MPAN

Mitochondrial-membrane Protein-Associated Neurodegeneration, is caused by mutations in the C19orf12 (chromosome 19 open reading frame 12) gene. This gene is believed to play a role in fatty acid metabolism. MPAN is one of the major forms of NBIA and has distinctive clinical symptoms that differentiate it from other forms of NBIA. It is characterized by gait changes in the beginning, followed by progressive spastic paresis, dystonia, neuropsychiatric abnormalities and in the vast majority of individuals affected with MPAN, the cognitive decline.

Onset occurs in childhood to early adulthood with spasticity that is more prominent than dystonia, weakness in muscles caused by motor axonal neuropathy, optic atrophy, and neuropsychiatric (mental disorder due to disease of the nervous system) changes.

Most affected individuals are still able to walk as they reach adulthood. Psychiatric signs are common, including impulsive or compulsive behavior, depression and frequent mood changes. Unlike most other forms of NBIA, develop progressive cognitive decline.

Symptoms

Start to appear typically during childhood to early adulthood, but also as late as age 30 is reported

Common symptoms

The most common symptoms are speech and gait difficulties, optic atrophy,, spasticity and generalized dystonia and parkinsonism.

• Impaired gait Difficulty with walking which is typically the first symptom
• Muscle problems Early spasticity (stiff/rigid muscles), sometimes followed by flaccid paresis (weak or reduced muscle tone)
• Spastic paraparesis Exaggerated tendon reflexes, muscle hypertonia (high muscle tone that leads to stiffness, lower limbs are affected earlier and more significantly
• Babinski sign (Plantar reflex) When the sole of the foot is rubbed with a blunt object, the big toe flexes upwards abnormally
• Dystonia (involuntarily muscle contraction and spasms) often in the hands and feet, may also be more generalized
• Neuropsychiatric changes (many types have been reported) Emotional lability (unpredictable changes in emotions), depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, hyperactivity
• Cognitive (mental) decline Can progress to more significant dementia in later disease
• Optic atrophy (deterioration of the nerve that connects the eye to the brain) Usually starts during childhood
• Dysarthria (speech problems) Difficulty using or controlling the muscles of the mouth, tongue, larynx or vocal cords which are used to make speech This can make a person’s speech difficult to understand in several different ways, including stuttering, slurring, or soft or raspy speech
• Dysphagia (difficulty swallowing)
• Parkinsonism (symptoms similar to Parkinson’s disease) Typically develops later in disease, during adulthood, Bradykinesia (slow movement execution), Rigidity (stiffness), Tremors (shaking), Postural instability (loss of balance that causes unsteadiness)
• REM sleep behavior disorder has rarely been reported
• Bowel/bladder incontinence (loss of control over bowel/bladder) Some individuals develop incontinence early in the disease

Diagnosis

An eye exam and a brain MRI of the brain (T2 –weighted) that shows iron accumulation in the globus pallidus and substantia nigra are keys to diagnosing MPAN.

Commonly, all age groups experience a decline in cognitive ability that progresses to dementia; prominent neuropsychiatric abnormalities; and movement problems caused by nerve cell abnormalities. Studies reveal a loss of nerve cells, widespread iron deposits, and abnormal axons (a part of nerve cells) called spheroid bodies, in the basal ganglia. Lewy neurites, which are abnormal clusters of protein that develop inside the nerve cells, are present in the globus pallidus, and Lewy bodies and neurites are widespread in other areas of the midbrain and in regions of the globus pallidus called the corpus striatum.

MRI findings for MPAN

Hypointensity (darkness) in the globus pallidus and substantia nigra on T2 MRI

• Dark patches indicate iron accumulation
• Does not have the “eye-of-the-tiger” sign seen in PKAN
• Some individuals have hyper intense (bright) streaking in the globus pallidus that might be mistaken for an “eye-of-the-tiger sign”

Less common MRI abnormalities include

• Generalized cortical atrophy
• Cerebellar atrophy (degeneration of the cerebellum)
• Hyperintensity (brightness) in the caudate nucleus and putamen on T1 MRI

Diagnosis of MPAN is confirmed through genetic testing of the C19orf12 gene to find two gene changes. At least one C19orf12 gene change is found through DNA sequence analysis in ~95% of individuals.

Sometimes an individual with the signs and symptoms of MPAN will have only one or even no C19orf12 gene changes identified. This can happen because the genetic testing is not perfect and has certain limitations. It does not mean the person does not have MPAN; but there is not yet the technology to find the hidden gene change. In these cases it becomes very important to have doctors experienced with MPAN review the MRI and the person’s symptoms very carefully to be as sure as possible of the diagnosis.

Management

Since there is no standard care a team of medical professionals that recommends treatments based on current symptoms is recommended.

In short Medical providers also may seek to manage the disease by performing regular eye exams, as well as neurological tests for dystonia, spasticity and parkinsonism. That may include evaluation of the affected individual’s ability to walk and speak for possible physical, occupational and/or speech therapy. Neuropsychiatric symptoms may require treatment by a psychiatrist.

To evaluate and determine the extent of the disease

• Neurologic examination for dystonia, spasticity, parkinsonism and neuropsychiatric changes
• Evaluation of ambulation and speech
• Developmental assessment
• Assessment for physical therapy, occupational therapy, and/or speech therapy
• Medical genetics consultation

Therapies to manage dystonia

• Intramuscular botulinum toxin: Botox is injected in spastic, dystonic muscles to help them relax for a period of time
• Artane (trihexyphenidyl), taken orally, usually divided into multiple doses each day
• Baclofen (oral or intrathecal): One of the main drugs used to treat dystonia, usually first taken orally and divided into several doses each day. In the intrathecal method, an implanted baclofen pump delivers medication directly into the spinal fluid
• Deep brain stimulation: Used increasingly more often in NBIA and has some evidence for benefit. A stimulator sends electrical impulses to the affected brain region to help muscles relax. It involves surgical implantation of a lead, extension and battery pack (IPG). The lead contains 4 electrodes and is implanted in the globus pallidus region of the brain. The extension connects the lead to the battery pack (IPG). The IPG is a battery-powered neurostimulator that is placed in the abdomen (or in some cases below the clavicle)
• Physical and occupational therapy. May or may not be indicated for those who are only mildly symptomatic

Medication to manage parkinsonism

The symptoms of parkinsonism and dystonia can be treated with the same medications used in Parkinson’s disease. Treatment with dopamine agonist drugs (like levodopa) must be started and monitored carefully. In the beginning, the dose is increased gradually until both the patient and doctor feel symptoms are under control. While taking dopaminergic drugs, individuals must be regularly monitored for adverse neuropsychiatric effects, psychiatric symptoms and worsening of parkinsonism.

It is common for individuals to have an initially dramatic positive response to the dopamine agonist drugs, but this response tends to be short-lived and is quickly followed by the development of motor fluctuations and dyskinesias (unwanted movement). Despite these side effects, treatment with dopamine agonist drugs is often continued because affected individuals typically experience benefits from the medication for some time while the dyskinesias are expected to decline after medication is discontinued.

Even after a diagnosis has been made and the appropriate therapies have been decided, it is recommended to continue long-term surveillance to decrease the impact of MPAN symptoms and increase quality of life.

Long-term surveillance for MPAN

Monitoring of individuals receiving dopaminergic drugs for parkinsonism for:

• Adverse neuropsychiatric effects
• Psychiatric symptoms
• Worsening of parkinsonism
• Treatment of neuropsychiatric symptoms by a psychiatrist
• Physical, occupational, speech, and other therapies (as indicated)
• Feeding modifications to prevent aspiration pneumonia and achieve adequate nutrition
• Addition of gastric feeding tube or tracheostomy (if needed)
• Routine eye exams

Genetics

MPAN is an inherited and in most cases autosomal recessive disorder. Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes on to their child, resulting in two disease-causing mutations. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a recessive carrier. Statistically, there is a one in four chance that two carriers would have an affected child. The chances are two in four the parents will have a child who is a carrier and one in four that the child will not receive the gene mutation. Carrier testing for at-risk relatives and prenatal testing for pregnancies can be done if both disease-causing mutations have been identified in an affected family member.

MPAN is also inherited in rare cases as autosomal dominant disorder. Affected individuals of the dominant mutated gene have just a mutation on one of their chromosomes. They are called dominant carrier and if the dominant mutation passes to their child, the child will be affected. Autosomal dominant mitochondrial membrane protein‐associated neurodegeneration (MPAN)

Mol Genet Genomic Med. 2019 Jul; 7(7): e00736. Published online 2019 May 13. doi: 10.1002/mgg3.736,PMCID: PMC6625130PMID: 31087512

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

PROGRESSION

The progression of MPAN is usually slow, with survival well into adulthood. However, rare individuals with abrupt adult onset and rapid progression have been reported. Individuals with MPAN learn to walk and are usually mobile into early adulthood.

The end stages of MPAN are characterized by progressive dementia, spasticity, dystonia, and parkinsonism. Limited speech, weight loss and bowel and/or bladder incontinence are also common. The average lifespan varies for individuals with MPAN, but due to improvements in medical care, more affected individuals are now living well into adulthood. Secondary complications, like aspiration pneumonia or other infections, are the most frequent cause of death.