# Central Dysmyelination in SSADH‐Deficient Humans and Mice

## TL;DR

This study explores how GABA and GHB accumulation in SSADHD affects myelination in humans and mice, revealing a link between these chemicals and delayed oligodendrocyte maturation.

## Contribution

The study identifies a novel connection between elevated GABA/GHB levels and dysmyelination in SSADHD, offering insights into myelination dynamics and potential monitoring strategies.

## Key findings

- SSADHD patients show significantly greater dysmyelination compared to healthy controls.
- Lower myelination scores in SSADHD correlate with younger age and higher plasma GABA/GHB levels.
- SSADHD mouse models exhibit reduced expression of key myelin-related genes.

## Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ‐aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.

Brain MRIs performed on 44 individuals (23 with SSADHD and 21 healthy controls) were independently reviewed by two neuroradiologists and scored using a disease‐specific myelination scoring system. Inter‐rater reliability (IRR) was assessed by the intraclass correlation coefficient. Myelination scores of SSADHD individuals were correlated with clinical, biochemical, magnetic resonance spectroscopy, and genetic data. Additionally, we investigated the expression of myelin‐related genes in a mouse SSADHD model.

Dysmyelination in SSADHD patients was overall mild, but significantly greater than in healthy controls (p < 0.001). In SSADHD patients, lower myelination scores were significantly correlated with younger age (R = 0.775, p < 0.001) and higher plasma GABA (R = −0.722, p < 0.001) and γ‐hydroxybutyric acid (GHB) (R = −0.683, p = 0.001). In SSADH‐deficient mice, there was reduced expression of genes encoding myelin basic protein (p = 0.001), myelin‐associated oligodendrocyte basic protein (p = 0.001), and mitochondrial aspartate transporter (p = 0.025).

Excessive GABA and GHB, which characterize SSADHD and are further pronounced in younger SSADHD individuals, may account for delayed oligodendrocyte maturation and altered myelination dynamics in this disorder. Studying the properties of dysmyelination in this unique disorder enhances our understanding of GABA's mediating role on myelination and may contribute to monitoring disease progression and managing other white‐matter neurological disorders.

NCT03758521