Multiple mitochondrial dysfunctions syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Multiple mitochondrial dysfunctions syndrome is a group of severe conditions that begin early in life.

There are at least five types of multiple mitochondrial dysfunctions syndrome. The types have overlapping but distinct patterns of signs and symptoms, and each differ in their genetic cause.

In general, infants with multiple mitochondrial dysfunctions syndrome typically have severe brain dysfunction (encephalopathy), which can contribute to developmental delays and a loss of mental abilities and acquired skills (developmental regression). Most babies with multiple mitochondrial dysfunctions syndrome have difficulty growing and gaining weight at the expected rate (faltering weight). Individuals with this condition often have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can be life-threatening. They may also have high levels of a molecule called glycine (hyperglycinemia) or elevated levels of sugar (hyperglycemia) in the blood. In most cases, people with multiple mitochondrial dysfunctions syndrome do not survive past early childhood.

Individuals with multiple mitochondrial dysfunctions syndrome type 1 often develop pulmonary arterial hypertension, a condition that is characterized by abnormally high blood pressure (hypertension) in the blood vessel that carries blood from the heart to the lungs (the pulmonary artery). Affected individuals can also have brief pauses in breathing (apnea) and muscle twitches (myoclonus).

Multiple mitochondrial dysfunctions syndrome type 2 is characterized by very severe encephalopathy and breathing difficulty (respiratory distress). About half of individuals with type 2 have a weakened heart muscle (cardiomyopathy). These individuals typically either have a thinning of the heart muscle (dilated cardiomyopathy) or a thickening of the heart muscle (hypertrophic cardiomyopathy). Both of these conditions prevent the heart from pumping blood efficiently and increase the risk of heart failure and sudden death.

Individuals with multiple mitochondrial dysfunctions syndrome type 3 can experience progressive muscle stiffness (spasticity) and paralysis of the arms and legs (quadriplegia). Nearly half of people with type 3 have vision problems resulting from the breakdown of the nerves that carry information from the eyes to the brain (optic atrophy). Although about half of people with multiple mitochondrial dysfunctions syndrome type 3 survive past early childhood, they rarely survive into adulthood.

Multiple mitochondrial dysfunctions syndrome type 4 is characterized by spasticity and vision problems. Affected individuals often have optic atrophy and involuntary movements of the eyes (nystagmus).

Multiple mitochondrial dysfunctions syndrome type 5 is characterized by nystagmus and spasticity.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Each type of multiple mitochondrial dysfunctions syndrome is caused by changes in one of these genes: NFU1, BOLA3, IBA57, ISCA2, and ISCA1.

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in these genes can cause the different forms of multiple mitochondrial dysfunctions syndrome:

The genes that are associated with multiple mitochondrial dysfunctions syndrome play important roles in the mitochondria, which are the energy-producing centers of cells. The genes provide instructions for making proteins that help create molecules called iron-sulfur (Fe-S) clusters or that help attach these clusters to other proteins. Many proteins require Fe-S clusters to perform certain cellular processes. For example, some of these proteins carry out a series of chemical steps within mitochondria called oxidative phosphorylation to convert the energy in food into a form that cells can use. Proteins that contain Fe-S clusters are involved in many functions in the body, including DNA repair and regulation of gene activity.

Some pathogenic variants in the genes that are associated with multiple mitochondrial dysfunctions syndrome reduce or eliminate the production of the affected protein, while other pathogenic variants prevent the protein from entering the mitochondria. This impairs the process of Fe-S cluster formation or attaching the clusters to proteins. Without Fe-S clusters, certain proteins cannot function normally. This reduces the amount of energy produced by mitochondria, contributing to the severe signs and symptoms seen in people with multiple mitochondrial dysfunctions syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

All types of multiple mitochondrial dysfunctions syndrome are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

At least 150 cases of multiple mitochondrial dysfunctions syndrome have been described in the scientific literature, although its exact prevalence is unknown. It is one of several conditions that are classified as mitochondrial disorders, which affect an estimated 1 in 5,000 people worldwide.

Which doctor should you see?

The suggested department for discussing Multiple mitochondrial dysfunctions syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

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.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Multiple mitochondrial dysfunctions syndrome. 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.