The diagnosis of LENAS is usually based on medical and family history, genetic testing, extensive imaging and other supplemental testing. As this disease is extremely rare, diagnosis is still very complex as many of these diagnostic criteria for LENAS can be mistaken for similar neurodegenerative disorders. The differential diagnosis of leukoencephalopathy in general is very extensive and specialized investigations are required to make an accurate diagnosis. Diagnostic Criteria Note: These criteria were established by a group consisting of board-certified neurologists from the Mayo Clinic, Niigata University, Shinshu University School of Medicine, Kyoto Prefectural University of Medicine, and Tokushima University Graduate School.Brain CT of brain showing white matter lesions (indicated by the red arrows) Core Features # Age at onset ≤ 60 years old # More than 2 findings of the following clinical signs and symptoms: ## Cognitive Impairment or Psychiatric Symptoms ## Pyramidal Signs ## Parkinsonism ## Epilepsy #Autosomal Dominant inheritance or sporadic occurrence #Brain CT/MRI findings: ## Bilateral Cerebral white matter lesions ## Thinning of the Corpus Callosum # Other causes of Leukoencephalopathy including vascular dementia, multiple sclerosis, or leukodystrophy can be excluded. Exclusionary Findings # Age at onset ≤ 10 years # Stroke-like episodes more than twice except for epilepsy # Prominent peripheral neuropathy Supportive Findings # Frontal lobe dysfunction shown by clinical features or cognitive battery test # Rapidly progressive course. Become bedridden within 5 years after onset # Spotty small calcifications in the white matter shown by brain CT # Neuropathologic findings compatible to LENAS +Diagnosis By Criteria Definite Probable Possible Fulfills core features 2,3 and 4A and confirmation of CSF1R mutation Fulfills core features 1-5, but genetic testing has not been performed Fulfills core features 2a, 3, and 4a, but genetic testing has not been performed Genetic Testing Single-Gene testing is first performed for sequence analysis of the CSF1R gene. A multi-gene panel that includes CSF1R gene and other genes of interest may be considered for differential diagnoses. If necessary, more comprehensive genomic testing (not always available though) can be performed. Further Evaluations * Complete neurologic assessment * Psychological and psychiatric assessments * Assessment of feeding/eating, digestive problems, and nutrition based on clinical history * EEG if seizure disorder suspected * Assessment of family and social structure to determine the availability of adequate support systems * Consultation with a clinical geneticist and/or genetic counselor
Leukoencephalopathy with neuroaxonal spheroids
Leukoencephalopathy with vanishing white matter
Megalencephalic leukoencephalopathy with subcortical cysts
Neurodegeneration with brain iron accumulation
Camel spongiform encephalopathy
Neurofibrillary tangle
Limbic-predominant age-related TDP-43 encephalopathy
Variably protease-sensitive prionopathy