Cure RTD

Exciting news from the neuromuscular world! The FDA has approved ISEMBYLD™ (apitegromab-mstn), the first muscle-targeted treatment for spinal muscular atrophy (SMA). It is approved for adults and children age 2 and older who are already receiving an SMN2-targeted therapy.

This is a major milestone for the SMA community, but it is also potentially exciting news for those fighting RTD. 💪

SMA is a genetic disease that causes degeneration of motor neurons, leading to progressive muscle weakness and wasting. While SMA and RTD are very different disorders, RTD also damages motor neurons causing similar muscle weakness to SMA.

Apitegromab works by inhibiting activation of myostatin, a protein that normally limits skeletal muscle growth. By reducing myostatin signaling, the treatment removes some of this biological brake on muscle growth and can improve muscle strength and function.

Importantly, apitegromab does not correct the underlying genetic defect in SMA or a treatment for SMA. Instead, it targets the muscle itself and is used on top of other SMA treatments, such as gene therapy.

That new treatment is particularly relevant to RTD. High-dose riboflavin, together with other adjunct treatments, can help stabilize RTD and sometimes lead to improvements in some patients, especially when treatment begins early. However, muscle weakness often persists, leaving some patients with profound long-term weakness. We currently have no approved therapy specifically designed to increase muscle strength or preserve muscle mass in RTD.

Gene therapies and other disease-modifying treatments for SMA have been available for years, yet many treated individuals continue to experience significant muscle weakness. We see a similar problem in RTD, where riboflavin treatment rarely fully restores muscle strength. That is exactly why a treatment that targets skeletal muscle directly that has been shown to work is so exciting.

To be clear, apitegromab has not been studied or approved for RTD. Determining whether it could benefit RTD patients would require preclinical studies followed by RTD-specific clinical research and an appropriate regulatory pathway. This is why Cure RTD exists!

Still, this approval provides an important proof of principle: targeting muscle biology can provide additional benefit even when patients are already receiving treatment directed at the underlying neurological disease.

⚾️ How cool is this?! 💙

Last week, Carson and Parker—two incredible brothers living with RTD Type 2—had the unforgettable opportunity to throw out the first pitch at a Houston Astros game!

Their dad, Dylan, a Cure RTD Board Member, joined them on the mound as they proudly helped raise awareness for Riboflavin Transporter Deficiency. Their mom, Rayme, was there cheering them on and supporting them every step of the way. 💙

This special experience was originally auctioned off at Vail’s first “C&P for Cure RTD” fundraiser last November. The winner so generously chose to give their winnings back to the Vail family, making it possible for Carson and Parker to have this incredible experience while shining a spotlight on RTD.

What an amazing moment for an amazing family—and such a beautiful example of how this community continues to show up for one another.

Way to go, Carson, Parker, and the entire Vail family!

Thank you for helping us spread awareness and bring RTD out of the shadows. Every story, every conversation, and every moment like this brings us one step closer to a future where no family has to face RTD alone.

K is for Km — The Michaelis Constant

Km may be one of the most important numbers for understanding why taking high-dose riboflavin (vitamin B2) helps in Riboflavin Transporter Deficiency (RTD).

A riboflavin transporter is a protein in the cell membrane that grabs riboflavin outside the cell and moves it inside. Think of it like a turnstile with a grip.

Two numbers help tell us how well it works........

Vmax is how fast the turnstile can spin. It is the maximum transport rate when riboflavin levels are very high outside the cell.

Km tells us how strong the grip is. It is the riboflavin concentration outside the cell needed for the transporter to reach half its maximum speed. In practical terms, Km reflects affinity.

A low Km means a strong grip. The transporter can capture riboflavin even when very little is available.

A high Km means a weak grip. Much more riboflavin must be present outside the cell before transport works efficiently.

The numbers for RFVT2.......

RFVT2 is the riboflavin transporter encoded by the SLC52A2 gene. Mutations in this gene cause RTD Type 2.

A healthy RFVT2 transporter has a Km of about 0.26 micromolar. Free riboflavin circulating in the blood is normally only in the tens of nanomolar, well below that Km value.

That matters.

When riboflavin levels outside a cell are far below the Km value, increasing the amount available can significantly increase how much enters the cell.

It also means the system becomes very sensitive to mutations that weaken the transporter’s grip.

What RTD mutations do..........

Research funded by Cure RTD found that all the SLC52A2 missense mutations studied increased the Km of RFVT2 roughly three- to nine-fold (3-9X). However, Vmax was only modestly decreased or not changed at all depending on the mutation.

That difference is critical.

The turnstile can still spin close to normal speed.

The bigger problem is that it can no longer grab riboflavin very well.

Why high-dose riboflavin works..........

Normal blood riboflavin levels are well below the transporter’s Km. If a mutation pushes Km several times higher, the same amount of riboflavin produces far less transport into the cell.

The riboflavin transporter may still be there and still work, but it simply needs much more riboflavin outside the cell to achieve the same level of transport as a normal transporter.

High-dose riboflavin therapy aims to overcome poor transporter affinity by dramatically increasing the amount of riboflavin available.

Why taking high dose riboflavin 3 to 4 times a day matters........

Riboflavin is water-soluble and does not remain at high levels in the bloodstream for long. Excess riboflavin is quickly filtered by the kidneys and eliminated in the urine.

That means one large daily dose creates a temporary spike in the blood followed by quickly falling levels. Splitting treatment into three or four doses helps keep more riboflavin available in the blood throughout the day, giving the weakened transporter repeated opportunities to move it into cells.

Why Km is not the whole story.......

Riboflavin is lifesaving in RTD, but it is not a cure.

Not every SLC52 gene mutation only affects Km. Some mutations produce transporters that never reach the cell membrane, are unstable, or are made in very small amounts.

In those cases, there may be little or no functional transporter for extra riboflavin to rescue.

With more than 70 reported SLC52A2 variants, treatment response should not be expected to be identical between patients.

Recent Cure RTD-funded research has also shown that abnormal RFVT proteins may cause problems beyond simply reducing riboflavin transport. Some mutant proteins may become trapped inside cells or disrupt processes involving cellular stress, calcium regulation, and mitochondrial function. As a result, cells may still be damaged even when riboflavin levels are normal. Riboflavin alone cannot correct these problems, suggesting that additional treatments targeting these other cellular abnormalities may be needed.

Evidence suggests that SLC52A3 gene mutations causing RTD Type 3 may disrupt riboflavin transport in similar ways by increasing Km. However, other mechanisms may also contribute, and their effects can vary depending on the specific gene mutation.

The takeaway........

Km tells us how much riboflavin a transporter needs around it to work efficiently.

For most SLC52 mutations causing RTD the riboflavin transporter is not destroyed. Instead, its grip on riboflavin just becomes much weaker.

The transporter can still work, but it needs riboflavin concentrations that a normal diet and normal blood levels cannot normally provide.

High-dose riboflavin tries to overcome that weakness by flooding the impaired transporter with riboflavin repeatedly throughout the day.

The fact that this works at all is remarkable.

The fact that it works only partially is exactly why RTD research still matters.

J is for Journey — The Diagnostic Odyssey

For many individuals and families living with Riboflavin Transporter Deficiency (RTD), getting the correct diagnosis becomes a journey all its own.

And far too often, it is a long and difficult one.

RTD can look like many other conditions, and there is no single way it begins. One child may start walking differently or falling more often. Another may begin holding objects closer as their vision fades. A teenager or adult may notice they are having more difficulty understanding speech because of hearing loss. Others may first develop swallowing problems, breathing difficulties, or unexplained weakness.

Another challenge is that these symptoms often do not appear at the same time. They may develop months or even years apart, making it easy to view each problem in isolation rather than as part of the same disease. Some older individuals with RTD may only ever develop a few symptoms, such as hearing or vision loss, which can make the underlying diagnosis even harder to recognize.

A child may first see an eye doctor. Months later, an audiologist. Then perhaps a neurologist or respiratory specialist. Blood tests and MRIs can be normal. One doctor may be looking at just hearing, another at vision, another at weakness, while the real cause remains hidden.

Every RTD journey is different.

For some families, the answer comes quickly. For others, it takes years of appointments, scans, blood tests, hospital visits and incorrect diagnoses, all while watching someone they love lose abilities without knowing why.

There is also a historical reason behind many of these stories. Until around 2010–2012, researchers did not understand that mutations in SLC52A2 and SLC52A3 caused RTD. Many older patients therefore spent years, sometimes decades, searching for an answer medicine simply could not give them at the time.

Today, the Cure RTD Patient Database includes more than 550 genetically confirmed RTD patients from around the world. Among diagnosed patients, the average time from first recognizable symptoms to diagnosis is about two years, but the range extends from a months to decades.

And those we know about may represent only a fraction of the people living with RTD. Based on the estimated frequency of disease-causing genes, there could still be thousands of undiagnosed patients worldwide, with new babies born with RTD every week.

Thankfully, the journey is starting to change.

For more than a decade, Cure RTD, along with the doctors and researchers we support, has worked to increase awareness. Every paper published, every patient story shared and every doctor who learns to recognize RTD increases the chance that the next person will be diagnosed sooner.

Genetic testing has also changed everything. Testing that was once expensive and difficult to access is now faster, cheaper and far more available. Whole-exome and other genetic testing can now uncover RTD even when doctors were originally looking for something completely different.

Artificial intelligence is becoming another useful tool. Families and physicians can enter unusual combinations of RTD symptoms into medical search and AI systems and uncover rare diseases that might once have taken years to consider. Increasingly, RTD is one of them.

None of these tools are perfect, but each has the potential to shorten the journey.

And with RTD, time matters.

Unlike most progressive genetic neurological diseases, RTD has a treatment.

High-dose riboflavin, often combined with other supportive treatments and supplements, can help stabilize the disease and sometimes lead to meaningful improvement. In general, patients treated closer to the start of their symptoms have better outcomes.

The reason is painfully simple. Some struggling nerves and cells may recover once treatment begins, but damage that progresses too far can become permanent. Hearing, vision, strength, breathing and mobility can sometimes be lost while a family is still searching for the name of the disease.

That is why awareness matters.

A physician who recognizes RTD one appointment earlier may change the course of someone's life. A family who shares their story may help another family finally find an answer.

Every new diagnosis marks the end of one difficult journey and the beginning of another, this time with a name, a treatment and hope.

J is for Journey.

Our hope is that one day the journey from the first symptom of RTD to diagnosis will no longer be measured in years.

It will be measured in days.

A huge thank you from Cure RTD to Federico Autunno in Italy for once again hosting his annual charity event in support of RTD research!

Federico is a University of Salerno student living with RTD Type 3. Having faced the challenges of RTD from a young age, he understands better than most just how important medical research is, and how much hope it can bring to families around the world.

Thank you as well to everyone who came out yesterday for a beautiful evening among the olive groves of San Biase di Ceraso. Your generosity, support and commitment to this cause mean more than you know.

Grazie, Federico, and thank you to everyone who continues to stand with the RTD community and push research forward!

I is for Intrafamilial Variability

Same family. Same two RTD gene mutations. Different journeys.

Among the more than 500 individuals in the Cure RTD Patient Registry, there are over 150 affected sibling. This is not surprising because Riboflavin Transporter Deficiency (RTD) is usually inherited in an autosomal recessive pattern.

When both parents carry an altered copy of the same RTD-associated gene, each pregnancy has a 25% chance of producing a child who inherits both altered copies and develops RTD.

What often surprises families and doctors is how differently RTD can affect siblings.

What is intrafamilial variability?

Intrafamilial variability describes differences in the age of onset, symptoms, severity, and progression of a condition within the same family.

In RTD, these differences can often be dramatic.

Two siblings may carry the exact same disease-causing variants (mutations) in the SLC52A2 or SLC52A3 genes, yet follow very different clinical paths.

Without riboflavin treatment, one child may become severely unwell during infancy and develop rapid neurological decline and even pass away. Their sibling may remain apparently healthy for many years before developing milder, and sometimes different and slower-progressing symptoms.

In some RTD families, one sibling may require extensive medical support while another with the same variants is much less affected.

How can the same mutations cause different outcomes?

There is no single proven explanation. The RTD-causing variants are important, but they are only part of the story.

Modifier genes

Siblings may share the same RTD-causing variants, but they do not share their entire genetic makeup. Other genes can influence many things important in RTD, including riboflavin metabolism, mitochondrial function, oxidative stress, and the body’s ability to compensate for reduced transporter activity. Depending on their effects, these modifier genes may make the overall presentation of RTD either milder or more severe.

Illness and metabolic stress

In more than half of people with RTD, the first symptoms appear shortly after a metabolic stressor. This may include an infection, prolonged fever, surgery, or another physical stress that increases the body’s energy demands. In someone already close to a metabolic threshold, a major stressor may trigger or accelerate symptoms. This could help explain why siblings exposed to different stresses throughout their lives can follow very different clinical paths.

Epigenetic and biological differences

Even when siblings share the same RTD variants, those genes may not behave in exactly the same way. Differences in growth, hormones, mitochondrial function, and other biological processes can affect when symptoms appear, how quickly they progress, and which areas of the body are most vulnerable.

Nutrition

In some young adults, RTD symptoms first appeared after a major diet change that sharply reduced riboflavin intake. This suggests that, before treatment begins, diet may also play a factor in determining when symptoms appear and how the disease progresses, which can be different between siblings.

Researchers are still trying to understand why these differences can be so large. Many of these explanations remain hypotheses rather than proven causes.

Why does this matter?

Doctors should never assume that an apparently healthy sibling is unaffected simply because they do not resemble the first family member diagnosed with RTD.

Once one person in a family is diagnosed with RTD, all biological siblings should be evaluated genetically as soon as possible. If an undiagnosed sibling shows symptoms consistent with RTD, riboflavin treatment should begin while genetic testing is still underway. Delaying treatment could allow avoidable and potentially permanent damage to occur.

The same RTD variants do not guarantee the same symptoms, severity, or age of onset.

In RTD, the first diagnosis should open the door to testing the entire family. Early identification may change the course of a sibling’s life.

H is for Heterozygous

Can one altered gene copy cause Riboflavin Transporter Deficiency?

RTD is a autosomal recessive genetic disorder. The basic idea is simple.

We inherit two copies of most genes, one from our mother and one from our father. In a recessive disorder, both copies need to be altered for the person to develop the disease.

• RTD Type 2 is linked to the SLC52A2 gene.

• RTD Type 3 is linked to the SLC52A3 gene.

Among the more than 500 patients in the Cure RTD Patient Registry, every person with RTD Type 2 has two identified SLC52A2 variants (mutations), one inherited from each parent.

RTD Type 3 is more complicated.

In approximately 20% of people with RTD Type 3, genetic testing finds only one SLC52A3 variant. This is called being heterozygous.

Think of a gene as an instruction manual. Someone who is heterozygous has one altered copy and one copy that appears normal.

Traditionally, this person would be considered a healthy “carrier” and develop no RTD symptoms. However, the growing number of RTD Type 3 cases with only one identified variant shows that the story is not always that simple.

These patients often develop symptoms later in life (normally 15 to 40+ years old) and can vary widely in severity. Many have a milder form of RTD than children who present early with two altered gene copies. In most reported cases, symptoms improve or stabilize with standard riboflavin treatment.

How can one altered copy cause symptoms?

The honest answer is that we do not fully know, but there are several possibilities.

It is possible that a second variant may be hiding. Genetic tests are very good at reading the main protein-coding regions of a gene, but they do not detect everything. A second variant may be deep inside the gene or in a region that controls how much RFVT3 protein is produced.

It is also possible that one altered copy may sometimes be enough to cause RTD in some people. Certain SLC52A3 variants may act in a dominant way, meaning one altered copy can increase the risk of disease. This does not mean everyone with the variant will develop symptoms.

This leads to two important genetic terms:

Reduced penetrance means some people with the variant develop symptoms while others remain healthy.

Variable expressivity means people with the same variant can have very different symptoms and levels of severity, even within the same family.

Other genes may influence the outcome. Additional genetic differences affecting areas such as riboflavin metabolism, energy metabolism or cell/nerve health may help determine whether symptoms develop.

Illness, infection or other biological stress may trigger symptoms in someone who had previously been coping with reduced transporter function. Many RTD patients developed or worsened after an infection, and more recently, major dietary changes have also been reported as possible triggers in a few RTD adults. The exact connection remains unclear.

The important message

A person with RTD-like symptoms should not be dismissed simply because testing found only one SLC52A3 variant.

At the same time, one variant does not automatically prove RTD. It must be considered alongside the person’s symptoms, family history, genetic findings and response to treatment.

RTD genetics are teaching us that biology does not always follow simple textbook rules. Sometimes one altered gene copy is only part of the answer. Sometimes it may be enough to matter.

H is for Heterozygous: one altered copy, many unanswered questions and a diagnosis that should never be overlooked.

H is for Homodimer

We talk a lot about RFVT2, the riboflavin transporter made by the SLC52A2 gene. Its job is to help move riboflavin (vitamin B2), into cells. When RFVT2 does not work properly, it causes Riboflavin Transporter Deficiency Type 2.

New Cure RTD funded research adds an important layer to this story.

RFVT2 does not appear to work as a single protein. It can pair with another RFVT2 protein to form what scientists call a homodimer.

That word sounds complicated, but it simply means two identical copies of the same protein working together. Think of it like a buddy system, a zipper, or two matching halves that help stabilize each other.

A recent study showed that this pairing may be an important part of how RFVT2 folds, stabilizes, reaches the cell membrane, and functions.

That matters because RTD-causing mutations can damage this pairing.

When RFVT2 cannot form a proper pair, several things may go wrong at once.

First, the protein may become unstable. A damaged copy may not fold correctly, and the cell may recognize it as defective. It can then get trapped in the endoplasmic reticulum (ER), which is the cell’s protein-folding factory.

When too much misfolded protein builds up in the ER, the cell turns on an alarm system called ER stress or the unfolded protein response. At first, this response is protective. The cell tries to refold the protein or clear it away. But if the stress continues, it can become harmful and push vulnerable neurons and other cells toward dysfunction or death.

That is what makes this research so important. RTD patient's motor neurons had large increases ER stress. Even more interesting, this happened despite normal cellular flavin levels (Riboflavin, FMN and FAD). That means RTD may not be only a “not enough riboflavin” problem. In some cases, the damaged RFVT2 protein itself may be causing stress inside the cell.

Second, pairing may help RFVT2 reach and remain stable on the cell surface. Many membrane proteins have quality-control checkpoints. If they fold and assemble correctly, they are sent to the cell membrane where they can do their job. If they do not, they may be held back inside the cell or degraded. A mutation that weakens dimer formation could mean fewer working transporters on the membrane.

Third, RFVT2 has loops that extend inside and outside the membrane. These loops may help the transporter fold, pair, move, and communicate with other proteins or cell-signaling systems. If mutations distort the structure, those loop interactions may also be affected. That could help explain why RTD cells show disrupted calcium signaling and struggling mitochondria.

Researchers have tested several RTD mutations. When mutant RFVT2 copies paired with the same mutant copy, dimer formation dropped by about 50% to 80% compared with normal RFVT2. But most patients carry two different mutations, one from each parent. When two different damaged copies were tested together, dimer formation dropped by more than 90%.

That could be a big clue.

It means two mutations may not simply add up. They may interact in a way that makes RFVT2 much harder to fold, pair, or stabilize. This could partially help explain why RTD can look so different from one person to another, along with many other genetic factors.

Some mutations may mostly affect riboflavin binding. Some may destabilize the protein. Some may trap it inside the cell. Some may damage dimer formation. Some may do several of these things at once.

This does not make riboflavin less important. High-dose riboflavin remains the core treatment and can be lifesaving, especially when started early. But this research helps explain why riboflavin alone may not fully solve the disease for every patient. It also raises an interesting possibility: riboflavin may be helping in more than one way. Beyond increasing riboflavin availability, it may also help some damaged RFVT2 proteins fold more correctly, become more stable, and form homodimers more effectively. That idea still needs more research, but it could help explain why some patients improve with high-dose riboflavin even when the biology is more complex than a simple vitamin shortage.

RTD may involve two connected problems: not enough riboflavin getting where it needs to go, and a damaged transporter protein that may cause additional stress and cell injury.

That opens the door to new research questions. Can we help RFVT2 fold better? Can we stabilize the transporter? Can we reduce ER stress? Can we protect mitochondria while riboflavin does its job? Could future treatments include chaperone-like compounds, ER stress modulators, mitochondrial support, or gene-based approaches?

The homodimer story gives us another piece of the RTD puzzle. In simple terms, RFVT2 works best with a partner. When mutations prevent that partnership, the effects can ripple through the entire cell.

And every new piece like this gives researchers another possible target.