Shared Genetic Roots: How Rare Metabolic Disorders Are Illuminating the Origins of Multiple Sclerosis

Multiple sclerosis (MS) has long puzzled scientists and clinicians alike — a disease where the body’s immune system turns against the brain and spinal cord, stripping away myelin, the insulating layer that allows neurons to communicate efficiently. It affects more than two million people worldwide, yet despite decades of research, its genetic underpinnings remain only partially understood.

A study led by Dr. Anthony Traboulsee and Dr. Carles Vilariño-Güell at the University of British Columbia takes a bold step toward filling that gap. Published in Human Genetics (2017), their work explores whether some cases of familial MS — where multiple members of a family are affected — might share a genetic origin with rare single-gene disorders that mimic MS clinically and radiologically.

Why Look at “MS-like” Monogenic Disorders?
Certain inherited diseases, such as leukodystrophies, mitochondrial disorders, and lysosomal storage diseases, can resemble MS on MRI scans and in clinical symptoms — from mobility problems and cognitive decline to visual disturbances. The researchers hypothesized that if these disorders look like MS, perhaps they share genetic roots.

To test this, they focused on 28 genes known to cause 24 single-gene neurological diseases with overlapping features. These included genes involved in cholesterol metabolism (like CYP27A1), lysosomal trafficking (LYST), and energy metabolism (PDHA1).

A Large-Scale Genetic Investigation
The team analyzed DNA from 2,131 MS patients and 830 healthy controls, drawn from the long-standing Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS). They also examined exome sequences — the protein-coding parts of the genome — from a focused subset of 270 MS patients, many from multi-incident families.

After identifying rare coding variants (those present in less than 1% of the population), they genotyped them across all participants and tested whether the variants tracked with disease in affected families.

Six Genes, Nine Mutations, and a Shared Genetic Signature
The analysis pinpointed nine rare variants in six genes (CYP27A1, LYST, PDHA1, CLCN2, GALC, and POLG) that segregated with MS in 13 families.

1. CYP27A1 – Cholesterol Metabolism Takes the Stage
Four variants in CYP27A1 stood out — including a known pathogenic mutation (p.R405W) that causes cerebrotendinous xanthomatosis (CTX), a lipid storage disorder. Surprisingly, heterozygous carriers of this mutation in one extended family presented with MS or other neurological symptoms, suggesting that partial disruption of cholesterol metabolism could predispose individuals to MS.

The link is particularly intriguing because CYP27A1 belongs to the same metabolic pathway as NR1H3 and CH25H, both previously associated with progressive forms of MS. Together, these genes regulate the production of oxysterols, cholesterol derivatives that act as immune modulators. This points to dysregulated cholesterol and oxysterol metabolism as a potentially unifying mechanism behind some cases of progressive MS.

2. LYST – The Lysosomal Connection
A mutation (p.V1678A) in LYST, a gene known for causing Chediak–Higashi syndrome when both copies are mutated, was found in five MS patients from three families. Heterozygous carriers showed adult-onset MS-like symptoms without the severe immune dysfunction typical of Chediak–Higashi, hinting at a milder, MS-resembling phenotype due to partial loss of lysosomal function.

3. PDHA1 – Linking Energy and Immunity
The PDHA1 gene, which encodes a subunit of the pyruvate dehydrogenase complex, also carried a rare variant (p.K387Q) in several MS families. This enzyme connects glucose metabolism to the synthesis of acetyl-CoA — a key precursor for both energy production and cholesterol synthesis. The overlap once again points to metabolic dysfunction as a contributor to MS pathophysiology.

4. Other Candidate Genes
Three additional genes — CLCN2, GALC, and POLG — each harbored single rare mutations that appeared to segregate with MS within individual families. Though sample sizes were small, these findings warrant further exploration.

A Broader View: Cholesterol, Immunity, and Neurodegeneration
Beyond identifying mutations, the study underscores an emerging paradigm: metabolic pathways, particularly cholesterol and oxysterol metabolism, are intertwined with neuroinflammation and myelin biology.

Oxysterols not only regulate lipid balance but also influence immune signaling and neuronal repair. Their concentrations in blood and cerebrospinal fluid have been shown to correlate with MRI lesion load and brain atrophy in MS patients — making them promising biomarkers of disease activity.

Why This Matters
This research provides a bridge between rare monogenic diseases and complex disorders like MS. It suggests that in some families, rare high-impact variants — rather than common small-effect variants — may drive susceptibility. This could explain why MS manifests so differently from person to person, and why some treatments are effective for certain patients but not others.

By uncovering these rare mutations, scientists move closer to personalized medicine in MS — tailoring prevention and therapy based on each patient’s genetic and metabolic profile.

The Takeaway
Rare variants in genes related to cholesterol metabolism, lysosomal function, and energy production may predispose individuals to familial MS.

The findings highlight cholesterol and oxysterol dysregulation as a recurring biological theme in MS and related disorders.

Future work should include functional studies and expanded sequencing to confirm these results and unravel how these pathways contribute to neuroinflammation and demyelination.

“Our data indicate that the genetic etiology of MS is highly heterogeneous,” the authors conclude. “Comprehensive genomic interrogation combined with detailed clinical assessment could help identify which treatments are more likely to be effective in individual patients.”

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Traboulsee, A.L., Sadovnick, A.D., Encarnacion, M. et al. Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Hum Genet 136, 705–714 (2017). https://doi.org/10.1007/s00439-017-1784-9