B Vitamin Deficiency Could Be One Factor in Fatigue with MS & Other Autoimmune Conditions

Fatigue is one of the most common and debilitating symptoms for people with MS. In this article, I'll explain how your family health history can help estimate your risk for severe fatigue, the surprising connection between B vitamins and energy production, and the practical steps you can take to address the root causes of exhaustion.

When Fatigue Takes Over

I was diagnosed with MS at age 45 and was still jogging every day. But within two years, I could no longer jog. I installed an Endless Pool and began swimming every morning instead. The following year I needed a tilt/recline wheelchair, but I kept up my daily swimming routine.

Despite staying active, I was experiencing worsening fatigue. My neurologist prescribed Provigil to treat it, which provided a small improvement — I was definitely more exhausted without it. But I was still completely drained by 10 in the morning.

Each year I seemed a bit worse than the year before. I asked myself: Was I doing everything I could to help myself? That question sent me back to PubMed.gov, where I started reading basic science papers about animal models of multiple sclerosis, Parkinson's, and Alzheimer's, looking for interventions I hadn't yet tried.

The Mitochondrial Connection

Mitochondria are tiny structures inside your cells that produce adenosine triphosphate (ATP), the molecule your cells use to power all their chemical reactions. Your brain and spinal cord require enormous amounts of ATP to function properly.

As I read through the research, I noticed a common theme across three different brain diseases —
multiple sclerosis, Alzheimer's, and Parkinson's. As mitochondria became less effective at producing ATP, symptoms worsened. I theorized that mitochondrial dysfunction could be driving disability in secondary and primary progressive MS. The logic was straightforward: If the brain doesn't have enough ATP, it can't work as well. This energy deficit could manifest as motor symptoms, sensory problems, mood changes, fatigue, or brain fog.

My Mitochondria Support Cocktail

Based on my reading, I created a cocktail of supplements to support my mitochondria that included lipoic acid, carnitine, coenzyme Q, and B vitamins. After six months, I didn’t feel any improvements in my energy, strength, or stamina. Frustrated, I stopped taking them.

After 36 hours, I couldn’t get out of bed or go to work. At 72 hours, my wife suggested I restart my supplements — so I did. The next morning, my baseline energy levels were back, and I could go to work!

I was super excited. Two weeks later, I retested the experiment. Again at 36 hours I could not get out of bed, and again after resuming them I regained my energy.

From there, I dove headfirst into all the research papers I could find, and I devoted myself to refining my supplement cocktail for mitochondrial health.

This discovery energized me to read more research and continue refining my supplement protocol. That was 2008. In the 14 years since, I've learned much more about B vitamin pathways, genetic variants, and homocysteine metabolism — knowledge I now use to help my patients address their own fatigue.

Understanding Genetic Risk by Looking at Your Family History

In my clinical practice, I ask patients detailed questions about their family health history. Do they have relatives with age-related macular degeneration (a leading cause of blindness)? Is there a family history of anxiety, depression, bipolar disorder, or schizophrenia? What about memory problems, dementia, Parkinson's, seizures, neuropathies, or restless legs? Does heart disease run in the family?

I also ask about their personal history with any of these same conditions.

In my own case, I have multiple aunts with age-related macular degeneration. I have family members with schizophrenia, bipolar disorder, seizures, restless legs, and neuropathies. Multiple uncles developed early heart disease. I also have relatives with rheumatoid arthritis, inflammatory bowel disease, and mononeuritis multiplex (nerve damage affecting multiple areas).

This family history matters because it reveals potential genetic vulnerabilities in how my body processes B vitamins — vulnerabilities that can contribute to problems with the brain, eyes, and heart.

How B Vitamins Support Your Brain, Heart, And Eyes

B vitamins help your cells complete chemical reactions that are essential for your brain, eyes, and heart. One crucial process they support is called methylation — the addition of a methyl group (a small cluster of atoms) to various molecules in your body.

When methylation doesn't work properly, people face higher risks of damage to their retinas, heart, and brain. The more family members you have with health issues affecting these three areas, the more likely you are to have genetic variants that affect how your cells manage methylation pathways. These variants can also increase the risk of autoimmune conditions.

Genetic Variants and B Vitamins

When you eat foods containing B vitamins, your cells need to activate those vitamins before they can participate in the chemical reactions your body needs. This activation process depends on enzymes (proteins that speed up chemical reactions), and how efficiently your enzymes work depends on your genetics.

Genetic variants called single nucleotide polymorphisms (SNPs) occur when a single building block in your DNA is swapped for a different one. Sometimes these swaps are beneficial and improve how your body functions. Other times they create inefficiencies that increase the probability of chronic symptoms. In rare cases, SNPs can even be fatal.

The B vitamins most affected by these genetic variants include folate (vitamin B9), cobalamin (vitamin B12), pyridoxine (vitamin B6), riboflavin (vitamin B2), and thiamin (vitamin B1). When your body can't efficiently activate these B vitamins, a compound called homocysteine builds up in your blood. High homocysteine is linked to higher rates of damage to the retina, heart, and brain — exactly the three areas where my family has significant health issues.

Why Your Homocysteine Level Matters

Homocysteine is a marker that reveals how efficiently your cells are using B vitamins. Elevated homocysteine is toxic to brain^4,7 and retinal cells^5,6 and indicates insufficient B vitamin levels. High homocysteine can contribute to the development of cardiovascular, neurological, and psychiatric disorders. ^4,7

When I checked my homocysteine level and my genetics around B vitamin activation, I discovered my homocysteine was significantly elevated. This confirmed that I don't have efficient methylation and that I carry multiple variants affecting how my B vitamins are activated.

My enzymes struggle to activate the B vitamins from food into the active forms needed for proper methylation. This is why my homocysteine was moderately to severely elevated, placing me at higher risk for cognitive decline, early heart disease, and vision problems.

In my clinical practice, I ask patients about their family and personal history of macular degeneration, neurological diseases, psychiatric conditions, and heart disease. I also check basic primary care labs including complete blood count, kidney function, liver function, and metabolic health markers.

The conventional cutoff for elevated homocysteine is 15 mmol/L, though some labs set the upper limit at 10 mmol/L. I monitor folate, vitamin B12, homocysteine, and methylmalonic acid (another B vitamin marker) to understand my patients' B vitamin status. I tell them the optimal homocysteine range is 5 to 10 mmol/L.

Here's how I categorize homocysteine elevations:

• Mild elevation: 10-15 mmol/L
• Moderate elevation: 16-30 mmol/L
• Severe elevation: 31-60 mmol/L
• Very severe elevation: greater than 60 mmol/L

After reviewing these lab results, I create a plan to address any B vitamin deficiencies.

Choosing the Right B Vitamin Supplement

I recommend that my patients avoid synthetic vitamin preparations. Instead, I suggest a B vitamin complex that uses activated forms of the vitamins, which bypass the problematic enzyme inefficiencies caused by SNPs.

The activated forms include methylcobalamin (vitamin B12), methylfolate (B9), and pyridoxal-5-phosphate (B6), which work together to reduce homocysteine to optimal levels. I also recommend benfotiamine (activated vitamin B1), which supports brain,⁸ retinal^9,10 and heart health11, and riboflavin ⁵ phosphate (activated vitamin B2) for patients with migraine and chronic headaches.^12,13

Other helpful activated B vitamins include niacin and niacinamide for migraine and chronic headache¹⁴; choline for cognition and mental health^15,16; and biotin, which supports myelin production (the protective coating around nerve fibers) ¹⁷.

All B vitamins work together synergistically to support your cells' function. This is why I recommend taking a B complex rather than individual B vitamins - it reduces the risk of creating new deficiencies while addressing existing ones.

How Activated B Vitamins Helped Me

Using activated B vitamins, I was able to bypass the inefficient enzymes that couldn't properly process the B vitamins from my food. I checked my genetics and those of my family members, confirming we carry multiple genetic variants affecting the methylation pathways for folate (vitamin B9), cobalamin (vitamin B12), pyridoxine (vitamin B6), and riboflavin (vitamin B2).

The activated B vitamins were helpful, but I needed even higher doses of activated folate and cobalamin. I monitored my homocysteine every six months until it reached the optimal range of 5 to 10 mmol/L. I was careful not to overcorrect, as that can create problems too.

My Approach with Patients

I start patients on activated B vitamins and recheck their homocysteine after three months, making adjustments based on the results. I continue monitoring every three months until we achieve an optimal homocysteine level and establish a stable supplement program.

You can ask your medical team to monitor your B vitamins and homocysteine. If you're unable to obtain these tests through your healthcare provider, you may be able to order them directly through services like Your Lab Work.

Why I Avoid Folic Acid

Most commercially available vitamin supplements use synthetic vitamins, which share many properties with naturally occurring vitamins but aren't quite as effective. Folic acid is a synthetic B vitamin added to white flour to reduce the risk of neural tube defects in developing babies. However, it has been associated with increased cancer risk, likely because it can suppress some of the activity of the natural form of folate.^1,2

This is another reason I recommend B vitamin complexes that use activated, naturally occurring forms rather than synthetic versions. The activated B vitamin formula I recommend contains the entire spectrum of B vitamins to support cardiovascular, neurological, and retinal health. It includes vitamins B2, B6, and B12; benfotiamine (a fat-soluble, more physiologically active form of thiamine); and folate as Quatrefolic®, which has greater stability, solubility, and bioavailability than synthetic folic acid. ^18,19

Tailoring The Approach to Homocysteine Levels

For people with mild to moderate homocysteine elevation (10-30 mmol/L), one to two capsules of Activated B vitamins daily often corrects the problem. Some people with moderate elevations can achieve optimal levels with two capsules daily.

However, people with severe or very severe elevations (greater than 30 mmol/L) typically need higher doses of activated folate, activated cobalamin, and other activated B vitamins, along with closer monitoring of their homocysteine levels. They're more likely to benefit from a specialized formula like MTHFR Complete.

My Resolution

My fatigue was resolved years ago. Since then, I've helped thousands of people address their fatigue using diet, lifestyle changes, and targeted supplement support. I take a careful history, asking about family health background and personal history, and order relevant lab tests. This allows me to provide specific recommendations to address B vitamin metabolism problems that contribute to fatigue and increase the risk of neurodegeneration, early heart disease, and age-related macular degeneration.

If you're struggling with persistent fatigue, consider asking your healthcare provider to check your homocysteine and B vitamin levels. Your family history might hold important clues about whether genetic variants are affecting your energy levels - and whether activated B vitamins could make a significant difference in how you feel.

Citations

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