Ptosis as Clinical Presentation in a Patient With Emery-Dreifuss Muscular Dystrophy Type 5

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Ptosis as Clinical Presentation in a Patient With Emery–Dreifuss Muscular Dystrophy Type 5 Konstantinos A. A. Douglas, MD, DVM, Vivian Paraskevi Douglas, MD, DVM, Eric D. Gaier, MD, PhD, Bart K. Chwalisz, MD E mery–Dreifuss muscular dystrophy (EDMD) is a rare and often slowly progressive genetic disorder that primarily affects skeletal muscles and cardiac muscle. Contractures along with joint deformities are also considered early features of the disease (1). Currently, 9 types of EDMD are recognized. The SYNE2 gene, located on chromosome 14q23 codes for a nuclear envelope protein; a heterogeneous mutation in this gene leads to EDMD Type 5 (EDMD5), an adult-onset, autosomal dominant muscular dystrophy (2). However, the disease phenotype is incompletely defined. We report a case of EDMD5 presenting with bilateral ptosis and mild muscular weakness. A 38-year-old right-handed woman presented with a chief complaint of ptosis. She reported slowly progressive painless and nonfluctuating bilateral eyelid ptosis. On further questioning, she recently also started having difficulty in swallowing. She had no dysarthria, dysphonia, dyspnea, or arm weakness but did feel that her legs were weak at the end of the day. Careful review of previous external photographs confirmed a gradual worsening of the ptosis since her twenties (Fig. 1). The patient had no significant medical history. She had immigrated to the United States from mainland Portugal. There was no family history of ocular, neurologic, or neuromuscular disease. The clinical examination showed asymmetric bilateral ptosis (left . right). The upper margin to light reflexes was 2 mm on the right and 0 mm on the left, with a total upper lid excursion of 13.5 mm on the right and 12 mm on the left. She had intact eye movements, and no ocular misalignment. There was mild orbi- cularis oculi weakness and mild neck flexion and extension weakness. In the extremities, there was mild weakness of biceps, triceps, deltoid, infraspinatus, and hip abductor muscles, but distal muscle groups had full strength. Muscle stretch reflexes were present but hypoactive. Sensory examination was normal. Serologic evaluation, including a myasthenia gravis antibody panel with MuSK and LRP4 antibodies, was significant only for increased CK levels (752 units/L). EMG was normal, including single-fiber EMG without abnormal jitter. A muscular dystrophy genetic panel (Medical Neurogenetics, LLC, Atlanta, GA) revealed a heterozygous variant in SYNE2 (Chr14:64676190, c.18434A.G, p.Tyr6145Cys, rs755990889, allele frequency: Department of Ophthalmology (KAAD, VPD, BKC) Massachusetts Eye and Ear Infirmary/Harvard Medical School, NeuroOphthalmology Service, Boston, Massachusetts; Department of Ophthalmology (EDG), Boston Children’s Hospital/Harvard Medical School, Boston, Massachusetts; Department of Brain and Cognitive Sciences (EDG, BKC), Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts; and Department of Neurology (BKC), Massachusetts General Hospital/Harvard Medical School, Boston Massachusetts. E. D. Gaier: NIH K08 EY030164. The authors report no conflicts of interest. K. A. A. Douglas and V. P. Douglas equally contributed to this work. The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Address correspondence to Bart K. Chwalisz, MD, MGH Neurology, WACC 835, 15 Parkman Street, Boston, MA 02114; E-mail: [e-mail] Douglas et al: J Neuro-Ophthalmol 2021; 41: e333-e334 FIG. 1. Gradual worsening of the ptosis was confirmed on review of previous photographs of the patient; (A) 1992, (B) 2005, (C) 2016, and (D) a year before presentation. e333 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Multimodal in silico analysis of SYNE2 missense variant Method Score GERP-RS (NE) 4.22 (5.35) MutationTaster 194 MutPred2 0.44 SIFT ,0.01 PolyPhen-2 0.30 PROVEAN 28.44 Condel* 0.54 CADD (scaled)* 24.4 Range Prediction (5) 212.36 to 6.18 (evolutionary constraint) 0–215 (benign—disease causing) 0.00–1.00 (probability of pathogenicity) 0.00–1.00 (deleterious—tolerated) 0.00–1.00 (benign—probably damaging) 213 to 4 (deleterious—neutral) 0.00–1.00 (neutral—deleterious) 1–99 (rank) Constrained Disease causing Pathogenic Deleterious Benign Deleterious Deleterious Deleterious Basis (4) Nucleotide conservation prediction Protein structure/function and evolutionary conservation Protein structure/function and evolutionary conservation Evolutionary conservation Protein structure/function and evolutionary conservation Alignment and measurement of similarity between variant sequence and protein sequence homolog Combines SIFT, PolyPhen-2, and MutationAssessor Contrasts annotations of fixed/nearly fixed derived alleles in humans with simulated variants *Integrate multiple methods. G = 0.000008) (Table 1). The affected nucleotide is highly conserved across vertebrate species. The resulting missense mutation localizes to the most conserved spectrin repeat domain within nespin-2 (52), which mediates homodimerization and other protein–protein interactions (3). Integrating these data, this variant is likely pathogenic (3 moderate criteria and 2 supporting criteria) (4). There was a heterozygous mutation in NEB (Chr2:152424912, c.17654 G.A, p.Trp5885Ter), which has been implicated in autosomal recessive nemaline myopathy Type 2 and causes a very different phenotype; this variant was deemed not significant and unlikely to compound the SYNE2 variant. Muscular dystrophies may present to the neuroophthalmologist when they cause ptosis and/or paretic strabismus. A myogenic etiology should be suspected in case of a nonfluctuating progressive worsening of ptosis over years that can be confirmed by a review of previous pictures. Detailed neurological examination may demonstrate specific patterns of muscular weakness, even when this is not the presenting problem. In the context of an abnormal CK, a likely pathogenic variant and a consistent clinical phenotype, muscle biopsy was not recommended. Diagnosis of a specific muscular dystrophy can be challenging in the setting of many disease-causing variants in multiple genes and wide clinical variability, thus next- e334 generation sequencing of expanding genetic panels is an increasingly important diagnostic resource for the clinician. A careful review of ambiguous results, often in collaboration with the testing company and/or a geneticist, is critical for accurate interpretation and attribution of disease manifestations to a genetic cause. REFERENCES 1. Merlini L, Maraldi NM. Emery-Dreifuss Muscular Dystrophy. In Neuromuscular Disorders in Clinical Practice (2014). Seattle, WA: University of Washington, 2020. 2. Zhang Q. Nesprin-1 and -2 are involved in the pathogenesis of Emery–Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007;16:2816–2833. 3. Autore F, Pfuhl M, Quan X, Williams A, Roberts RG, Shanahan CM, Fraternali F. Large-scale modelling of the divergent spectrin repeats in nesprins: giant modular proteins. PLoS One. 2013;8:e63633. 4. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for molecular pathology. Genet Med. 2015;8:405–424. 5. Dong C, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K, Liu X. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24:2125–2137. Douglas et al: J Neuro-Ophthalmol 2021; 41: e333-e334 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.