Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

Abstract

Background and purpose To establish and validate diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony‐stimulating factor 1 receptor (CSF1R) mutation. Methods We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation‐negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results Among the CSF1R mutation‐positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation‐negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

Partial loss of function of colony‐stimulating factor 1 receptor in a patient with white matter abnormalities

“…Considering that genome‐wide association studies have not identified any associations near CSF1R gene in ischemic stroke cohorts and any disease associations of p.Glu573Lys variant have not been reported in the Cerebrovascular Disease Knowledge Portal , it is unlikely that the p.Glu573Lys variant is directly associated with the patient's stroke. The patient did not have typical clinical findings of ALSP and did not fulfill the diagnostic criteria for ALSP , but white matter abnormalities unrelated to the recent infarct were evident. However, the patient had vascular risks.…”

Remarkable behavioural signs and progressive non‐fluent aphasia in a patient with adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia

“…). Computed tomography of the head did not demonstrate calcifications, which are helpful in diagnosing ALSP . According to Konno et al , however, calcifications may often be overlooked because they are extremely small, which could have been the case with this patient.…”

“…Computed tomography of the head did not demonstrate calcifications, which are helpful in diagnosing ALSP. 1 According to Konno et al, 1 however, calcifications may often be overlooked because they are extremely small, which could have been the case with this patient. Single-photon emission computed tomography with technetium-99m ethyl cysteinate dimer revealed relative hypoperfusion mainly in the bilateral frontal lobe areas, including the left Broca's area.…”

“…Also, the patient's father died in his 50s with symptoms similar to his and his sister's. The patient's molecular genetic analysis revealed a colony stimulating factor 1 receptor (CSF1R) mutation (p.G765D), which confirmed the diagnosis of ALSP …”

“…Adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, in particular, the frontal subcortical areas and the corpus callosum. 1 Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease-related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural signs and progressive non-fluent aphasia, which resemble signs of frontotemporal lobar degeneration (FTLD).…”