MERFF Syndrome

What Causes MERFF Syndrome?

MERFF syndrome is caused by abnormal changes (mutations) in genes vital for the function of mitochondria, microscopic structures inside cells that generate energy. The gene mutations cause deficiencies of crucial proteins without which mitochondria can’t function properly. Impairment of mitochondrial function leads to the symptoms of MERFF syndrome, although scientists don’t yet know precisely how.

It is possible for the gene mutations associated with MERFF syndrome to affect mitochondria in some cells more than others. If a cell or group of cells contains a relatively high proportion of normal mitochondria, those cells will be less affected. This helps explain why the disorder affects some parts of the body and not others. In general, the cells most affected seem to be those with the highest energy requirements, including the brain, muscles, and eyes.

Is MERFF Syndrome Hereditary?

MERFF syndrome is inherited in most cases. Researchers have identified mutations in at least four genes associated with the disorder. Mutations in one specific gene, MT-TK, account for more than 90% of all cases.

The disorder is inherited in a mitochondrial pattern, also known as a maternal pattern. The gene mutations associated with MERFF syndrome lie in DNA contained only in the mitochondria (mtDNA). These genes are inherited only from the mother, so all inherited cases of MERFF syndrome are inherited from a child’s mother. Sperm cells do not contribute mtDNA to a developing embryo, so the disorder can’t be inherited from the father. However, MERFF syndrome can be inherited by both males and females.

In a small number of cases, MERFF syndrome occurs when there is no family history of the disorder. These cases seem to be caused by a gene mutation that happens spontaneously during the early development of an embryo.

How Is MERFF Syndrome Detected?

Children with MERFF syndrome usually develop typically before symptoms begin. Symptoms most commonly first appear in childhood or adolescence, but the age of onset varies widely from case to case.

Early signs in childhood may include:

• Jerking spasms (myoclonus)
• Seizures
• Problems with coordination
• Muscle weakness
• Difficulty tolerating exercise
• Short stature

How Is MERFF Syndrome Diagnosed?

A doctor may suspect MERFF syndrome if a child presents the disorder’s characteristic symptoms, particularly myoclonus, epileptic seizures, ataxia, and abnormal muscle cells. Diagnostic procedures will aim to rule out other potential causes for the symptoms and confirm a diagnosis of MERFF syndrome.

Diagnostic steps may include:

• A physical exam. This exam aims to rule out physical conditions that could be causing the symptoms.
• Muscle biopsy. This test examines a sample of muscle tissue, which usually shows the presence of the ragged-red fibers characteristic of MERFF syndrome.
• Laboratory tests. Various tests may be used to look for signs of MERFF syndrome, such as excess lactic acid in the muscles or elevated protein levels in the cerebrospinal fluid (CSF).
• Magnetic resonance imaging (MRI). This imaging exam may be used to look for stroke-like damage to the brain.
• Electrocardiogram/echocardiogram. These tests may be used to look for heart abnormalities.
• Genetic testing. These tests can identify the mtDNA mutations associated with MERFF syndrome.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is MERFF Syndrome Treated?

MERFF syndrome has no cure, and no treatment will reverse the effects of its symptoms. Treatment approaches vary depending on the symptoms present. Medications and therapies focus on reducing the impact of symptoms and preventing complications.

Potential treatment options include:

• Anti-convulsant medications to control seizures
• Coenzyme q10 and L-carnitine may improve symptoms in some cases
• The supplements ubiquinol, alpha lipoic acid, vitamin E, vitamin B complex, and creatine may improve symptoms in some patients
• Cochlear implants or hearing aids for deafness
• Physical therapy
• Occupational therapy
• Appropriate exercise as directed by a doctor
• Avoidance of aminoglycoside antibiotics, linezolid, tobacco, and alcohol

How Does MERFF Syndrome Progress?

Degeneration of muscle tissue, nerve tissue, and other vital organs typically causes progressively worsening symptoms in people with MERFF syndrome. These complications can be life-threatening, and people with the disorder may have a shortened life span. However, the severity of symptoms varies widely, even among cases within the same family, and some people may have relatively mild impairments.

Long-term effects of MERFF syndrome may include:

• Dementia
• Vision loss
• Hearing loss
• Heart problems

How Is MERFF Syndrome Prevented?

There is no known way to prevent MERFF syndrome. People with a family history of the disorder or who have another child with the condition are advised to consult with a genetic counselor to assess their risk before having children.

MERFF Syndrome Caregiver Tips

Many people with MERFF syndrome also suffer from other brain and mental health-related issues, a situation called co-morbidity. Here are a few of the disorders commonly associated with MERFF syndrome and other mitochondrial disorders:

• Mood disorders are common in people with MERFF syndrome, including depression or anxiety disorders.
• Personality disorders such as avoidant personality disorder may be co-morbid with MERFF syndrome.
• People with MERFF syndrome may exhibit behaviors similar to obsessive-compulsive disorder (OCD). 

MERFF Syndrome Brain Science

MERFF syndrome commonly presents with symptoms that show the involvement of the brain in the disorder. Seizures, coordination difficulties, cognitive decline, and dementia all suggest that the brain is a significant focus of the disease, along with the muscles and other parts of the body.

Magnetic resonance imaging (MRI) scans may show degeneration or damage in various parts of the brain, including:

• Shrinkage of the brain’s outer layer (cortical atrophy)
• Hardened deposits (calcification) in the basal ganglia
• Shrinkage of the cerebellum and/or  brain stem
• Loss of myelin in the brain’s white matter (leukodystrophy)

MERFF Syndrome Research

Title: North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC) (NAMDC)

Stage: Recruiting

Study Director: Michio Hirano, MD

Columbia University

New York, NY

Mitochondrial diseases comprise a group of relatively rare (~1 in 5000 adults) but very serious genetic disorders. Mitochondria are often called the “powerhouses of the cell” because they provide the energy our cells need to live. Mitochondria have their own DNA (mtDNA), but they also rely on DNA from the nucleus (nDNA). Mitochondrial diseases are caused by mutations in either mitochondrial or nuclear DNA that result in poorly functioning mitochondria. This can cause various symptoms, including muscle weakness, seizures, mental retardation, dementia, hearing loss, blindness, strokes, diabetes, and premature death. Most mitochondrial diseases are progressive, and we are unable to cure most of these diseases with currently available treatments.

Research into mitochondrial diseases has been hampered by the low frequency of these disorders and by under-diagnosis by clinicians. This has hindered patient recruitment for research studies and clinical trials. The North American Mitochondrial Disease Consortium (NAMDC) was established to help surmount these issues. Led jointly by Drs. Michio Hirano and Salvatore DiMauro, NAMDC is a consortium of several clinicians and researchers with an interest in mitochondrial disease research in the United States and Canada.

By creating a mechanism for the sharing of patient samples with researchers, data, and patient contact information, NAMDC will make it easier to conduct clinical and basic laboratory research.

Patient information will be shared through the use of the “Patient Data Registry,” a specially-designed database, and patient tissue samples will be shared through the use of the “Patient Sample Biorepository,” a storage facility in which patient-derived biological samples will be maintained. The Registry and the Biorepository will hopefully accelerate progress in the understanding and treatment of mitochondrial disease.

Patients can enroll at any of the NAMDC member sites. A web-based remote enrollment is also available at www.namdc.org for eligible patients who reside far from any of the NAMDC participating sites.

Title: A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy (MIT-E)

Stage: Recruiting

Study Director: Vinay Penematsa, MD  

PTC Therapeutics

This is a parallel-arm, double-blind, placebo-controlled study with a screening phase that includes a 28-day run-in phase to establish baseline seizure frequency, followed by a 24-week, randomized, placebo-controlled phase. After completing the randomized, placebo-controlled phase, participants may enter a 48-week, long-term extension phase during which they will receive open-label treatment with vatiquinone.

Title: Acute Infection in Mitochondrial Disease: Metabolism, Infection, and Immunity During the COVID19 Pandemic

Stage: Recruiting

Principal investigator: Eliza M Gordon-Lipkin, MD  

National Human Genome Research Institute

Bethesda, MD

Infection is a major cause of morbidity and mortality in individuals with mitochondrial disease, frequently triggering metabolic decompensation, multiorgan dysfunction, and neurologic deterioration. In the context of the recent COVID19 pandemic, people with mitochondrial disease are at increased risk for severe disease and poor outcomes if infected. However, the mechanisms for this link between infection and clinical decline are incompletely understood. Given that people with mitochondrial disease are particularly susceptible to infection and may experience delayed recovery, we hypothesize that this is partly due to immune factors that influence host-pathogen interactions. This protocol aims to collect biological specimens to identify immune signatures that contribute to the phenotype of infection and outcomes in patients with mitochondrial disease who become ill during the COVID19 pandemic. To compare these cases with others of similar genetic backgrounds and environmental exposures, we will also collect specimens from family members. We will then examine how these signatures correlate with comprehensive quantifiable clinical measures throughout the course of the disease, from presenting symptoms through acute decompensation, stabilization, and convalescence. While this protocol was developed during the COVID-19 pandemic, with a focus on a specific infectious pathogen, researchers hope this study will extend beyond the pandemic to more broadly understand acute infectious illness in patients with mitochondrial disease. Additionally, it will serve as a remote adjunct to the NIH MINI Study, a natural history study focused on the immunophenotype of mitochondrial disease conducted at the NIH Clinical Center.