Recently, a novel leukoencephalopathy syndrome was described in eight patients with a distinct pattern of MRI abnormalities. Here we describe the clinical, laboratory, and MRI findings in five new, unrelated patients. The clinical picture was homogeneous with onset in childhood, a slowly progressive course, variable mental deficits, signs of pyramidal and cerebellar dysfunction and sometimes dorsal column dysfunction. In two patients, a minor head trauma was followed by neurological deterioration and fever. No underlying metabolic defect was found. In two patients serum lactate was elevated, but no evidence of a mitochondrial defect was found. MRI showed variably extensive, diffuse, or spotty cerebral white matter abnormalities and a selective involvement of particular brainstem tracts. The tracts involved included the pyramidal tracts, sensory tracts, superior and inferior cerebellar peduncles, and intraparenchymal trajectories of the trigeminal nerve. In four patients spinal MRI was performed and revealed involvement of tracts over the entire length depicted. Single voxel proton MRS in three patients revealed increased lactate within the abnormal white matter. The uniform and highly characteristic MRI findings, in combination with the similarities in clinical and MRS findings, provide evidence for a distinct nosological entity.