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PubMed This is a summary of 20 peer-reviewed journal articles Updated
Neurology

The Science Behind LCC: Genes, Cells, and Look-Alikes

At a Glance

LCC results from changes in both copies of SNORD118, a gene that helps cells build their protein-making machinery. This cellular stress may affect small blood vessels in the brain, and genetic testing helps distinguish LCC from Coats plus syndrome.

To understand Leukoencephalopathy with calcifications and cysts (LCC), it helps to look deep inside your cells at a process that every part of your body relies on: building proteins. While the symptoms of LCC appear in the brain, researchers believe the underlying cause is a subtle glitch in the “machinery” that helps cells grow and maintain themselves.

The Genetic Blueprint: SNORD118

Every person has two copies of a gene called SNORD118—one from each parent. In people with LCC, both copies of this gene have a mutation. This is known as biallelic inheritance [1][2].

Most genes provide the instructions for making proteins, but SNORD118 is different. It is a non-coding gene, meaning it produces a specialized molecule called U8 small nucleolar RNA (U8 snoRNA) [3]. Because standard genetic tests often focus only on protein-coding genes, these mutations can be easily missed unless a doctor specifically orders a test that looks at the non-coding regions of your DNA [4][5].

Ribosomes and “Cellular Stress”

The well-established job of the U8 snoRNA molecule is to help assemble ribosomes. Think of ribosomes as the “protein factories” of the cell. They are responsible for reading your genetic code and building the proteins that keep your body’s tissues healthy.

In LCC, the mutations in SNORD118 mean that the U8 snoRNA is either missing, misshapen, or cannot interact with other molecules correctly [3][6]. This leads to impaired assembly, where the cell struggles to create mature ribosomes [3]. When a cell cannot make enough ribosomes, it triggers a stress response. This can slow down cell growth and interfere with how the cell functions [7]. For reasons that scientists are still studying, the small blood vessels in the brain seem particularly sensitive to this “ribosome stress” [8][3].

Proposed Mechanisms of Brain Changes

While the exact downstream mechanisms are still being researched and are not yet completely understood, current pathological findings suggest a few hypotheses for how this cellular stress leads to the three features seen on your scans:

  1. Small Vessel Disease: It is hypothesized that vessels become blocked or scarred (sclerosis), which reduces blood flow to the brain’s white matter [8].
  2. Blood-Brain Barrier Leakage: Researchers believe the walls of these vessels may become “leaky.” This may allow fluid to seep into the brain tissue, potentially contributing to the formation and growth of cysts [9][10].
  3. Mineral Buildup: Some researchers hypothesize that damage to the vessels and microscopic amounts of bleeding may cause calcium to deposit in the brain tissue over time, creating calcifications [10][11].

LCC vs. Coats Plus Syndrome: Spotting the Difference

There is another rare condition that looks almost identical on a brain scan: Coats plus syndrome (also known as CRMCC). Because they both can cause the same “triad” of white matter disease, calcifications, and cysts, they are often confused [12]. However, they are caused by different genetic mutations and affect the body in different ways.

Feature LCC (Labrune Syndrome) Coats Plus Syndrome (CRMCC)
Gene Mutation SNORD118 [13] CTC1 (major cause); STN1 or POT1 (associated with related telomere-biology phenotypes) [14]
Primary Mechanism Ribosome assembly defect [3] Telomere (DNA end-cap) defect [12]
Body Systems Affected Typically purely neurological [15] Multisystem (brain, eyes, gut, bones) [16]

Why the Distinction Matters

While the brain symptoms of LCC and Coats Plus are similar, Coats Plus involves several systemic (body-wide) issues that are typically not present in molecularly confirmed LCC. These include:

  • Eye Issues: Abnormal blood vessels in the back of the eye (retinal telangiectasia) that can cause vision loss [17][18].
  • Digestive Issues: “Leaky” or abnormal blood vessels in the stomach or intestines, which can lead to internal bleeding or liver-related issues like portal hypertension [16][19].
  • Bone Health: People with Coats Plus may have thin bones (osteopenia) and are more likely to experience fractures from minor injuries [20][16].
  • Blood Counts: Coats Plus can affect the bone marrow, leading to low counts of red blood cells (anemia), white blood cells, or platelets [14].

Confirming a diagnosis of LCC through genetic testing for SNORD118 is the best way to help guide your care. While confirmed LCC typically lacks these multisystem features, your treating team will decide whether any eye, blood, bone, or gastrointestinal evaluations are appropriate based on your specific clinical findings and if testing remains inconclusive [5][4].

Common questions in this guide

What gene causes leukoencephalopathy with calcifications and cysts?
LCC is caused by disease-causing changes in both copies of the SNORD118 gene, with one copy inherited from each parent. SNORD118 is a non-protein-coding gene that produces U8 small nucleolar RNA, which helps cells assemble ribosomes.
How do SNORD118 mutations affect the brain?
SNORD118 mutations can make U8 small nucleolar RNA missing, misshapen, or unable to work correctly, impairing the assembly of mature ribosomes. This creates cellular stress, and researchers think small blood vessels in the brain may be especially vulnerable, contributing to white matter changes, cysts, and calcifications.
Can a standard genetic test miss LCC?
Yes. SNORD118 is a non-coding gene, while many standard genetic panels focus mainly on protein-coding genes, so LCC may be missed unless non-coding regions are included. Ask whether testing specifically covered SNORD118 and the relevant non-coding regions.
How is LCC different from Coats plus syndrome?
Both conditions can cause white matter disease, brain calcifications, and cysts, but LCC is linked to SNORD118 and impaired ribosome assembly, while Coats plus is most often linked to CTC1 and telomere biology. Coats plus more often affects organs outside the brain, including the eyes, digestive system, bones, and blood-forming marrow.
What tests may be considered if LCC genetic testing is negative?
A genetics team may first review whether testing included the non-coding SNORD118 gene and may consider additional testing, including CTC1, when results remain inconclusive or features suggest Coats plus. Eye, blood, bone, or gastrointestinal evaluations may be recommended based on symptoms and clinical findings rather than automatically for everyone.

Get notified when new evidence is published on Leukoencephalopathy with calcifications and cysts.

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References

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This page explains the genetics and proposed cellular mechanisms of LCC for educational purposes only and does not replace medical advice. Discuss genetic testing and any evaluation for Coats plus syndrome with your neurologist or genetics team.

Guide contents Leukoencephalopathy with calcifications and cysts
Research & Literature
01 Understanding Labrune Syndrome (LCC) 03 Imaging and Genetics