The insidious degeneration of white matter and cognitive decline in Fabry disease

Fabry disease is a rare X-linked deficiency of lysosomal
alpha-galactosidase that causes glycolipid accumulation in tissues,
including the brain. The most common neurologic sequelae of Fabry are
cognitive decline and white matter lesions (WMLs) on brain magnetic
resonance imaging (MRI). In the at-large population, however, WMLs are
non-specific, highly prevalent, and most are clinically silent. Thus, we
compared Fabry to typical brain aging to identify factors unique to
Fabry-related cognitive decline. Twenty adult Fabry patients (75% female;
median age 36.4 yrs, range: 19.8-63.2 yrs; 95% on enzyme replacement
therapy) without a history of stroke or other neurologic diseases and 20
age/sex-matched healthy controls were enrolled in a case-control study.
All participants underwent a neurocognitive assessment and a 3.0 T MRI
study of the brain that used structural MRI (e.g., fluid-attenuated
inversion recovery, FLAIR), semi-quantitative MRI (e.g., normalized FLAIR
signal intensity), and quantitative MRI (diffusion tensor imaging,
bound-pool fraction imaging). During a blinded review of structural MRIs,
a neuroradiologist’s categorization of case-control status did not
correspond to disease status (Fisher’s test, P>0.99) but rather to
age (P=0.004), indicating qualitative changes associated with Fabry were
similar to normal age-related brain alterations. Using quantitative MRI,
however, we detected evidence of microstructural damage in the white
matter of younger Fabry adults (<40 yrs). With age, WML severity
increased and the corpus callosum atrophied in Fabry, phenomena absent in
controls and consistent with progressive tissue damage. Neurocognitive
assessments identified trends for lower verbal intelligence quotient and
executive function in the younger Fabry participants, which became
statistically significant in the older Fabry patients. Our data suggest
that the early onset of microstructural damage in Fabry drives the
insidious degeneration of white matter, leading to impaired cognition.
Aging Fabry patients may benefit from serial cognitive assessments to
identify unmet therapeutic needs.