Very late onset distal myopathy caused by a novel LDB3 variant



Poster Number: 191


Yigit Karasozen, MD, UCLA, Payam Soltanzadeh, MD, UCLA

We present the case of a 75 year-old white man who was referred to our clinic for progressive weakness that he noticed for the first time at age 73. He was unable to run or play tennis due to leg weakness after taking a break during the COVID-19 pandemic. Initial diagnostic focus was the lumbar spine and incidental imaging findings led to multiple specialist consultations, repeat imaging and electrodiagnostic studies. On our evaluation patient had weakness predominantly in plantar flexors but also affecting the hip girdle muscles and normal sensory examination. Repeat electrodiagnostic studies at our center and the clinical picture were thought to be consistent with an irritable myopathy involving distal more than proximal muscles. MRI of bilateral lower extremities demonstrated intramuscular edema with areas of superimposed fatty replacement in both legs, more prominent in the posterior compartments. Genetic testing with Invitae Comprehensive Neuromuscular Disorders Panel including 255 genes showed the heterozygous variant p.Gly259Ser (or p.Gly144Ser in shorter muscle transcript) LDB3 gene (previously known as ZASP). Mutations in LDB3can cause autosomal dominant myofibrillar myopathy. This variant was extremely rare in population databases (gnomAD allele frequency 0.000004007) and was reported three times in ClinVar database. This variant was thought to be consistent with the patient’s phenotype. A muscle biopsy of tibialis anterior was performed and demonstrated classic features of a chronic myopathy with fiber atrophy, splitting and internal nucleation. On electron microscopy, ultrastructural myofibrillar loss, core formation, abundant ultrastructural granulofilamentous bundles, and Z-disc abnormalities were seen, confirming the diagnosis of a myofibrillar myopathy. Our case presentation demonstrates the value of genetic testing in patients with sporadic very late onset distal leg weakness and describes a novel potentially pathogenic LDB3 variant.