Hereditary myopathy with early respiratory failure (HMERF) is a rare, autosomal dominant titinopathy of adult onset, characterized by slowly progressive weakness and disproportionately early diaphragmatic weakness (1). Hallmark findings include titin A-band mutation, early semitendinosus involvement on muscle MRI and distinctive histopathologic features (1). Due to the phenotypic variability and relatively recent recognition of causative mutations, HMERF is likely underdiagnosed and presents a diagnostic challenge (2, 3, 4).

A 61-year-old male presented with 3 years of progressive weakness in lower and then upper extremities, along with distal paresthesia and muscle cramping. He denied respiratory symptoms or family history of neuromuscular disease.  

The examination revealed mild right hip flexion, bilateral finger abduction and neck extension weakness with bilateral quadriceps atrophy. Sensation was diminished distally to vibration and pinprick, with normal reflexes aside from trace ankle jerks bilaterally. Prior nerve conduction study (NCS) concluded possible chronic inflammatory demyelinating polyneuropathy (CIDP), based on absent H-reflexes and mildly prolonged peroneal F-wave responses. IVIG treatment was ineffective with course complicated by sigmoid abscess.

Updated electromyography and NCS demonstrated myopathic motor units in the right iliopsoas with no demyelinating features. MRI showed multifocal muscle edema preferentially involving semimembranosus and long biceps femoris muscles. Creatinine kinase was elevated to 605 U/L (30-200 U/L).  Metabolic myopathy gene panel resulted in pathogenic missense mutation c.95195C>T (p.Pro31732Leu) in the titin gene, consistent with diagnosis of HMERF.

Atypical features such as sensory symptoms, no known family history, later age of onset and absence of respiratory involvement can obscure the diagnosis of HMERF. Careful clinical and electrodiagnostic re-evaluation followed by MRI and genetic testing revised the diagnosis from CIDP to HMERF with discontinuation of unnecessary immunotherapy. This case contributes to recognizing a more comprehensive breadth of phenotypic presentations in HMERF patients.