Background: Weakness is frequently a reason to attend neurology consultation which entails a challenge due to its wide range of diagnostic possibilities. We present the case of an elderly woman with long-standing right upper limb weakness. Methods: Patient data was obtained from medical records and an extensive neuropathological evaluation was performed. Results: Weakness started off in her right hand, which progressed insidiously to her right hemibody. with hyperreflexia, atrophy, fasciculations and foot drop. Subsequently, bulbar and left hemibody deterioration began. She died due to ventilatory failure four years after the first symptom appeared. A tigroid pattern in the neuroimaging studies suggest white matter involvement, while the neuropathological studies showed loss of motor neurons in the spinal cord. Conclusions: The available evidence does not allow us to dismiss the hypothesis of a motor neuron disease or a leukodystrophy. Cases like this one establish a diagnostic challenge due to their complexity and unusual etiology.