Ptosis as clinical presentation in a patient with Emery-Dreifuss muscular dystrophy type 5

Emery-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, nine types of EDMD are recognized. The SYNE2 gene, located on chromosome 14q23 codes for a nuclear envelope protein; heterogenous 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 non-fluctuating 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 prior external photographs confirmed gradual worsening of the ptosis since her twenties (Figure). The patient had no significant past medical history. She had immigrated to the United States from mainland Portugal. There was no family history of ocular, neurologic, or neuromuscular disease.

Figure.

1992, B-2005, C-2016, D-A year prior to presentation

The clinical examination showed asymmetric bilateral ptosis (left>right), Upper margin to light reflexes were 2mm on the right and 0mm on the left, with total upper lid excursion of 13.5mm right and 12mm left. She had intact eye movements, and no ocular misalignment. There was mild orbicularis 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/liter). EMG was normal, including single fiber EMG without abnormal jitter. A muscular dystrophy genetic panel (Medical Neurogenetics, LLC, Atlanta, GA, USA) revealed a heterozygous variant in SYNE2 (Chr14:64676190, c.18434A>G, p.Tyr6145Cys, rs755990889, Allele frequency: G=0.000008) (Table). 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.17654G>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.

Table.

Multimodal in silico analysis of SYNE2 missense variant.

Method	Score	Range	Prediction5	Basis4
GERP-RS (NE)	4.22 (5.35)	−12.36 – 6.18 (Evolutionary constraint)	Constrained	Nucleotide conservation prediction
MutationTaster	194	0 – 215 (Benign – Disease causing)	Disease causing	Protein structure/function and evolutionary conservation
MutPred2	0.44	0.00−1.00 (Probability of pathogenicity)	Pathogenic	Protein structure/function and evolutionary conservation
SIFT	<0.01	0.00 – 1.00 (Deleterious – Tolerated)	Deleterious	Evolutionary conservation
PolyPhen-2	0.30	0.00 – 1.00 (Benign – Probably Damaging)	Benign	Protein structure/function and evolutionary conservation
PROVEAN	−8.44	−13 – 4 (Deleterious – Neutral)	Deleterious	Alignment and measurement of similarity between variant sequence and protein sequence homolog
Condel*	0.54	0.00 – 1.00 (Neutral – Deleterious)	Deleterious	Combines SIFT, PolyPhen-2 and MutationAssessor
CADD (scaled)*	24.4	1 – 99 (Rank)	Deleterious	Contrasts annotations of fixed/nearly fixed derived alleles in humans with simulated variants

^*Integrate multiple methods

Muscular dystrophies may present to the neuro-ophthalmologist when they cause ptosis and/or paretic strabismus. A myogenic etiology should be suspected in case of a non-fluctuating progressive worsening of ptosis over years that can be confirmed by review of prior pictures. Detailed neurological exam which 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 generation sequencing of expanding genetic panels are an increasingly important diagnostic resource for the clinician. 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.