Characterize the clinical phenotype of ALSP through a comprehensive chart review study.

ALSP is a fatal, rare genetic disease characterized by neuronal and glial cell pathology and rapidly progressive neurological symptoms (executive dysfunction, motor impairment, neuropsychiatric complications). ALSP is underrecognized with an estimated prevalence of 10,000 in the U.S. alone and frequently misdiagnosed for atypical forms of common CNS disorders i.e., multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

We conducted an IRB-approved, multicenter (3 North American sites), retrospective study of patients with clinically or neuropathologically confirmed diagnosis of ALSP. Data were acquired through medical review of EHRs/medical records. Data collected included demographics, medical/family history, disease manifestations at onset, symptom progression, and therapeutic interventions.

EHR/medical records from 57 patients were included in the analysis population (F:34/M:23). Mean age at diagnosis was 47.4±12.6 yrs. Initial consultation occurred in various settings: movement disorders, dementia, leukodystrophy, and multiple sclerosis clinics. 59.6% of patients had a family history of ALSP. Cognitive impairment (n=52, 91.9%) was the most frequent initial manifestation, followed by psychiatric symptoms (n=47, 82.5%). Cognitive symptoms included executive dysfunction (77.2%), word finding difficulty (64.4%), confusion (57.9%), and memory loss (52.6%). The most common psychiatric symptoms included depression (54.4%), agitation (31.6%), and insomnia (28.1%). Almost all patients had at least one abnormality on MRI (mostly white matter lesions and brain atrophy). Thirty-five deaths were reported with a mean interval of 5.2±7.0 years after diagnosis.

This study confirms that ALSP has a diverse phenotype and can be easily misdiagnosed. To avoid misdiagnosis, screening patients for family history, pattern of MRI abnormalities consistent with ALSP, early-onset cognitive impairment with behavioral and/or motor dysfunction should be considered. This combination of symptoms should generate suspicion for ALSP and genetic testing. Increased disease awareness and genetic testing is expected to improve diagnostic accuracy.