustrates a woman with ptosis and mitochondrial myopathy due to a single large scale deletion of mtDNA. Ptosis in mitochondrial diseases is usually slowly progressive and appears in the context of chronic progressive external ophthalmoplegia (CPEO). It can also be associated with systemic features of mitochondrial dysfunction (CPEO plus). When accompanied by a non-fluctuating ophthalmoparesis a mitochondrial myopathy is considered in the differential diagnosis. As sometimes ptosis can precede ophthalmoparesis by months or even years, differentiating it from other diseases, notably myasthenia gravis can be difficult. Traditionally, PEO is clinically distinguished from ocular myasthenia gravis (oMG) by the absence of diplopia and the lack of aggravation by fatigue. However, 28% to 62.5% of PEO patients demonstrate diplopia,, while sometimes, eyelid ptosis is aggravated by fatigue and/or patients report a feeling of generalized exhaustion. Differentiating PEO from oMG is further complicated by the occasional presence of abnormal jitter in single-fiber EMG. In such cases, a lack of response to cholinesterase inhibitors and/or a negative ice-peak test, should alert for an alternative diagnosis. High blood lactate levels point towards a mitochondriopathy. When a mitochondrial disorder is considered, a muscle biopsy should be performed to illustrate the pathological hallmarks of the disease, the presence of ragged-red, and cytochrome oxidase negative fibers. Nevertheless, in PEO, muscle biopsy exhibits a relatively low sensitivity for revealing mitochondrial abnormalities and in case of high clinical suspicion, genetic testing should be undertaken, usually in muscle. In most cases, the underlying genetic cause is a sporadic large scale mtDNA deletion ranging in size from 1.1 to 10 kb, usually a de novo event occurring in the oocyte or during embryogenesis, with a low chance of transmission., Some patients with familial PEO will show multiple mtDNA deletions due to mutations in genes involved in mtDNA maintenance [Table 2],, or maternally inherited mtDNA mutations.
The second patient suffered from oculopharyngeal muscular dystrophy (OPMD), an autosomal dominant disorder characterized by slowly progressive ptosis, dysphagia, and proximal weakness. Ptosis in OPMD is bilateral and even asymmetric at the early stages. The mean age of onset for ptosis is 48 years and usually precedes the appearance of dysphagia. The underlying genetic defect is a short GCG expansion in the PABPN1 gene., Ptosis associated with dysphagia and an autosomal dominant trait of inheritance is suggestive of this disease. The failure to recognize the mode of inheritance and the absence of dysphagia, as in our case, may delay the correct diagnosis. In such instances, a muscle biopsy is helpful, showing a dystrophic process with rimmed vacuoles, while electron microscopy can reveal the presence of intranuclear tubular filaments. Although classically considered a late-onset disorder, heterozygous, compound heterozygous, and homozygous for GCN repeats patients, with the disease of variable age of onset and severity and correlating with repeat size have been reported. The disease should be suspected in cases of familial ptosis, especially when associated with dysphagia or if there are characteristic findings in the muscle biopsy.
The third patient suffers from myotonic dystrophy type 1, the commonest inherited neuromuscular disorder in adults, due to a CTG expansion of more than 50 repeats in the DMPKgene. DM1 is a frequent cause of myogenic ptosis only second to mitochondrial myopathies in a retrospective study. Ptosis can be associated with symptoms resembling mitochondrial PEO such as limited extraocular motility and orbicularis oculi weakness, although the latter is usually more important in DM1. Systemic and characteristic clinical features suggestive of DM1 warrant appropriate genetic testing. Early diagnosis is important not only for genetic counseling but also for preventing disease complications.
The last patient suffers from a congenital myopathy due to recessive RYR1 gene mutations. Congenital myopathies are heterogeneous diseases, with typically early-onset weakness and characteristic histopathological features on muscle biopsy. Patients usually present with hypotonia since birth or during the first year of life, delayed motor milestones and muscle weakness. Facial weakness associated with ptosis and sometimes ophthalmoplegia is common. Various subtypes, usually those related to MTM1, BIN1, DNM2, TPM2, TPM3, and RYR1 mutations, can be complicated by myasthenic features such as impaired neuromuscular transmission on electrophysiologic studies and a positive response to anticholinesterase therapy. RYR1 related disorders may present with subtle features since childhood and remain unrecognized until adulthood. Patients can present with features ranging from muscle weakness to asymptomatic hyperCKemia or exercise-induced rhabdomyolys is and ptosis sometimes associated with ophthalmopares is can be part of the clinical spectrum. Ptosis without muscle weakness has also been reported to various adult-onset centro nuclear myopathies.,
In conclusion, myogenic causes, although rare, should be considered in the differential diagnosis of ptosis. Lack of clear-cut aggravation of symptoms by fatigue, no response to cholinesterase inhibitors, presence of limb or extraocular muscle weakness, positive family history, and evidence of a multisystemic disorder prompt for appropriate evaluation for a myopathic disorder.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]