Title : Hereditary myopathy with early respiratory failure associated with an incidental COL4A5 variant: A case report
Abstract:
Background: Hereditary myopathy with early respiratory failure (HMERF) is a rare, autosomal dominant titinopathy caused by pathogenic variants in the TTN gene. It typically presents in adulthood with progressive distal lower-limb weakness, calf hypertrophy, and early respiratory muscle involvement. Variants in COL4A5, by contrast, are classically linked to X-linked Alport syndrome, a disorder of the kidney, ear, and eye. The co-occurrence of pathogenic variants in both genes within a single patient has not been previously documented.
Case Presentation: We report a 34-year-old male who developed progressive lower-limb weakness beginning at age 30, accompanied by gait disturbance, difficulty rising from a seated position, nocturnal hypoventilation, and a 16-kg weight loss. Family history was notable for a mother who died of an undiagnosed progressive neuromuscular disorder and a similarly affected older sister. Examination revealed bilateral calf hypertrophy and absent lower-limb deep tendon reflexes, with no upper-limb or axial involvement. MRI demonstrated diffuse atrophy and fatty replacement of the psoas and gluteal muscles. Needle electromyography showed absent motor unit potentials in the tibialis anterior, consistent with advanced myopathic change, though it was not relied upon as the primary diagnostic tool. Whole-exome sequencing identified a heterozygous pathogenic TTN variant (c.95126C>G, p.Pro31709Arg), confirming HMERF. Sequencing also revealed a hemizygous COL4A5 variant (c.4891C>T, p.Arg1631Cys); however, in the absence of renal, auditory, or ocular abnormalities and given conflicting database classifications, this finding was interpreted as an incidental variant of uncertain significance rather than evidence of Alport syndrome.
Discussion and Conclusion: This case illustrates a genetically confirmed phenotype of HMERF together with an incidental COL4A5 variant lacking clinical correlation. It highlights the diagnostic value of comprehensive genomic testing in atypical neuromuscular presentations, while underscoring the importance of cautious, clinically correlated interpretation of incidental findings to avoid misdiagnosis or unnecessary patient anxiety. Multidisciplinary management, including respiratory monitoring and supportive physiotherapy, remains central to optimizing outcomes in patients with HMERF.
