Clinical Reasoning: Bilateral ptosis, dysphagia, and progressive weakness in a patient of French-Canadian background

Section 1

A 40-year-old man presented with slowly progressive weakness and eyelid droopiness. His symptoms began in his early 30s as increased fatigue with exertion. In his mid 30s, he developed droopy eyelids without double vision. About 3 years before presentation, he started having progressive difficulty swallowing, initially with solid food but later with both solid and liquid consistencies. He also reported the food getting stuck in his throat. He had been treated for aspiration pneumonia once. A year later, he noticed slowly progressive limb weakness affecting his hands and proximal lower limbs, described as difficulty holding a tablet at church, frequently dropping objects from his hands, and difficulty with standing up from a seated position. More recently, he started experiencing dyspnea on exertion and mild orthopnea. He occasionally experienced blurry vision without diplopia, mild head drop, and hoarseness of voice, mainly towards the end of the day or when he was tired. He was diagnosed with seronegative myasthenia gravis at a local facility, with negative acetylcholine receptor, muscle-specific kinase, and low-density lipoprotein receptor-related protein 4 antibodies. His medical and social history were otherwise unremarkable. The patient's father was French Canadian. The patient also had Native American and African American ancestry. There was no family history of myopathy or any neuromuscular disorder. Neurologic examination was significant for moderate bilateral ptosis, bilateral ophthalmoparesis with limited upward gaze and to a lesser extent horizontal gaze (both eye abduction and adduction), mild weakness of both upper and lower facial muscles, moderate weakness of the proximal lower extremities most prominent at the hip abductors (Medical Research Council [MRC] grade 3 to 4-/5), and mild (MRC grade 4) weakness of finger extensors and intrinsic hand muscles. He had no demonstrable fatigable weakness on examination in any of the affected muscles. He had a mildly waddling gait and absent ankle jerks bilaterally. Sensory and coordination evaluations were unremarkable.

Section 2

The pattern of weakness manifesting with bilateral symmetric distal upper and proximal lower limb weakness, without any upper motor neuron signs, and the presence of marked bilateral ptosis would be unusual for a CNS etiology and indicates a peripheral nervous system disorder. While any defect along the motor pathways can result in dysphagia and dyspnea, especially at advanced stages, the predominant ptosis and extraocular muscle involvement are more suggestive of a neuromuscular transmission defect or a myopathy, rather than a motor neuropathy or neuronopathy. With no evidence of demonstrable fatigability on examination, the patient-reported fluctuation of the weakness with diurnal variation is not necessarily specific for a neuromuscular transmission defect, and hence a myopathy should be considered. Furthermore, patients with myopathy can have a component of muscle fatigue. It is noteworthy that the presence of ophthalmoparesis without diplopia would be unusual for myasthenia gravis, and is more likely to be due to a slowly developing process such as a hereditary myopathy. The slow progression rate and the clinical phenotype with ptosis and ophthalmoparesis would make an acquired myopathy, such as an inflammatory myopathy, less likely.

To further refine the localization, electrodiagnostic testing was performed. Upper and lower limbs and sensory and motor nerve conduction studies were normal except for a borderline low sural sensory nerve action potential amplitude of 6 µV (normal >6 µV). Two-Hz repetitive nerve stimulation of the facial, spinal accessory, and ulnar nerves, at rest and after exercise, were normal. Needle EMG showed early recruitment of short duration, low-amplitude motor unit potentials, often with increased phases and turns, in proximal and distal, upper, and lower limb muscles as well as in cranial muscles. Fibrillation potentials were present in cranial muscles, proximal upper limb muscles, and tibialis anterior. These electrodiagnostic findings were consistent with a myopathic process.

Laboratory workup was remarkable for an elevated creatine kinase of 550 (normal 52–336 U/L). Blood tests including liver function, renal function, thyroid-stimulating hormone, and lactate level were normal. Myositis autoantibody panel and acetylcholine receptor binding antibodies were normal as well. A video swallow study showed moderate oropharyngeal dysphagia with marked prominence of the cricopharyngeus muscle (figure 1). Pulmonary function tests showed a normal vital capacity, but a decreased maximal expiratory pressure. Overnight oximetry showed evidence of mild sleep-related disordered breathing.

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Figure 1 Barium video-swallow evaluation

Barium video-swallow showing significant prominence of the cricopharyngeus, which covers well over half of the luminal diameter (left), markedly improved after cricopharyngeal myotomy (right).

Section 3

The electrodiagnostic testing confirmed the presence of a myopathy. The slowly progressive clinical course is suggestive of a hereditary myopathy. With the absence of other affected family members, the mode of inheritance remains unclear. While the pattern of weakness predominantly affecting hip girdle muscle can be seen with a wide spectrum of hereditary myopathies, the marked ptosis and ophthalmoparesis help narrow down the differential diagnosis to include oculopharyngeal muscular dystrophy (OPMD), mitochondrial myopathy, or a congenital myopathy.¹ Among the congenital myopathies, RYR1-related myopathy can have prominent ptosis with or without ophthalmoplegia.^2,3 In its classical form, RYR1-related myopathy is usually associated with central core disease on muscle histopathology and is inherited in an autosomal dominant pattern. However, autosomal recessive forms, which can be associated with multiminicore disease or centronuclear myohistopathology, can have more prominent ptosis. Interestingly, mutations in other genes associated with a centronuclear myopathy, such as MTM and DNM2, and congenital fiber type disproportion or a cap myopathy such as TPM2 or TPM3, can also cause a myopathy with neuromuscular transmission defect, associated with prominent ptosis with or without ophthalmoparesis.^4,–,6 On the other hand, marked ptosis is relatively common in congenital myasthenic syndromes, and the presence of a myopathy with fibrillation potentials does not rule out such conditions, as many of the genes such as ALG2, ALG14, DPAGT1, GMPPB, PLEC, and GFPT1 can cause both a myasthenic syndrome and a myopathy.⁷ Furthermore, congenital myasthenic syndromes can rarely present with normal repetitive nerve stimulation. Based on the clinical phenotype with the prominent dysphagia and the markedly prominent cricopharyngeus muscle, in a patient of French Canadian–Native American background, we had strong suspicion for OPMD. Subsequently, the patient was tested for this condition but had no GCN repeat expansions in the polyadenine binding protein nuclear (PABPN1) gene.

Section 4

OPMD is an autosomal dominant condition secondary to expansion of a GCN trinucleotide repeat in exon 1 of the PABPN1 gene. However, point mutations have also been reported and had to be ruled out.⁸ Therefore, sequencing of the PABPN1 gene was performed in our patient but showed no mutations. At this point, we decided to pursue a left gluteus medius muscle biopsy to guide further genetic testing. It showed frequent ragged-red, ragged-blue, and cytochrome C oxidase–negative fibers with rare atrophic and regenerating fibers indicating a mitochondrial myopathy (figure 2). Subsequently, we performed mitochondrial genome analysis on the muscle specimen, which was normal with no mutations or deletions. Thereafter, we obtained a mitochondrial nuclear gene panel, which showed 2 mutations in polymerase γ (POLG): (1) p.Arg1096His (c.3287G>A), an established pathogenic mutation; and (2) p.Arg953Cys (c.2857C>T), a likely pathogenic mutation. The patient's asymptomatic mother and brother both were tested and carried the p.Arg1096His mutation, indicating that the 2 mutations were heteroallelic.

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Figure 2 Muscle biopsy findings

Left gluteus medius muscle biopsy. (A) Modified Gomori trichrome–stained section showing scattered ragged-red fibers, most prominent in the fibers indicated by a star. (B) Cytochrome C oxidase–stained section showing multiple fibers (stars) with absent enzyme reactivity (cytochrome C oxidase–negative fibers).