Background: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), a rare autosomal dominant inherited leukodystrophy, is associated with the genetic mutations of colony stimulating factor 1 receptor (CSF1R). The clinical manifestations may be a combination of mental, neurological and physical symptoms that are easily misdiagnosed. And the magnetic resonance imaging (MRI) showed asymmetric white matter damage. Case presentation: We report a case which genetically confirmed hereditary diffuse leukoencephalopathy with spheroids with anti-GABAbR antibody positivity. A 30-year-old woman presented with a 30-month history of progressive limb weakness, aphasia, stiff and cognitive decline. Brain MRI revealed persistent white matter hyperintensities on diffusion-weighted images for 24 months. Sequence analysis of CSF1R showed a novel missense mutation c.1736G>A (p.R579Q). The presence of anti-GABAbR antibody did not report in patients with HDLS. After immunoglobulin and methylprednisolone steroid pulse therapy, the patient's condition improved and the Barthel index scale of daily living ability was increased from 40 to 60. Conclusions: HDLS is often misdiagnosed due to the diverse clinical manifestations and the lack of reliable laboratory indicators. The case may helpful for clinicians to further understand the disease. If a patient whose manifestations are progressive limb weakness and cognitive impairment with anti-GABAbR antibody positivity and the MRI shows asymmetric white matter damage, clinicians should consider the possibility of HDLS and recommend genetic testing.