A 51-year-old woman, who had no family history of neuropsychiatric diseases, began noticing gait disturbance at the age of 45 years and upper limb weakness at the age of 46 years. These symptoms gradually worsened. Her personality showed a mild change. She developed depression associated with obsessive behavior and difficulty understanding everyday speech at the age of 49 years. She began using a wheelchair for transport at the age of 50 years. Finally, she was admitted to a psychiatric hospital because she was easily distracted and behaved violently throughout the day. Her past medical history revealed a transient ischemic attack at the age of 41 years. Neurological examination at the age of 46 years showed that the patient had mild muscular weakness of the four limbs with left distal dominance. Amyotrophy was unremarkable. Her hand grip was 18 kg in the right hand and 11 kg in the left hand. She showed hyperreflexia and spasticity in all four extremities with left dominance, and her jaw reflex was increased. Furthermore, her Babinski reflexes were positive bilaterally, and her gait was spastic. There were no abnormalities in the cranial nerves. Sensory, autonomic, and cerebellar functions were normal. Nerve conduction studies revealed that F-wave occurrences were reduced in the median nerve bilaterally (right: 56%, left: 25%; normal values: 70% <). Amplitudes of compound muscle action potentials, motor conduction velocities, amplitudes of sensory nerve action potentials, and sensory conduction velocities were normal in all nerves tested (i.e., the bilateral median, ulnar, tibial, and sural nerves). Neurogenic changes were detected in the biceps brachii muscle, the first interossei dorsalis muscle, the thoracic paraspinal muscle, the quadriceps femoris muscle, and the tibialis anterior muscle using needle electromyography. Upon neurological examination at the age of 50 years, the patient showed attention disturbances, transcortical sensory aphasia, and a positive snout reflex. Hyperreflexia, spasticity, and weakness in all four extremities had worsened, and bilateral ankle contracture was observed. She was unable to maintain a standing position. Her hand grip was 16 kg in the right hand and 6 kg in the left hand. There were no abnormalities in the cranial nerves or sensory, autonomic, and cerebellar functions. Her Mini-Mental State Examination score was 16/30, Frontal Assessment Battery score was 5/18, Alzheimer's Disease Assessment Scale was 29.3/70, and Raven's Colored Progressive Matrices was 32/36.
The cerebrospinal fluid examination was negative, as were the test results for oligoclonal bands and immunoglobulin G indices at the ages of 41, 46, 48, and 50 years. Furthermore, the levels of serum creatine kinase and alkaline phosphatase were normal throughout her clinical course. Longitudinal brain MRI revealed progressive brain atrophy with temporal dominance (Figure 1A), non-progressive cerebellar atrophy (Figure 1A), and some non-specific white matter intensities (data not shown). Brain N-isopropyl-p-[123I] iodoamphetamine single photon emission computed tomography (SPECT) at the age of 50 years showed hypoperfusion in the bilateral temporal lobe with left dominance and the cerebellar hemispheres (Figure 1B). Neither the cervical MRI acquired at the age of 41 years nor the whole spinal MRI acquired at the age of 46 years showed abnormalities.
Preliminary genetic analyses confirmed the absence of repeat expansions in 11 genes known to be associated with cerebellar atrophy: ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8, ATXN10, PPP2R2B, TBP, NOP56, and ATN1.
Her clinical or electrophysiological findings showed upper and lower motor neuron signs which met clinically probable ALS of the Awaji criteria (Table 1). Also, she did not exhibit any clinical or laboratory findings suggestive of myopathy or PDB throughout her clinical course.