Saturday, November 26, 2011

Polymicrogyria and Mitochondrial Disease

POLYMICROGYRIA (also known as PMG or Polymicrogyriacephaly):
Polymicrogyria is a condition characterized by abnormal development of the brain before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small. The name of this condition literally means too many (poly) small (micro) folds (gyria) in the surface of the brain.

Polymicrogyria can affect part of the brain or the whole brain. When the condition affects one side of the brain, researchers describe it as unilateral. When it affects both sides of the brain, it is described as bilateral. The signs and symptoms associated with polymicrogyria depend on how much of the brain, and which particular brain regions, are affected.

Polymicrogyria most often occurs as an isolated feature, although it can occur with other brain abnormalities. It is also a feature of several genetic syndromes characterized by intellectual disability and multiple birth defects. These include 22q11.2 deletion syndrome, Adams-Oliver syndrome, Aicardi syndrome, Galloway-Mowat syndrome, Joubert syndrome, and Zellweger spectrum

Mitochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body except red blood cells. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is becoming more and more common.

Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

Polymicrogyria: Researchers have identified multiple forms of polymicrogyria. The mildest form is known as unilateral focal polymicrogyria. This form of the condition affects a relatively small area on one side of the brain. It may cause minor neurological problems, such as mild seizures that can be easily controlled with medication. Some people with unilateral focal polymicrogyria do not have any problems associated with the condition.

Bilateral forms of polymicrogyria tend to cause more severe neurological problems. Signs and symptoms of these conditions can include recurrent seizures (epilepsy), delayed development, crossed eyes, problems with speech and swallowing, and muscle weakness or paralysis. The most severe form of the disorder, bilateral generalized polymicrogyria, affects the entire brain. This condition causes severe intellectual disability, problems with movement, and seizures that are difficult or impossible to control with medication.

Mitochondrial Disease: Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness (called hypotonia) and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, absent reflexes, seizures, visual/hearing problems, lactic acidosis, global developmental delays, susceptibility to infection, and inability to regulate the body’s autonomic functions (i.e. temperature, heart rate, blood pressure, blood sugars, respirations, etc.).

It is thought that any combination of three of more of these severe symptoms could point toward suspected mitochondrial disease in an undiagnosed patient.  Children with mitochondrial disease are often misdiagnosed with atypical cerebral palsy, atypical autism with complex medical issues, or encephalopathy, nos.

Polymicrogyria: With increased use of
imaging techniques such as MRI and CT, polymicrogyria is becoming more widely diagnosed. However, polymicrogyria is often misdiagnosed as pachygyria or lissencephaly, even by experienced radiologists, since the differences between these conditions can be difficult to see on an MRI or CT scan

Mitochondrial Disease:
Mitochondrial diseases are difficult to diagnose. Referral to an appropriate research center is critical. If experienced physicians are involved, however, diagnoses can be made through a combination of clinical observations, laboratory evaluation, cerebral imaging, and muscle biopsies. Despite these advances, many cases do not receive a specific diagnosis.

Most hospitals do not have a metabolic laboratory and therefore can run only the most basic tests. However, most hospitals will send specimens to any laboratory in the country. Not all laboratory tests are required for all patients, and your physician may decide that some of these tests are not necessary. In addition, a single blood or urine lab test with normal results does not rule out a mitochondrial disease. This is true for organic acids, lactic acid, carnitine analysis and amino acid analysis. Even muscle biopsies are not 100% accurate.

Recently there have been diagnostic developments in disease typing.  There are many types of mitochondrial diseases that have a very specific set of symptoms and clinical identifiers which have been broken into mitochondrial disease typing (with specific complexes, factors, and names).

For children suspected of mitochondrial disease, a complete medical history of both biological parents, the child’s siblings and extended family are often researched and can shed light on a possible history of the disease or if further genetic testing is required.  Genetic testing may be key to a diagnosis, and is worthy of pursuit.  Genetic counseling is always recommended in parents of affected children who want to have subsequent biological children.

There is no cure.  Management of issues arising from PMG including, physical therapy, pharmacologic management, orthotic devices, and surgery for those with spastic motor impairment; speech therapy for language and swallowing impairment; feeding tube for dysphagia, occupational therapy for fine motor difficulties; antiepileptic drugs for seizures; assessment of educational needs and evaluations for speech, vision, and hearing difficulties in infancy and preschool years.

Mitochondrial Disease: There is no cure.  Treatment includes,
standard regimens for some symptoms (anticonvulsant medication for epilepsy, physical therapy for motor problems, etc.) , dietary,  vitamins and supplements, avoidance of stressful factors, hydration, control of environmental factors to avoid triggers,  tailored treatment by  the patient's physician to meet that patient's need. Many of these therapies are totally ineffective in some mitochondrial disorders and would be a waste of time, money and effort. In some cases, the treatment could be dangerous.  A child diagnosed with confirmed mitochondrial disease before the age of 3 is likely to have a shorter life expectancy (early teens) depending on the severity and progression of the disease.

RESOURCES AND SUPPORTPolymicrogyriaChristopher A. Walsh, MD, PhD
Phone: (617) 919-2923
Fax: (617) 919-2010
300 Longwood Ave CLS-15604
Boston, MA 02115

Walsh Lab
Phone: (617) 919-4795
Fax: (617) 919-2300

Dr. William Dobyns, Genetics
Seattle Children's Research Institute
C9S -10 - Integrative Brain Research
1900 - 9th Ave
Seattle, WA 98101

Dr. Gary Clark, Neurologist

6701 Fannin Street, Clinical Care Center
9th Floor, MC CC 950.04
Houston, TX 77030
Blue Bird Clinic for Pediatric Neurology at 832-822-5046

(Support) The Lissencephaly Launch Pad (support for families with children who have brain malformations of varying types):

Mitochondrial:The United Mitochondrial Disease Foundation
8085 Saltsburg Road, Suite 201
Pittsburgh, PA 15239
Toll Free: 1-888-317-UMDF (8633)
Support groups can be found in local chapters on the UMDF website.

14 Pembroke Street
Medford MA 02155
888-MITOACTION (888-648-6228)

1 of 3 reported children in the world with the combination of PMG and mitochondrial disease.  Little Miracle ~ Owen.

Anita's Story of her miracle, Owen:
After a textbook pregnancy and delivery, we welcomed our first child into the world during an Ohio blizzard in February 2007.  He was perfect, 8lb 1oz, ten fingers and ten toes, a head of beautiful blonde hair and deep blue eyes.  We named him Owen.  It wasn’t long after we got home that I started to suspect that something was terribly wrong with Owen.  His crying was not what I expected from a newborn, it was high pitched and constant.  I was told it was colic. He never took to breastfeeding but even with a bottle of just a few ounces it would take him hours to finish eating; we had a bottle in his mouth literally around the clock.  He gained weight and again I was told he was okay.  As he got older and older other issues began to emerge, he would “startle” easily as if someone had scared him.  I was told it was just an immature nervous system.  His eyes were severely uncoordinated, as if lizard-like, one eye would go one direction and the other would go the opposite direction.  Sometimes it looked as if he was watching a really fast tennis match with his eyes darting back and forth quickly but never truly looking at anything.  I was told that it can take months for a child’s eyes to coordinate.  He didn’t smile or make sounds, other than the high pitched crying.  Head control didn’t come.  He was diagnosed with a severe case of torticollis (a neck posturing problem) and he had plagiocephaly (head flattening) that became severe.  Everything was dismissed by doctors, and I know my family thought I was an irrational new mother.  I wasn’t.  So after finding a pediatrician who would finally listen to me, we were referred to neurology.  After 4 months of testing, MRI’s, CT scans, EEG’s, repeat EEG’s, metabolic testing, genetic testing, extensive family history screening, physical/occupational/speech therapy consults, developmental tests, swallow studies, and a sudden onslaught of seizures that landed our son in the ER and for what would be one of countless hospital admissions, Owen was diagnosed with polymicrogyriacephaly (also known as polymicrogyria) and a POLG1 mitochondrial disease.  Double whammy.  Both with no cures, both devastating with the potential for early terminal outcomes.

Owen is now 4 years, old and beating the odds each and every day.  He has outlived his initial expiration date by 2 years, and we look forward to many many more.  We have learned that doctors give highly educated, researched, and experienced guesses…but they are still guesses. Owen currently has a laundry list of issues that could be contributed to either the polymicrogyria or the mitochondrial disease, for us it is hard to distinguish which disease is causing which problem.

Our earliest indications that something was very wrong were as follows with the official diagnosis in (parenthesis):
- Uncoordinated Eye Movements (nystagmus)
- Floppy muscle tone and poor-no head control (hypotonia)
- High pitched crying around the clock for the first year of life (neurological crying)
- Inability to feed appropriately with severe vomiting episodes (Dysphagia with GERD)
- Chronic Constipation
- Severe Eye Tearing During Feeds (aspiration)
- “Startling” or quick full body “jerking” movements (infantile spasms/myoclonic seizures) 
- Lack of eye gaze, cooing, expression, no mimicking (global developmental delay)
- Aversions to textures and sounds (sensory processing disorder)

Owen is currently ventilator dependent via tracheostomy tube due to a bout of pneumonia last year that he could not recover from.  His infantile spasms progressed to a wide variety of seizure types, and to its most recent stage called Lennox Gastaut Syndrome (the most severe form of childhood epilepsy) though he is currently well controlled.  He is tube fed via gtube through a MIC KEY button. He is non-ambulatory and non-verbal, with severe developmental delays and receives home based therapy and school services. He is 100% caregiver dependent.  He has had countless hospital admissions, and surgeries.  He receives over 18 medications per day, and he has as many as 15 specialists. He is also the quirkiest little guy you could ever meet, with a smile that melts the hearts of all he comes into contact with.  He has an obsessive love of television, music, books, and Gerber Cereal Puffs (the only thing he eats by mouth).  His daddy is the love of his life. 

Being Owen’s mother is bittersweet.  The constant care giving is exhausting, the worry is overwhelming, the fear is all consuming, and the grief is beyond description.  But Owen is my hero, and I am his biggest fan.  He is a true angel on this earth who just happens to be trapped in a broken body.  I know one day he will be free…but until that day, I am going to love him with everything I have, fight for him with my inner momma-bear, and be there to hold his hand when God decides it is time for his wings to take flight.  He is not a diagnosis…he is my baby and I am so honored to be his mommy.
Anita Birk, mother of four year old Owen, is Founder and President of Mommies of Miracles.  She is a stay-at-home MOM and wife of a methodist Pastor.  The Birk Family lives in Southern, Ohio and have lived in many communities throughout Ohio during their eight years of marriage.  A former Clinical Research Associate for the National Cancer Institute, Anita is passionate about supporting mother's who have children with complex medical needs, rare or undiagnosed conditions, and developmental delays.

Monday, November 21, 2011

Myasthenia Gravis and Congenital Myasthenic Syndrome

Myasthenia Gravis (“grave muscle weakness”) is a condition where the neurotransmitters are unable to make the "jump" across the synapse between the neurons and the muscles.  The brain sends the messages but the muscles don't receive them properly.  This condition causes muscle weakness that worsens with continuous use and improves with rest.  Often muscles in the face are affected the most, so patients have trouble eating/swallowing and often have ptosis (droopy eye). I can also cause muscle weakness in the neck, torso, and limbs.  There are medications that treat myasthenia by helping to get the neurotransmitters to the muscles properly. 
There are two forms of myasthenia. The first and more common form is an autoimmune disease where the body produces antibodies that attack its own neurotransmitters.  This is what is commonly referred to as “MG”.  The onset for this autoimmune form usually occurs in women under 40 or men over 60.  Rarely, it can begin in childhood or adolescence but not usually in infancy. 
The second form of myasthenia is called Congenital Myasthenic Syndrome or “CMS.” In CMS the problem is not due to an autoimmune disease, as in MG, but a genetic defect. CMS is caused by a physiological problem at the connection between neurons and muscles. For one reason or another, the chemical signal from the nervous system to the muscle does not make it across the small gap between the neuron and muscle called the synapse, and as a result the muscle cannot carry out the commands coming from the brain. The chemical can fail to be produced or released in large enough quantities, or the muscle can fail to detect it properly. There are at least 10 different forms of CMS to date with new ones still being discovered. CMS is something that patients are born with and symptoms are usually present at birth or appear shortly after.  CMS is extremely rare (estimates range from 1 in 500,000 to 1 in 2 million). However, this is so under-diagnosed that it probably isn’t as rare as those estimates reflect. 

In both MG and CMS the symptoms can vary greatly from person to person.  Babies who are born with CMS will often present with very low muscle tone and be very lethargic. They can have feeding problems that range from difficulty breastfeeding, to requiring tube feeding.  They will be late with their gross motor milestones and can also have speech delays. They often have trouble clearing their secretions which can result in stridor breathing and sometimes necessitate a tracheostomy. Since the lungs are considered “voluntary” muscles, severe cases can cause respiratory problems that may require ventilator assistance.  Less severe cases that may go undiagnosed in infancy will later result in unusual fatigability, poor coordination, tendency to fall, and other neuromuscular symptoms. Over time, orthopedic issues can arise.  Ptosis, or “droopy eye” is one of the hallmark symptoms of CMS/MG, but is not always present.   MG has more of a gradual onset and is uncommon during childhood but not impossible.  In both cases, symptoms can “come and go”.  Heat and illness tend to exacerbate symptoms. 

Testing for the autoimmune form – MG – is much easier.  Blood tests can detect the antibodies that are attacking the neurotransmitters.  Another test, referred to as a Tensilon Test, is where a trial dose of the medication is administered to look for improvements in muscle tone.  If it is done later in the day when the patient is tired, their strength should improve and usually the most notable sign is that the eyes will no longer droop.
Testing for CMS is much more difficult. There will not be any antibodies present, so there is no blood test.  Often doctors will try EMG’s or muscle biopsies in these children to try and uncover the problem.  However, these results are not very reliable tests for CMS, especially in young children whose muscle fibers are very small.  So these tests can come back as “normal” even when there are serious problems of neuromuscular transmission. Many doctors are familiar with MG but not CMS and may associate a child’s symptoms with MG and therefore test the child for antibodies.  However, this test will come back negative in children with CMS leading the doctors to mistakenly “cross it off their list” of things to check for and move on.   All of this results in children going undiagnosed for months, even years.  It is usually recommended to do a trial of the medication and see if the baby improves.  Often that is the only definitive test for CMS.  Genetic testing can be performed at the Mayo Clinic, but routine genetic testing will not detect it.

Mestinon is the most common treatment for both MG and CMS.  It increases the amount of neurotransmitters.  Patients with autoimmune MG can also take immunosuppressant drugs, such as prednisone, to suppress the immune system.  Patients with CMS should not take these immunosuppressant drugs because they need to be able to fight off respiratory viruses which can be very dangerous for them.
Depending on which genetic defect is present in CMS, there may be additional drugs that can be used to correct the problem.  There are some very rare cases of CMS where Mestinon will actually worsen the symptoms, and there are other medications that those patients can take.  Many doctors are unaware of this.  So if a patient worsens with the medication, it COULD still be CMS just another form.  This is a VERY complex disorder.

                                                               Before Mestinon

                                                                   After Mestinon

The Mayo Clinic in Rochester, MN, is the center of excellence and research for CMS in the United States.  This is where the disorder was discovered.  This is the only place in the US that is able to conduct the genetic testing needed to identify the genetic nature of the disorder.  If you suspect your child has CMS, you should have your neurologist contact the Mayo Clinic for guidance.

The Myasthenia Gravis Foundation of America supports patients with MG.  There is not currently an organization devoted entirely to supporting CMS patients and their families.

Dedicated with love to my daughter, Ellen, and our new little buddy, Isaac!