Adult-onset genetic leukoencephalopathies: A MRI pattern-based approach in a comprehensive study of 154 patients

Abstract

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.

Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL

“…A worldwide prevalence of pathogenic NOTCH3 mutations of 3.4/1000 individuals implies that these mutations may be a major contributor to cerebral small vessel disease in the general population. Indeed, a recent study in patients with adult‐onset leukoencephalopathy showed that 21% of these individuals had a pathogenic NOTCH3 mutation . Similarly, high NOTCH3 mutation frequencies (18%) were found in a Korean cohort of patients with subcortical vascular cognitive impairment .…”

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases

“…Accordingly, such features in patients with patchy WMH, along with the absence of T2* microbleeds, help distinguish acquired or inherited vascular leukoencephalopathy from ALSP. 7,8,20 Similarly, of the 6 patients with pontine hyperintensities, only 3 had lesions suggestive of a vascular origin, whereas the other patients had corticospinal tract hyperintensities.…”

Vascular Parkinsonism: Deconstructing a Syndrome

“…Remarkably, none of these patients were reported to have parkinsonism, but exhibited, instead, depression, apathy, cognitive impairment, or migraine. 36 Some nonvascular leukodystrophies (e.g., hereditary diffuse leukoencephalopathy with axonal spheroids resulting from CSF1R mutations) are rarely associated with parkinsonism. 36,37 Even in some of these, parkinsonian-like phenotypes (e.g., apathetic depression, pyramidal weakness, i.e., "pseudo-parkinsonism") may have been misinterpreted as parkinsonism.…”