Groundbreaking research reveals the progressive nature of CTD in adulthood and a promising treatment pathway that could change lives.
Imagine your brain running on empty—not from lack of sleep or food, but because its fundamental energy currency cannot reach where it's desperately needed. This is the reality for individuals with Creatine Transporter Deficiency (CTD), a rare genetic disorder that cripples the brain's ability to maintain its energy supply. For decades, research has focused almost exclusively on children with this condition, leaving adults in the shadows. Now, a groundbreaking study of two adult brothers is rewriting the textbook on CTD, revealing both the progressive nature of this disorder into adulthood and a promising treatment pathway that could change lives .
When we think of metabolic disorders, we often picture conditions managed in childhood, but CTD tells a different story—one that continues to unfold across a lifetime. The journey of these two brothers, aged 31 and 36, provides a compelling window into both the challenges of adult CTD and the potential for meaningful intervention even later in life .
To understand CTD, we must first appreciate the role of creatine in the body. Think of creatine as the brain's battery system—it stores and shuttles energy to places where it's needed most, particularly during moments of high demand like learning, processing information, or even simply thinking 2 .
Normally, our bodies either obtain creatine from protein-rich foods or synthesize it internally through a two-step process involving the liver, kidneys, and pancreas. This creatine then travels through the bloodstream and enters tissues via specialized doorway proteins called creatine transporters. In the brain, these transporters are crucial because the blood-brain barrier prevents most externally supplied creatine from freely entering 4 .
CTD occurs when there's a malfunction in the SLC6A8 gene located on the X chromosome. This gene provides the blueprint for creating the brain's creatine transport proteins. When mutated, these transporters cannot properly bring creatine into brain cells, leaving neurons energy-depleted 2 5 .
As an X-linked disorder, CTD primarily affects males, who have only one X chromosome. Females with a mutation on one of their two X chromosomes may show milder symptoms or be asymptomatic, depending on which X chromosome is active in their cells—a process called X-inactivation 3 4 . Approximately 30% of CTD cases result from spontaneous mutations not inherited from either parent 6 .
Without adequate creatine, brain cells struggle to maintain their energy balance, leading to:
The severity of these symptoms varies significantly between patients, likely reflecting different types of mutations in the SLC6A8 gene and their impact on the transporter's function 5 .
For adults with CTD, the path to diagnosis is often long and frustrating. While the condition is typically identified in childhood, many adults spent their childhoods without a clear explanation for their challenges. Recent data shows that the average diagnosis age for girls with CTD is 11.8 years, but many likely reach adulthood undiagnosed, particularly females with milder symptoms 3 .
Unlike the static condition once assumed, CTD appears to be progressive in adulthood. The two brothers in the recent study experienced worsening symptoms in their third and fourth decades of life, including:
This progression contradicts the earlier belief that CTD stabilizes after childhood, highlighting the need for ongoing management throughout life.
Until recently, no treatment studies had focused specifically on adults with CTD . Standard approaches for pediatric patients—including high-dose creatine supplementation, often combined with arginine and glycine—have shown limited effectiveness for most patients, as the defective transporter still prevents creatine from entering brain cells 2 8 .
This left adults with CTD without proven therapeutic options, even as their symptoms progressed and quality of life declined. The brothers in the case study had reached a point where their deterioration threatened their ability to perform basic life functions, creating an urgent need for intervention .
Developmental delays, speech issues, behavioral concerns
Learning difficulties, social challenges, possible seizures
Continued cognitive challenges, behavioral issues
Progressive decline in motor function, speech, feeding ability
Faced with progressive decline in these two adult patients, clinicians designed a novel treatment approach centered on betaine, a naturally occurring compound found in foods like quinoa and spinach. Their methodology followed a careful, stepwise process:
When the standard approach with arginine and glycine caused adverse effects, the team shifted focus to betaine alone, marking a significant departure from conventional CTD treatment strategies.
The outcomes of this experimental intervention were compelling:
| Patient Age | Previous Treatment Response | Betaine Treatment Effects | Adverse Effects |
|---|---|---|---|
| 36 years | Adverse effects to arginine/glycine | Improved balance, speech clarity, and feeding ability; functional recovery after deterioration when stopped | None reported |
| 31 years | Not detailed in study | Reduced exhaustion, improved feeding ability, weight stabilization, able to resume protected work | None reported |
Both patients tolerated betaine well without the side effects experienced with earlier supplements. Most importantly, they experienced meaningful functional improvements that enhanced their quality of life and independence .
The researchers theorized that betaine might help through multiple mechanisms. Beyond potentially supporting alternative creatine transport pathways, betaine may function similarly to bumetanide—a medication showing promise for autism and epilepsy—by antagonizing NKCC1 channels in the brain .
Tolerance to betaine without adverse effects
Patients showed functional improvements
Relapse after treatment cessation
| Method/Reagent | Primary Function | Research Application |
|---|---|---|
| LC-MS/MS or GC-MS | Measure creatine, GAA, and creatinine levels | Biochemical diagnosis through blood/urine analysis 4 |
| MR Spectroscopy | Detect creatine levels in the brain | Non-invasive assessment of cerebral creatine deficiency 2 |
| Fibroblast Culture with Radiolabeled Creatine | Assess creatine uptake capacity | Confirm CTD diagnosis and test transporter function 6 7 |
| DNA Sequencing of SLC6A8 | Identify genetic mutations | Confirmatory diagnosis and variant characterization 2 |
| In Silico Protein Modeling | Predict impact of genetic variants | Understand how mutations affect transporter structure/function 5 |
The toolkit for understanding CTD continues to expand with sophisticated new approaches:
Using mass spectrometry to identify how SLC6A8 interacts with other proteins, and how these interactions are disrupted by disease-causing mutations 5 .
Creating three-dimensional models of mutated transporters to visualize how specific genetic changes disrupt the protein's shape and function 5 .
Evaluating compounds like cyclocreatine in animal models, which may bypass the defective transporter altogether 7 .
These advanced techniques are moving the field beyond diagnosis toward meaningful interventions that address the root cause of CTD rather than just managing symptoms.
The case of the two adult brothers treated with betaine opens exciting new avenues for CTD management, particularly for adults who have long been therapeutic orphans. While betaine shows promise, researchers continue to pursue multiple treatment strategies:
Approaches that deliver functional SLC6A8 genes directly to brain cells, potentially correcting the underlying defect 7 .
Developing methods to identify CTD early through dried blood spot testing, allowing intervention before symptoms appear 7 .
Investigating modified creatine molecules that might bypass the defective transporter and enter brain cells through alternative pathways 8 .
The future of CTD treatment likely lies in personalized approaches—matching specific interventions to individual genetic profiles and stages of life. As research increasingly includes adults and recognizes the progressive nature of this disorder, the prospects for meaningful interventions across the lifespan continue to brighten.
The story of CTD is evolving from a static childhood disorder to a lifelong condition requiring ongoing management. The courageous participation of adult patients in research ensures that the next chapter will include solutions for all ages, offering hope where little existed before.