Variants in tumor suppressor genes and in genes encoding DNA repairing proteins are associated with syndromes conferring neurologic features and increased risk for malignancy. The best example for these conditions is ataxia-telangiectasia (AT). A more rare and recent disease is an ataxia-pancytopenia syndrome (ATXPC) associated with heterozygous gain-of-function variants in the tumor suppressor gene SAMD9L (MIM 159550). Here, we describe a patient with a complex cerebellar syndrome associated with a novel SAMD9L pathogenic variant.
Case PresentationA 54-year-old Swedish man presented with progressive gait difficulties, impaired coordination, dizziness, falls, slurred speech, and urinary urgency. Age at onset was 42 years. Later, recurrent episodes with profuse sweating and crawling in both calves started to occur. There was no family history of movement disorders or other neurologic diseases. His mother died of glioblastoma at age 65 years and his father of cardiac disease. His medical history was unremarkable. Examination revealed dysmetria, inability to perform tandem gait, reduced arm swing, dysarthria, positive Romberg test, conjunctival telangiectasias, nystagmus, and pes cavus (Video 1). Reflexes were brisk, with mild spasticity in the legs. Muscle tone in the arms, sensation to pinprick, strength, and proprioception were normal, and the Babinski sign was absent, but vibration was reduced in both malleoli. At age 50 years, his Scale for the Assessment and Rating of Ataxia score was 10 p, and 3 years later, it was 11.5 p (range 0-40 points). 1 There were no signs of orthostatism, and the patient denied gastrointestinal symptoms. ENeG and quantitative sensory testing demonstrated a demyelinating sensorimotor neuropathy and elevated thresholds for heat and cold. EMG revealed chronic mild neurogenic abnormalities in the distal leg and arm muscles with no signs of active denervation, whereas motor evoked potential yielded normal findings. A mild symmetric sensorineural hearing loss was found, but the patient does not require hearing aids. Ophthalmologic evaluation, which included optical coherence tomography and eye-bottom examination, demonstrated presbyopia but no evidence of retinal pathology.Brain MRI with contrast demonstrated marked cerebellar atrophy and confluent periventricular hyperintensities. Additional hyperintensities were found in deep white matter regions that included the corpus callosum's left trunk. There were multiple cysts ranging in size between 1.5 and 3 mm within the hyperintensities and increased T2-weighted signal in the putamen, caudate, and dentate nuclei (Figure). A CT scan ruled out calcifications in the brain. A large
