RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy (RRM2B-MDS) is a severe condition that begins in infancy and affects multiple body systems. It is associated with brain dysfunction combined with muscle weakness (encephalomyopathy). Many affected individuals also have a kidney dysfunction known as renal tubulopathy.

Infants with RRM2B-MDS have weak muscle tone (hypotonia) and do not grow or gain weight at the expected rate (faltering weight). Many have a smaller-than-normal head size (microcephaly). Due to muscle weakness, affected infants typically have difficulty controlling head movement and may have delayed development of other motor skills, such as rolling over or sitting. Weakness of the muscles used for breathing leads to serious breathing difficulties and can result in life-threatening respiratory failure. Most affected infants have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can also be life-threatening.

Some individuals with RRM2B-MDS have a digestion problem known as gastrointestinal dysmotility, in which the muscles and nerves of the digestive system do not move food through the digestive tract efficiently. This disorder may lead to swallowing difficulties, vomiting, and diarrhea and can contribute to faltering weight. Less commonly, individuals with RRM2B-MDS develop seizures or hearing loss that is caused by nerve damage in the inner ear (sensorineural hearing loss).

Because of the severity of the signs and symptoms, people with RRM2B-MDS usually live only into early childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

As the condition name suggests, mutations in the RRM2B gene cause RRM2B-MDS. The RRM2B gene provides instructions for making one piece, called the p53 inducible small subunit (p53R2), of a protein called ribonucleotide reductase (RNR). RNR helps produce DNA building blocks (nucleotides), which are joined to one another in a particular order to form DNA.

RNRs containing p53R2 make nucleotides that are used for the formation of DNA in specialized cell structures called mitochondria. Although most DNA is packaged in chromosomes within the cell's nucleus (nuclear DNA), mitochondria also have a small amount of their own DNA (mitochondrial DNA or mtDNA). Mitochondria are the energy-producing centers in cells, and the DNA in these structures contains genes essential for the process of energy production (called oxidative phosphorylation). The production of nucleotides by p53R2 helps maintain a normal amount of mtDNA in cells.

RRM2B gene mutations reduce the activity or amount of RNR, which likely impairs production of mtDNA nucleotides. A shortage of nucleotides available for the production of mtDNA molecules leads to a reduction in the amount of mtDNA (known as mtDNA depletion), which impairs mitochondrial function.

It is unclear why mtDNA depletion particularly affects the brain and kidneys in people with RRM2B-MDS, but the high energy demands of these tissues may make them especially susceptible to cell death when mtDNA is lost and less energy is produced in cells.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

RRM2B-MDS is a rare condition; the exact prevalence is unknown. At least 15 cases have been reported in the medical literature.

Which doctor should you see?

The suggested department for discussing RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy is Nephrology, with a nephrologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• How is kidney function being assessed over time?
• Are any current medicines or supplements relevant to kidney safety?
• Is there an individual recommendation about fluids, diet or blood pressure?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.