Skogholt’s disease: multimodal evidence for choroid plexus–centred clearance failure

Abstract Background Choroid plexus dysfunction has been proposed to reduce CSF production and impair brain solute clearance, but the in vivo consequences of sustained clearance failure for biomarker profiles and disease mechanisms remain poorly defined. We examined Skogholt’s disease, a rare, maternally inherited neurodegenerative syndrome as a natural human model to test whether primary choroid plexus failure can reshape CSF dynamics and biomarker profiles independently of overt neurodegeneration. Methods Multimodal assessment of 40 individuals (mean age 57.8 years; 16 affected individuals and 24 controls) was used to evaluate clearance dynamics, diffusion properties, and CSF–plasma biomarker relationships, including model-free analysis of dynamic contrast-enhanced MRI washout of the choroid plexus. Results We observed convergent evidence for a choroid plexus-centred clearance defect. Affected individuals had markedly reduced choroid plexus volume (Cohen’s |d| = 2.64) and prolonged contrast washout (time-above-half-peak |d| = 4.9) without cerebral parenchymal blood–brain barrier disruption. Diffusion MRI showed widespread reductions in mean diffusivity (|d| ≈ 1.0 in white matter; 0.85–0.89 in cortex), opposite to changes typical of neurodegeneration. CSF tau, amyloid β species, β-trace, neurofilament light and glial fibrillary acidic protein were elevated up to 12-fold, whereas plasma levels were normal or reduced, indicating marked CSF–plasma dissociation. Directional trace-metal shifts suggested impaired ATP-dependent transport. Mitochondrial genome sequencing identified a rare homoplasmic MT-RNR2 (m.1681G > A) variant that segregates with disease and is absent as a homoplasmic variant in public mitochondrial reference datasets. The variant localises to a highly conserved structural element of the mitochondrial 16S ribosomal RNA, supporting its candidacy as a pathogenic variant pending functional validation. Conclusions These findings provide in vivo evidence for choroid plexus dysfunction in a maternally inherited disorder with convergent evidence supporting a mitochondrial aetiology, associated with reduced CSF production and impaired blood–CSF barrier transport, substantially altering biomarker profiles in the absence of cortical atrophy or blood–brain barrier disruption. Elevated CSF but normal or low plasma neurodegeneration markers most parsimoniously reflect impaired CSF-to-blood clearance, highlighting a clearance-sensitive dimension of biomarker biology. Dynamic contrast-enhanced MRI choroid plexus washout and CSF–plasma coupling emerge as complementary in vivo markers of clearance capacity. This syndrome may represent a prototype of disorders defined by primary CSF clearance failure rather than neuronal degeneration.