McLeod syndrome mimicking mitochondrial myopathy due to a novel in-frame duplication in the XK gene.

McLeod syndrome (MLS) is an ultra-rare X-linked multisystem disorder characterized by neurological involvement and distinctive hematological features, including acanthocytosis and specific blood group antigens. The clinical picture is typically dominated by central nervous system manifestations, such as movement disorders, cognitive and psychiatric disturbances, and epilepsy, while subclinical neuromuscular involvement is common. The function of the XK protein and the disease pathophysiology remain poorly understood. We report a unique case of MLS presenting with exercise intolerance due to isolated myopathy associated with mitochondrial Complex I deficiency, in the absence of central nervous system involvement or neuropathy. Whole-genome sequencing identified a novel in-frame duplication introducing an additional leucine at a highly conserved site within the transmembrane domain of the XK protein, resulting in impaired XK protein expression. This case expands the phenotypic spectrum of MLS and underscores the need to include MLS in the differential diagnosis of unexplained metabolic myopathies. Further studies are warranted to elucidate a potential role of the XK protein in mitochondrial function.