Kleefstra Syndrome

Overview

Kleefstra Syndrome is a rare genetic condition. A small piece of the long arm of one of the child's 9^th chromosomes is missing. As a result, a gene, called Eu-chromatin-Histone Methyl Transferase  or EHMT1, is missing from the chromosome. It is this missing gene that is thought to cause the majority of the symptoms these children exhibit (Rare Chromosome, 2). Researchers have discovered that EHMT1, causes other genes to be silenced (not active). In the case of Kleefstra Syndrome, one copy of the EHMT1 gene is lost, therefore less protein will be formed and the silencing of its target genes is not sufficient anymore. This is called 'loss of function' or 'haploinsufficiency' of EHMT1 (Kleefstra, T. 2009).  Basically, EHMT1 blocks unwanted gene activity. Without sufficient amounts of this protein, undesirable characteristics can develop. These range from serious heart defects, seizures and renal issues to minor characteristics such as a “uni-brow” or a slightly upturned nose. Both of which are physical characteristics common in Kleefstra Syndrome.

Until recently it was thought that the size of the child's deletion was directly related to the number and severity of symptoms the child would experience. It is now known that it is not the size of the deletion but the location of the break on the chromosomal arm that is important. Often more then just one gene is affected in a deletion, which will cause a variety of issues depending on which genes are affected. However, it is the deletion of EHMT1 specifically that results in a diagnosis of Kleefstra Syndrome (Kleefstra and Yatsenko, 2009).

Symptoms

Kleefstra Syndrome is characterized by cognitive delay, gross motor delay caused by childhood hypotonia, distinct facial features, immature sexual organs in males, and a lack of expressive speech. A “complex pattern” of secondary characteristics have also been observed. These can include heart defects, renal defects, severe respiratory infections, GERD, epilepsy/febrile seizures, autistic-like behaviours, and extreme aggression (males) or catatonic-like (females) features after the onset of puberty (Kleefstra, 2010).

Physical Characteristics Males and females are affected equally. Birth weight is usually within the normal or above normal range whereas in childhood weight increases leading to obesity. The facial appearance is characterized by a small head circumference, broad forehead, synophrys or “uni-brow”,  mildly up slanting eye lids, mid facial hypoplasia (the jaw and cheekbones do not develop as quickly as the rest of the face), thickened ear helices, short nose with an upturned tip, cupid bowed upper lip, and protruding tongue (Kleefstra, T. 2009). Many of these characteristics are what may lead a doctor to suggest genetic testing. They are common in a number of genetic defects (Belanger, 2010). Education of geneticists in these characteristics may one day lead to Kleefstra Syndrome being diagnosed at birth and not after years of testing for other syndromes.

Behaviour Children with Kleefstra Syndrome are described as sociable, passive, mellow, loving and outgoing. Generally the children relate better to adults than their peers and have little to no stranger anxiety. Children often prefer to observe rather then play with peers or in groups. Problem behaviours include aggression (biting, hitting, hair pulling) and unpredictable mood swings. Difficulties with  high pain tolerance, being easily frightened, feeling insecure and disliking changes in routine also lead to behaviour issues (Kleefstra Syndrome.org, Behaviours). Children with Kleefstra Syndrome are often placed on the Autism Spectrum. Due to their outgoing personality, Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS) is a common diagnosis (Belanger, 2011b).

Testing/Diagnosis 

Kleefstra syndrome can only be diagnosed through a relatively new method of genetic testing called  Fluorescence in situ hybridization or FISH (MEH Research Foundation, 2010). This testing is not available in Canada which may attribute to the lower rate of diagnosis in Canada (Belanger, 2010).

Until April 2010, this Syndrome was known as 9q34.3 deletion syndrome; After the location of the missing gene on the affected chromosome. The name was recently changed to Kleefstra Syndrome (April 2010) after Doctor Tjitske Kleefstra, a clinical geneticist in the Department of Human Genetics at Radboud University Nijmegen Medical Centre in the Netherlands (Jeans for Genes, press release). Dr. Kleefstra was the researcher who discovered the pattern in symptoms with children with this specific 9q deletion.

The majority of Kleefstra Syndrome cases are de novo or random. Only one case of transference has been documented and in that case the mother was a carrier as she has an EHMT1 mutation, not a deletion. There are no documented cases of a person with Kleefstra Syndrome reproducing (Kleefstra, T. 2009).

With the limited availability of the testing for this Syndrome, it is thought that more children may have Kleefstra Syndrome but may have received, and are being treated for, other diagnoses and/or syndromes (Belanger, 2010). Many children have lived for years with diagnoses of Angelman's Syndrome, Atypical Rhett's Syndrome and Fragile X before recently discovering they actually had Kleefstra Syndrome (Belanger, 2011).

Treatments

Early intervention is key. Early referral to age-appropriate early childhood intervention programs, special education programs, or vocational training to help the child reach his or her full potential.

Speech and Language Therapy While expressive speech may be absent or severely delayed, other forms of communication are heightened and sign language and/or a Picture Exchange Communication System may be quite successful (Kleefstra Syndrome.org, Communication). Therefore referral to Speech and Language Therapy is important.   

Physical Therapy Virtually all children with Kleefstra syndrome have low muscle tone (Hypotonia). Physical therapy provides support for a child with gross motor delays. Therapists will assist the child in building gross motor skills such as rolling, crawling, walking, and climbing stairs (Kleefstra Syndrome.org, Early Intervention). It is hoped that children with Kleefstra Syndrome will walk by the time they enter school. However, the low tone may make then tired or unable to walk long distances or stand for a great amount of time (Rare Chromosome, 12).

Occupational therapy will help develop fine motor skills as well as help the child acquire self help skills. Occupational therapy in addition to Speech therapy may help with GERD and feeding and swallowing issues. Sensory integration therapy has been successful in many cases of Kleefstra Syndrome to alleviate behaviours and help the child better integrate with their environment (Belanger, 2011).

Vision Consultation Children with Kleefstra Syndrome often have some degree of visual impairment despite having structurally typical eyes. This is called cortical visual impairment; The brain does not process accurately what the eyes are seeing. Strabismus or a squint is common, as is being near sighted. Glasses are often prescribed. Referral to a specialist with experience in children with special needs is important (Rare Chromosome, 21).

Specialized care for those with extreme behaviour problems, movement disorders, sleep disorders, epilepsy should be sought on an as needed basis. Some parents are reluctant to medicate their children for behaviour but the right medication in the right dose can be trans-formative. Puberty hormones seem to bring a sudden increase in difficult behaviours and moods. There is some recovery in adulthood but psychiatric care may be needed during the teen years. (Kleefstra Syndrome.org, Behaviour). Melatonin has been known to help the frequent night awakenings common to children with Kleefstra Syndrome. However, often families still require regular respite care (Kleefstra Syndrome.org, Sleep).  Standard treatment courses for cardiac, renal, hearing loss, and other medical issues should be prescribed by the family doctor or pediatrician. Ongoing routine monitoring by a multidisciplinary team specializing in the care of children or adults with intellectual disability, including endocrinology and a neurologist is standard (Kleefstra, T. 2010). Some families have had success with using the fundamentals of Applied Behaviour Analysis and Intensive Behaviour Intervention with their children. Often the repetitive teaching is the only way for the children to learn new tasks (Rare Chromosome, 9).

Resources

Jeans for Genes

http://www.jeansforgenes.com

Kleefstra Syndrome.org

http://www.kleefstrasyndrome.org

Rare Chromosome Support Group

http://www.rarechromo.org

Current Research

Dr. Kleefstra is currently focused on trying to answer the following question. “What function has this EHMT1 exactly during development and in the brain cells?” She states, “when we have answers to this and know the biological mechanisms causing the clinical features, we eventually hope that we can influence such a pathway by treatment some day.” (Kleefstra, T., 2011b). It is however, unlikely a treatment will be available in our generation. The focus now is on education, “We publish (case) reports in the medical literature and give presentations on international meetings, to spread knowledge on the syndrome in order to inform other medical professionals on the variation in clinical symptoms that have been observed. This will lead to a better recognition, diagnosis and optimalization of care of people with the syndrome (Kleefstra, T., 2011b).

Research in two other areas regarding Kleefstra Syndrome are also taking place. Dr. Monique Balemans has created a mouse with Kleefstra Syndrome. She is hoping to use this mouse to “look further into the mechanisms that underlie this syndrome” (Kleefstra Syndrome.org, Mouse Studies). Dr. Jamie Kramer has also developed fruit flies with Kleefstra Syndrome. Because fruit flies have similar genes as humans and their biological processes are very similar, they are a model organism for comparative research. Dr. Kramer hopes that his fruit flies will one day be able to be test subjects for future treatments for Kleefstra Syndrome (Kleefstra Syndrome.org, Fruit fly Studies)

Owen's Story 

Your child has behaviours on the Autism Spectrum, low vision, poor hearing, a heart defect, a speech delay, fine motor delay, gross motor delay, feeding concerns, immature sexual organs, cognitive delay, Gastroesophageal Reflux Disease (GERD), an umbilical hernia, hypotonia, and the list goes on and on. Doctors treat each symptom separately, no one seeing your child as a whole. As a parent you know there has to be more. It is not possible all these random factors are not linked in some way. You are not a doctor, but somehow you just know. You push for round after round of genetic testing and suddenly you have an answer. None of these symptoms are random, your child has Kleefstra Syndrome. Vindication! Your sense of elation is short lived when you discover your child is one of 124 children with this diagnosis in the world and one of only four children in Canada. No doctor in your area has heard of the diagnosis, including the geneticist who broke the news to your family. You are told to go home and research 9q deletions. The support you craved is still not there. You got your answer, but now there are just more questions. 

 

My child has Kleefstra Syndrome and this topic is very personal to me. I was told to go online and research, learn how to advocate for my son. Doctors, trained medical professionals with decades of experience, wanted me to learn about my child's diagnosis, so I could teach them. So I have and this is what I've learned. A team approach to early intervention is key. Continuing to treat my child as if he is simply a sum of his various diagnoses is not productive. Medical professionals from all fields must work together and communicate to ensure appropriate treatment in all areas of need.

Kleefstra Syndrome is a prime example of the lack of education when it comes to children with multiple diagnoses. This diagnosis, more often then not, comes only after the parents push for further testing. Doctors and therapists are only too happy to focus on their area of expertise and not look at the child as a whole. My fight was only 15 months long, but that was a year longer then it needed to be. The amazing families I have spoken with while on this journey have been fighting much longer then I have. Once doctors, therapists and families are all on the same page when it comes to care for children with special needs, our children can not help but benefit. With a little bit of education, comes hope. 

Contributed by MOM Andrea Belanger

Batten Disease

Overview:

Batten Disease is the most common form of a group of disorders called Neuronal Ceroid Lipofuscinoses (or NCLs).   Although Batten Disease is usually regarded as the juvenile form of NCL, it has now become the term to encompass all forms of NCL.  Batten Disease/NCL is relatively rare, occurring in an estimated 2 to 4 of every 100,000 births in the United States but no one really knows how many children there may be in North America or anywhere else in the world. The diseases have been identified worldwide. Although NCLs are classified as rare diseases, they often strike more than one person in families that carry the defective gene.  The forms of NCL are classified by age of onset and have the same basic cause, progression and outcome but are all genetically different, meaning each is the result of a different gene.  There are four main types of NCL, including two forms that begin earlier in childhood and a very rare form that strikes adults. The symptoms are similar but they become apparent at different ages and progress at different rates.

Forms of NCL/Batten Disease:

• Infantile NCL (Santavuori-Haltia disease): begins between about 6 months and 2 years of age and progresses rapidly. Affected children fail to thrive and have abnormally small heads (microcephaly). Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. The infantile form has the most rapid progression and children live into their mid childhood years.
• Late Infantile NCL (Jansky-Bielschowsky disease): begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures along with progressive mental deterioration.. This form progresses rapidly and ends in death between ages 8 and 12.
• Juvenile NCL (Batten Disease): begins between the ages of 5 and 8 years of age. The typical early signs are progressive vision loss, seizures, ataxia or clumsiness. This form progresses less rapidly and ends in death in the late teens or early 20s, although some may live into their 30s.
• Adult NCL (Kufs Disease or Parry's Disease): generally begins before the age of 40, causes milder symptoms that progress slowly, and does not cause blindness. Although age of death is variable among affected individuals, this form does shorten life expectancy.

Symptoms:

Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight and motor skills. Eventually, children with Batten Disease/NCL become blind, bedridden, and unable to communicate and it is presently always fatal.

Testing/Diagnosis:

Diagnostic tests used for Batten Disease/NCLs include:

• Skin or tissue sampling. The doctor can examine a small piece of tissue under an electron microscope. The powerful magnification of the microscope helps the doctor spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. See inclusion body pictures in question above.
• Electroencephalogram or EEG. An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.
• Electrical studies of the eyes. These tests, which include visual-evoked responses (VER) and electro-retinagrams (ERG), can detect various eye problems common in childhood Batten Disease/NCLs.
• Brain scans. Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. A second imaging technique that is increasingly common is magnetic resonance imaging, or MRI. MRI uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.
• Enzyme assay. A recent development in diagnosis of Batten Disease/NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for Infantile and Late Infantile only. This is a quick and easy diagnostic test. Genetic/DNA testing. Each 'form' of Batten disease is the result of a different gene. Genes for eight of the ten forms have been identified. Testing for these is available for diagnosis as well as carrier and prenatal status.

Treatments (NONE!):

As yet, no specific treatment is known that can halt or reverse the symptoms of Batten Disease/NCL. However, seizures can be reduced or controlled with anticonvulsant drugs, and other medical problems can be treated appropriately as they arise. At the same time, physical and occupational therapy may help patients retain function as long as possible.

Resources:

The Batten Disease Support and Research Association enables affected children, adults, and families to share common concerns and experiences. Meanwhile, scientists pursue medical research that will someday yield an effective treatment.

(www.bdsra.org)

Jake's Story:

Jake is our sweet 7-year-old boy who is suffering from a neurodegenerative disease called late infantile Neuronal Ceroid Lipofuscinosis, or Batten Disease.  Jake was born a healthy baby boy on September 24, 2004. He was developing normally until age three, when he began having seizures and losing skills he had already learned. By age four and a half Jake had lost his abilities to walk and talk, was losing his eyesight, and was no longer able to do anything for himself. By age five he was finally diagnosed with late infantile Batten Disease. The symptoms of Jake's disease are mental impairment, worsening seizures, and progressive loss of sight and motor skills. Batten Disease is a genetic disorder linked to a buildup of substances called lipopigments in the body's tissues. Lipopigments are made up of fats and proteins. The lipopigments build up in cells of the brain and the eyes as well as in skin, muscle, and many other tissues. Jake lacks an enzyme that would normally filter out these fats and proteins. There is currently no treatment or cure for Batten Disease, and the life expectancy for Jake's form of the disease is between ages 8-12.  Jake is now tube fed and is almost completely blind. He is surrounded by loving friends and family, including his mom and dad, Dean and Jennifer, and his big sisters, Caroline and Anna. Jake enjoys his time spent at his school, Mandarin Oaks Elementary in Jacksonville, Florida, where he is well taken care of by dedicated teachers, nurses, and therapists.  He loves listening to music and watching "Dora the Explorer", and loves being outdoors. Our family has received many blessings through Jake. Thanks for taking the time to read Jake's story.

Contributed by MOM Jennifer Medley

Laryngeal Cleft

Is a rare abnormality of the separation between the larynx and the esophagus.  When the larynx develops normally it is completely separate from the esophagus, so swallowed foods and liquids go directly into the stomach.  A laryngeal cleft creates an opening between the larynx and the esophagus so food and liquid are in danger of passing through the larynx into the lungs.  They are classified into four types according to length.  Type I extends no further down than the vocal cords, type II extends below the vocal cords and into the crinoid cartilage, type III extends into the cervical section oft he trachea and type IV extends the furthest- into the thoracic section of the trachea. Occurs in less than 0.1 percent of the population. 

Symptoms:  Swallowing problems, coughing, gagging, frequent respiratory infections and chronic lung disease, cyanosis, failure to gain weight overtime, pulmonary infections.

Tests:  Diagnosed through a comprehensive aero-digestive evaluation.  A barium swallow study or FEES swallow study will determine if aspiration on liquids/foods is happening.  It is diagnosed through a endoscopic examination (microlaryngoscopy and bronchoscopy). 

Treatment:  Depends on the length and resulting severity of symptoms.  A type I cleft may not require surgical intervention.  Symptoms can be managed by thickening liquids and foods.  A slightly longer cleft is repaired endoscopically (long type I and short type II).  A cleft that is longer (type II or type III) is repaired directly through the neck with a tracheotomy. 

Resources:  Dr. Cotton (513) 636-4355 at Children's Hospital in Cincinnati
Dr. Rahbar (617) 355-6460 at Children's Hospital of Boston
Online Support Group- http://laryngealcleftkids.ning.com/

Photo: Marcelle and her little miracle, Aiden

Marcelle's Story:Our son, Aiden, is 2 years old and has a laryngeal cleft.  He was diagnosed with a type II laryngeal cleft when he was 2 months old.  We first saw symptoms such as choking and having apnea spells with these feeds.  He was admitted to Children's Hospital for a week of testing.  While there Aiden was spiking fevers after his feeds.  After numerous tests and procedures, he had a swallow study that showed aspiration on thin liquids.  He then had a bronchoscopy which showed a type II laryngeal cleft.  His laryngeal cleft was surgically (endoscopically) repaired when he was 6 months old.  Aiden has been in swallow therapy since he was 5 months old.  Despite the repair and swallow therapy he continues to aspirate on thin liquids.  We will continue swallow therapy and repeated swallow studies to ensure he is making improvements in his ability to swallow liquids.

Hypoxic Ischemic Encephalopathy (HIE)

Overview
Hypoxic Ischemic Encephalopathy (HIE) is a brain injury caused by a lack of oxygen.  The injury affects the brain as a whole as opposed to a part of the brain.  There are many things that can cause low oxygen levels in the brain.  Most often HIE refers to new born infants.  HIE can apply to many other brain injuries as well (near drownings, drug overdose, respiratory failure, smoke inhalation, choking, blood loss, etc.).  Low oxygen levels may lead to an HIE diagnosis- not all low oxygen events result in HIE however.

1996 guidelines from the AAP and ACOG indicate that there must also be a profound metabolic or mixed academia in the cord blood (if obtained), the APGAR must be between 0-3 for more than 5 minutes, there needs to be evidence of neurological events (seizure, coma, hypotonia, etc.) and the event must involve multiple organs.   Some cases of HIE do not fit the AAP and ACOG guidelines.  There are many cases reported where the symptoms do not present until minutes, hours, or even days after the event.

HIE is scored on 3 levels, mild, moderate or severe.  The most commonly used grade is the Sarnat Staging System developed by Sarnat and Sarnat in 1976.  If you are interested in more details on how the Sarnat Stages work, please click HERE.

It is estimated that HIE is seen in 1-8 of every 1000 births.  The mortality rate is said to be 25-50% (most deaths occur within the first week due to other organ failures, aspiration pneumonias, or systemic infections).  Currently about 80% of infants that survive a severe HIE event suffer serious health complications.  About 10-20% suffer mild-moderate health complications.  

Symptoms
Symptoms vary for all HIE patients.  I recently heard someone say “We know more about the brain than any other organ- and still we know the least about what to do with it.”  This hits home with anyone dealing with a HIE.  Tests can show that damage to the brain occurred.  However, everyone reacts different and some brains seem to recover some of the lost or damaged areas while other brains do not.  Many HIE patients will experience some muscle issues (Cerebral Palsy).  It is often common to see many patients have problems with their complex reflexes (either the lack of reflexes, or over sensitivity).  These reflexes include gag, suck, swallow, blink, startle and light sensitivity.  Seizures, blindness and deafness are also often seen in HIE patients.  Many patients will also suffer from heart, GI, and pulmonary complications.  The severity of these symptoms will vary, and many patients have additional health complications as well (some secondary- some from the initial event).

Testing and Diagnosis
There are many tests that can be done to diagnose HIE.  Some of these include Brain MRI, Head CT Scan, EEG, Head PET Scan, cord blood gas, and a handful of others.  As previously stated however, diagnosing HIE is only the beginning.  Each patient has to be monitored and fully examined for any type of medical prognosis. 

Treatments
In the past 3-5 years there has been a lot done to improve the expectations for brain injured infants.  If the event is caught early, and treatments start within the first 6 hours, recent studies show that cooling (hypothermia) is giving these babies much better prognosis.  Just as you ice a sprained ankle, if you cool a brain while it is swelling (or other organs swelling as a result of the brain swell) the cooling reduces the swelling leading to less global necrosis (cell death).  Originally the cooling was done just on the brain by use of cooling caps.  Now there are also cooling blankets used in NICUs to cool the entire body.  The NICU staff has to maintain the core temperature very closely.  Not all NICU’s or ICU’s have the cooling equipment.  Most level IV and some level III NICU’s across the US are now able to cool babies that have suffered a brain injury.

Often after a full medical work up, HIE patients are given very poor expectations.  Doctors don’t always know what to tell parents. A lot of this is due to advances in medicine.  Doctors are able to revive and save many children that would not have previously survived.  The life saving skills have improved, but the rest of the medical field left to support the survivors are still catching up.  As time goes by there will hopefully be more statistics and data for HIE patients.  As the data becomes available hopefully there will be a more consistent, productive approach to the treatment, prevention, and rehabilitation of HIE patients.

Currently doctors treat the symptoms.  HIE patients often see a team of specialists.  These specialists can include just about any area.  Orthopedics often help patients dealing with muscle issues.  The ortho may recommend medications to loosen or stiffen muscles (such as Botox injections, baclofen or clonazepam to name a few).  Some may suggest surgery to help with range of motion, relieve pain, or help with positioning.  Pulmonologists are usually members on the medical team.  Many HIE patients have issues with swallowing with leads to aspirations and other airway issues.  The gag, suck and swallow issues usually lead to a gtube or some other form on non-oral feeding adding a GI to the team.  Seizures are almost expected with HIE patients.  A neurologist is usually on board to monitor the brain as the child develops as well as to manage seizures.  In addition to a team of medical specialists, most HIE patients also see a team of therapists (occupational, speech, physical, vision, etc.).

There are a few non-standard treatments.  Non-standard is also non-covered.  These treatments can be expensive, often require travel, and depending on the relationship with the current medical team, the patient may or may not get a lot of support for related follow-ups and/or possible complications.  These treatments are at the discretion of each patient (and his/her caregivers).  If you decide to pursue these treatments, please let your medical team know. 

Hyperbaric Oxygen Therapy (HBOT) is one option.  The patient is put into a pressure controlled tank with high levels of oxygen.  The idea is that the increased oxygen will increase blood flow to the brain.  Just like HIE is due to a lack of oxygen, many people feel that the increased oxygen through HBOT will help repair some of the damaged cells.

Stem Cell Therapy is another option.  Currently Stem Cell Therapy for brain injuries is not an FDA approved treatment.  If you chose to get stem cell injections you will have to leave the US.  There are a few countries (Mexico, China, Russia to name some) that do offer Stem Cell Therapy.  The idea behind stem cells is that stem cells are smart cells.  When stem cells are injected into the body they travel through the body looking for cells that signal distress.  When they see an area of distress they basically set up camp and work to replace those cells.  There are many different types of stem cells as well.  The controversy is over embryonic cells (cells from a fetus).  However, stems cells can also be harvested from umbilical cords, sharks, fat tissue, and even some studies have shown successful harvesting from menstrual discharge.  The source of stem cells is growing every day.

There are occasionally stem cell studies done in the US for brain injuries.  These studies do not guarantee acceptance for all that inquire.   Currently Duke is doing some studies.  If you are interested in participating in one of these studies, please contact Dr. Joanne Kurtzberg, director of the Pediatric Blood and Marrow Transplant Program at Duke University.

Resources
Brain Injury Association of America
National Institute of Neurological Disorders and Stroke

2 HIE Yahoo support groups-
HIESC@yahoogroups.com
HIE@yahoogroups.com

Facebook-
Hope for HIE
Newborn Brain Cooling
Hope for HIE
Beautiful Faces of HIE (Secret Support Group)
For those interested in joining, please message one of the Admins. (Lori Sproul, Shannon Rice Bourdeaux, Kristi McConnell, Candice Lindley or Sam Lees) and give a brief reason for wishing to join their group

Casey’s Story
Casey was born on April 23rd 2006 just short of 37 weeks.  Casey came early, but not easily.  I had a uterine rupture.  Some ruptures are really just tears; however mine split the uterus completely in half.  When the uterus ruptured, Casey and her placenta left the uterus and floated in my abdominal cavity.

Luckily we made it to the hospital very quickly.  The doctors and nurses worked very fast to get Casey out.  Based on the blood gas taken from her umbilical cord Casey went about 30 minutes with limited to no oxygen.  The APGAR was 0 at birth, no breath, no heart beat.  After 5 minutes the resuscitation team had a heart beat; after 10 minutes they had gasping breaths.  Casey was taken to the NICU where she stayed for the first 2 months of life.

The official diagnosis of HIE (Hypoxic Ischemic Encephalopathy) was given.  Casey has many side effects/complications.  Casey has Quadriplegia CP (Cerebral Palsy).  Casey's CP is a stiffness in her arms and legs.  The stiffness in her legs has lead to a deformation in her feet as well as a dislocation of both hips and elbows.  The stiffness in her hands lead to cortical thumbs (pointing inward).  Casey has a barrel chest that adds to complications in positioning, airway management and gtube positioning (so LEAKY).  In addition to CP, Casey also has all of her complex reflexes missing.  Casey is not able to suck, swallow, gag nor blink.  Without the ability to swallow Casey's air way is in constant risk.  Suction equipment is needed to remove secretions, and anything else in her mouth/throat, in order for her to breath.  Also, without the ability to swallow Casey cannot eat by mouth.  All of Casey's nutrients and calories come in liquid form through a G-Tube.  Without the ability to blink, eye safety is another issue.  Moisture is supplied often with drops and lube, and Casey's eyes have to be covered when there is high risk for foreign objects near the eye.  Casey also has moderate hearing and vision loss.  She is legally blind, but the eye doctors believe with help she can eventually see.  Her eyes work, she is just not able to comprehend everything she sees.  The same can be said for her hearing.  She hears some, and with hearing aids she hears a little better, but the loss is more about her brain not comprehending the sounds than it is about her ears not working.

Over time Casey has aspirated fluid into her lungs a few times due to the lack of swallow.  These aspirations led to a few hospital stays with very serious pneumonias that were escalated to Acute Respiratory Distress Syndrome - ARDS.  The ARDS has put Casey into a category of lung and respiratory related issues as well. Even though she was not born with respiratory issues, they can still be considered complications of HIE, just secondary.

When Casey was born the cooling cap method was in trial in 1 US hospital- not the hospital we were in.  In the first year we tried 40- 1 hour sessions of HBOT as well as an injection of 1 million umbilical stem cells.  The second year we went back for a second round of stem cells where 2 million were injected.  We saw some improvements around these times, but it is too hard to say for sure how much (if any) the non-standard treatments contributed.  Sadly this is part of the reason these treatments have not been able to pass FDA regulations yet.

Casey has many serious complications, and has had a very hard start to her life.  Regardless of the challenge or the pain Casey has fought through it all.  She is without a doubt the strongest and most amazing child I have ever met.  Doctors originally gave a very grim expectation for Casey.  Some said she would never go home at all.  Others said if she did go home it was most likely she would not see her first birthday.  Casey has proven them all wrong.  She has a huge, wonderful personality to go with her amazing will and strength.  She may be disabled; she is definitely determined.  

Marty Barnes, mother of five year-old Casey, is one of the admins for Mommies of Miracles.  She is a stay-at-home MOM and wife.  The Barnes family live in Austin, Texas.  Marty has a background in IT (specifically databases).  She uses this experience toward maintaining her daughter's site- Caseybarnes.org as well as her grassroots inCLUsion Campaign- CLU.  Marty is on the Parent Advisory Council at the local children's hospital and works with local organizations such as Hand to Hold and Texas Parent to Parent.

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 DISEASE:
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.

SYMPTOMS:
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.

TESTING AND DIAGNOSIS:
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.

TREATMENTS:
Polymicrogyria: 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.


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

Walsh Lab
Phone: (617) 919-4795
Fax: (617) 919-2300walshresearch@childrens.harvard.edu
www.walshlab.org

Dr. William Dobyns, GeneticsSeattle Children's Research Institute
C9S -10 - Integrative Brain Research
1900 - 9th Ave
Seattle, WA 98101
206-884-1025

Dr. Gary Clark, Neurologistgdclark@texaschildrens.org
832-822-5046
6701 Fannin Street, Clinical Care Center
9th Floor, MC CC 950.04
Houston, TX 77030Blue Bird Clinic for Pediatric Neurology at 832-822-5046 nri_info@texaschildrens.org

(Support) The Lissencephaly Launch Pad (support for families with children who have brain malformations of varying types): http://homepage.ntlworld.com/foliot/liss/

Mitochondrial:The United Mitochondrial Disease Foundation
8085 Saltsburg Road, Suite 201
Pittsburgh, PA 15239 412-793-8077
Toll Free: 1-888-317-UMDF (8633)
info@umdf.org
www.UMDF.org
Support groups can be found in local chapters on the UMDF website.

MitoAction
14 Pembroke Street
Medford MA 02155
888-MITOACTION (888-648-6228)www.mitoaction.org

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.

Myasthenia Gravis and Congenital Myasthenic Syndrome

Overview

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. 

Symptoms

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/Diagnosing

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.

Treatments

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

Resources

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.

http://www.myasthenia.org/

http://www.ncbi.nlm.nih.gov/books/NBK1168/


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