MDDS, or mitochondrial DNA depletion syndrome, is a group of rare inherited disorders in which a baby’s cells cannot maintain enough mitochondrial DNA to produce the energy their organs need to function. Most forms appear during infancy or the first two years of life, and they can affect the muscles, brain, liver, or multiple organs at once. MDDS is not a single disease but rather a spectrum of related conditions, each linked to a different gene mutation.
How MDDS Affects a Baby’s Cells
Every cell relies on mitochondria to convert nutrients into usable energy. Mitochondria carry their own small set of DNA, separate from the DNA in the cell’s nucleus. That mitochondrial DNA contains instructions for building critical parts of the cell’s energy-production machinery. In MDDS, the amount of mitochondrial DNA in affected tissues drops severely, sometimes to a fraction of normal levels. Without enough of these instructions, cells can’t assemble the components they need to generate energy.
The organs hit hardest are the ones with the highest energy demands: the brain, muscles, and liver. When those tissues can’t keep up with their energy needs, they begin to malfunction. Which organs are affected, and how severely, depends on the specific genetic mutation a baby carries.
The Three Main Types
MDDS is broadly grouped into three clinical forms based on which parts of the body are most involved.
Myopathic (Muscle-Dominant)
This form primarily attacks skeletal muscle. Babies typically show signs before age 2, including low muscle tone (hypotonia), progressive muscle weakness, and difficulty with feeding or breathing as the muscles that support those functions weaken.
Encephalomyopathic (Brain and Muscle)
This type usually appears during infancy with a combination of low muscle tone and prominent neurological problems. Affected babies may have developmental delays, movement difficulties, seizures, or hearing loss. The brain involvement distinguishes this form from the purely muscular type.
Hepatocerebral (Liver and Brain)
This is one of the most commonly diagnosed forms in infants. It causes early-onset liver dysfunction alongside neurological symptoms. In one study of 23 patients with hepatocerebral MDDS, 91% developed cholestasis (a backup of bile that causes jaundice), and about 68% had an enlarged liver. Babies with this form often present with yellowing of the skin and eyes, pale stools, poor growth, low muscle tone, and in severe cases, acute liver failure.
Early Signs to Recognize
Because MDDS can affect different organs, symptoms vary, but several warning signs are common across the types:
- Low muscle tone (hypotonia): A baby may feel unusually floppy when held and have difficulty supporting their head or limbs.
- Poor feeding and failure to thrive: Weakness in the muscles involved in sucking and swallowing can make feeding exhausting, leading to slow weight gain.
- Jaundice and liver problems: Yellowed skin, dark urine, or pale stools can signal that the liver is failing to process bile properly.
- Developmental regression: A baby who had been meeting milestones may begin losing skills they previously acquired.
- Seizures or abnormal eye movements: Neurological involvement can produce involuntary eye jerking (nystagmus) or seizure activity.
These symptoms often overlap with other conditions, which can delay diagnosis. A baby showing a combination of unexplained muscle weakness and organ dysfunction, particularly involving the liver, raises suspicion for MDDS.
What Causes It Genetically
MDDS follows an autosomal recessive inheritance pattern, meaning a baby must inherit a faulty copy of the same gene from each parent. Parents are typically healthy carriers with no symptoms of their own. At least ten nuclear genes have been linked to MDDS, including TK2, DGUOK, SUCLA2, SUCLG1, RRM2B, POLG, MPV17, C10orf2, FBXL4, and MGME1.
Each of these genes plays a role in either building the raw materials mitochondrial DNA needs to copy itself or in the copying process directly. When one of these genes is mutated, the cell’s ability to maintain its supply of mitochondrial DNA breaks down. Some mutations are extremely rare. Variants in the SUCLA2 gene, for instance, have been documented in only about 56 cases worldwide, with a cluster of cases traced to the Faroe Islands where a specific mutation is more prevalent in the population.
How MDDS Is Diagnosed
Diagnosing MDDS typically involves several steps, starting with blood tests that reveal clues like elevated lactic acid (a sign cells are struggling to produce energy normally) and abnormal liver enzymes. If a doctor suspects a mitochondrial disorder, more specific testing follows.
A muscle biopsy can measure the actual amount of mitochondrial DNA in tissue and assess how well the energy-production machinery is working. This was historically the gold standard for confirming the diagnosis. Today, genetic testing has become the most definitive tool. Whole-exome sequencing or targeted gene panels can identify the specific mutation responsible, which helps determine the type of MDDS and guides expectations for how the disease may progress. In many cases, genetic testing can confirm a diagnosis without needing a biopsy at all.
Treatment and Outlook
There is currently no cure for any form of MDDS. Treatment focuses on managing symptoms and preventing complications. For babies with feeding difficulties, this may mean nutritional support through a feeding tube. Seizures are managed with appropriate medications. Physical therapy can help maintain muscle function as long as possible.
For the hepatocerebral form, liver transplantation is sometimes considered, though it is only an option when the brain is not severely affected. Stem cell transplantation has been used in a small number of cases. Both are aggressive interventions with significant risks, and outcomes depend heavily on the specific mutation and how much the nervous system is involved.
Researchers are actively investigating targeted therapies, including approaches that try to restore the balance of DNA building blocks that mitochondria need, as well as gene therapy delivered through viral vectors. Some of these have reached early clinical trials or compassionate-use cases, but none are yet standard treatments. MDDS carries a poor prognosis for most patients, particularly when symptoms appear in the first months of life and involve multiple organ systems. The specific gene mutation, the degree of mitochondrial DNA loss, and which organs are affected all influence how the disease progresses.
MDDS vs. MdDS: A Note on the Name
If you came across “MdDS” rather than “MDDS,” you may have been reading about a completely different condition called Mal de Débarquement Syndrome, a balance disorder that causes a persistent sensation of rocking or swaying, typically after travel by boat or plane. MdDS has been reported almost exclusively in adults. A 2023 case series described just three pediatric patients with the condition, making it extraordinarily uncommon in children and essentially unreported in babies. If your child’s doctor used the abbreviation MDDS, they are almost certainly referring to the mitochondrial DNA depletion syndrome described above.