Miller-Dieker lissencephaly syndrome

The LIS1 (PAFAH1B1) gene provides instructions for making a protein that is part of a complex called platelet activating factor acetyl hydrolase 1B. This is where the PAFAH1B1 gene name comes from. This complex regulates substances that are important for the movement of nerve cells in the brain and for normal brain development and function. Two working copies of this gene are required for normal development of the brain. When one copy of the LIS1 gene is deleted, the brain does not develop properly and this results in lissencephaly.

Genetic testing can be offered to other family members if someone is found to have Miller-Dieker lissencephaly syndrome. If a baby or child is found to be affected, testing, such as a chromosome karyotype analysis, should be offered to parents to see if they carry a balanced chromosome rearrangement. If a parent is found to have a balanced chromosome rearrangement, testing should then be offered to other children who have medical concerns and developmental delays, and to siblings and parents to see if they also carry a balanced chromosome rearrangement.

Each family’s situation is different, and it is beneficial to meet with a geneticist and genetic counselor to discuss risks to other family members and who testing is appropriate for. To find a genetic counselor near you, use the Find a genetic counselor tool on the National Society of Genetic Counselors website.

The onset of seizures in people with Miller-Dieker syndrome can vary but typically happens during the first months to year of life.Over 90% of infants with MDS will develop seizures by 6 months of age. The type and severity of seizures can also vary. Some people have better control over the seizures with medications which allows a person to achieve more developmental milestones. The test called an electroencephlogram (EEG) which measures brain activity and can detect seizures is also often abnormal in people with MDS. There is a specific pattern than can be seen on an EEG that is seen in people with lissencephaly.

The best person to diagnose and manage seizures associated with MDS is a neurologist. If your child does not have a neurologist, ask your main doctor who they would recommend or use the Find a Neurologist tool through the American academy of Neurology.

Treatment for Miller-Dieker Lissencephaly syndrome involves helping with the symptoms of the condition. However, because of the poor prognosis, some families may chose to do supportive care. Supportive care usually involves avoiding invasive procedures and not intervening if the infant/child would need resuscitation (stop breathing).
Seizures are typically treated with medications, though this is not effective for every person.
Feeding difficulties may be severe enough to require a feeding tube (gastronomy tube) which gives nutrition directly into the stomach. This is placed during a surgical procedure. Breathing and feeding difficulties tend to worsen during periods of illness.

It is important that families discuss all options for treatment/management prior to making any decisions. Since every person with MDS is different, the decisions regarding treatment/management are also based on individuals situation.

The prognosis for individuals with Miller-Dieker lissencephaly syndrome is poor. The best developmental level achieved by children with this condition corresponds to that of a 3-5 month old. Seizures are also typically severe and may not respond to medications. Death usually occurs within the first two years of life. Only a few children have reached 10 years of age. There has been one individual with Miller-Dieker lissencephaly syndrome who passed away at 17 years of age.

Miller-Dieker lissencephaly syndrome is a genetic condition identified by a pattern of abnormal brain development known. This is known in medical terms as lissencephaly. The normal brain has many folds and grooves and individuals with Miller-Dieker lissencephaly syndrome have fewer folds and grooves or what looks like an abnormally smooth brain. Because of this condition, individuals have severe intellectual disability, seizures, developmental delay, a floppy baby appearance that is called hypotonia, as well as abnormal muscle stiffness. Feed difficulties are also problematic. For many, the less folds and grooves found in the brain, the more severe the associated symptoms are.

In addition to fewer folds and grooves found in the brain, those with lissencephaly Miller-Dieker syndrome tend to display distinctive facial features such as a prominent forehead; a sunken appearance seen in the middle of the face; a small, upturned nose; low-set and abnormally shaped ears; a small jaw; and a thick upper lip.

Rarely, affected individuals will have heart or kidney problems. Also rare, but having been reported, is an opening in the wall of the abdomen, The medical term for this is an omphalocele, which allows the abdominal organs to protrude through the belly button. Unfortunately, individuals with Miller-Dieker syndrome do not survive beyond childhood.

People with Miller-Dieker lissencephaly syndrome do not have good control of their airway. Because of this, food, liquids, saliva, and vomit are breathed into the lungs instead of being swallowed into the esophagus and stomach. This causes swelling and infection in the lungs. The term for this is “aspiration pneumonia.” This causes death in many people with Miller-Dieker lissencephaly syndrome.

The missing piece of chromosome 17 that causes Miller-Dieker lissencephaly syndrome has several genes that are located there. One gene is especially critical for Miller-Dieker lissencephaly syndrome. This gene name is LIS1. Another name for LIS1 is PAFAH1B1. Having a deletion or disruption of this gene appears to cause lissencephaly (smooth brain). Another critical gene is called YWHAE. When this gene is deleted, the severity of Miller-Dieker lissencephaly syndrome is greater.

To understand what genes are missing on your child’s chromosome 17, discuss the genetic testing results with your main doctor or genetics specialist (geneticist or genetic counselor).

Every person has 23 pairs of chromosomes, which are packages that hold our genetic information. Genetic information, also called DNA, are the instructions for our bodies on how to develop and continue to work properly over time. In the first 22 chromosomes (1- 22) one chromosome in each pair comes from our mother and one chromosome in each pair comes from our father. The 23rd pair of chromosomes is the sex chromosomes (chromosomes X and Y) which help to determine if a person is male or female. When someone is missing (deletion) specific genetic material on one copy of chromosome 17p13.3 that contains specific important genes, they have Miller-Dieker lissencephaly syndrome.

Deletions of 17p13.3 can be different. Specifically Miller-Dieker lissencephaly syndrome happens when two specific genes, LIS1 (also called PAFAH1B1) and YWHAE are missing (deleted). If a deletion of 17p13.3 does not involve both of these genes, a person may not show features of Miller-Dieker syndrome. The best person to explain chromosomes and what it means to have a missing piece of genetic material is a genetics doctor or a genetic counselor. To find a genetic counselor in a specific location, use the Find a Genetic counselor tool through the National Society of Genetic Counselors.

Facial differences usually seen in Miller-Dieker lissencephaly syndrome include a small head size (microcephaly), a sunken appearance in the middle of the face, a broad and high forehead, a relatively wide face, a small jaw (micrognathia), a long and thick upper lip, a short nose with upturned nostrils, and low set ears that may be malformed. Some affected individuals can have extra fingers or toes (polydactyly) and abnormal creases on the palms of their hands. Every person is an individual and will also resemble features of family members. While people with MDS have similar features to one another, not every person with MDS has all of the facial features listed.

All of our genetic information is held in packages called chromosomes. Every chromosome has two arms. These are named the “p” arm and the “q” arm. The “p” arm is the short arm (p comes from the French word petit meaning small) and typically shown as the top of the chromosome. The “q” arm is the long arm and typically shown as the bottom of the chromosome. The “p” and “q” arms are separated by something called the centromere, the center area between the two arms of the chromosome. The number “13.3” is the specific place on the short arm of chromosome 17 where the missing piece (deletion) is located. Knowing where a specific deletion of genetic material is located helps the genetics doctor to understand what features a person may develop.

The best person to explain chromosomes and what it means to have a missing piece of genetic material is a genetics doctor or a genetic counselor. To find a genetic counselor in a specific location, use the Find a Genetic counselor tool through the National Society of Genetic Counselors.

The usual abbreviations for Miller-Dieker lissencephaly syndrome are MDLS and MDS.

The main symptoms of Miller-Dieker lissencephaly are:

Less common medical concerns seen in people with Miller-Dieker lissencephaly syndrome include differences in how other organs in the body developed. These can include heart abnormalities, abdominal wall abnormalities such as omphalocele (this is when the abdominal organs develop in a skin covered sac outside of the abdominal cavity), genital abnormalities, and kidney abnormalities.

If you are unsure if a medical problem is related to the diagnosis of MDS, ask your main doctor or a genetics specialist (geneticist or genetic counselor).

There is testing that can be performed during the pregnancy to see if a baby has Miller-Dieker lissencephaly syndrome.

If a mother or father is a known carrier of a balanced chromosome rearrangement that increases the chance to have a baby with Miller-Dieker lissencephaly syndrome or if this condition is suspected based on ultrasound findings, genetic testing can be performed during the pregnancy to see if their baby is affected. Testing available includes chorionic villus sampling (CVS) and amniocentesis. These tests are invasive but are considered diagnostic. CVS involves removing a piece of the placenta and sending the sample to a laboratory for genetic testing. CVS can be performed around 10-12 weeks of gestation. Amniocentesis involves taking a sample of amniotic fluid and sending it to the laboratory for genetic testing. This testing can be performed starting at 15 weeks of gestation. To note, clinical features cannot be predicted before birth. Because both CVS and amniocentesis are invasive, there is a small risk for miscarriage. If a couple is interested in this prenatal diagnostic testing, they can speak with a reproductive genetic counselor in their area. Genetic counselors can be found using the website http://nsgc.org

As of January 21, 2016, there is a clinical trial that is currently recruiting participants. Their goal is to offer a clinical non-invasive prenatal test to mothers for chromosome conditions including Miller-Dieker lissencephaly syndrome. This is currently available for some chromosome conditions, but not for Miller-Dieker lissencephaly syndrome. This test requires a blood draw from mother. There are fragments of baby’s genetic information (DNA) floating in the mother’s blood stream and testing can be done on this free-floating DNA. This is not considered diagnostic testing, but is considered a screen that can indicate high or low risk. Indications for this testing may include family history and suspicious findings on ultrasound. More information about clinical trials can be found on clinicaltrials.gov

Each state has a newborn screen that includes a group of genetic conditions. Miller-Dieker lissencephaly syndrome is not included in any newborn screens in the United States. If there is a family history of a balanced chromosome rearrangement that increases the chance to have a child with Miller-Dieker lissencephaly syndrome or if Miller-Dieker lissencephaly syndrome is suspected at birth, genetic testing can be performed by getting a blood sample from the baby.

There is more than one test for Miller-Dieker lissencephaly syndrome. They are the following:

1) Chromosome analysis (karyotype, G-banding). This test looks at the chromosomes under the microscope. If the chromosome 17p13.3 deletion is large enough, chromosome analysis can detect it (depends on the lab, usually larger than 5,000,000 base pairs). If there is a chromosome rearrangement, this testing can usually identify it.
2) Fluorescent in situ hybridization (FISH). This test uses specific fluorescent probes for the chromosome 17p13.3 critical region for Miller-Dieker lissencephaly syndrome and can detect if there is a deletion or chromosome difference at this specific location.
3) Chromosome microarray. This test is more detailed than the chromosome analysis and can detect smaller chromosome deletions. This is the most common test ordered for infants with birth malformations such as lissencephaly
4) Prenatal testing (chorionic villus sampling and amniocentesis). These tests are invasive procedure performed on a pregnant woman to detect MDS during a pregnancy.

As of January 21, 2016, there is clinical research for Miller-Dieker lissencephaly syndrome that aims at developing non-invasive prenatal testing. It is the following;

1) Development of Non-invasive Prenatal Test for Microdeletion and Other Genetic Syndromes Based on Cell Free DNA (Microdel Triad)
-The purpose of this study is to collect blood from families with a child who has been diagnosed with a chromosomal disorder including microdeletions in order to further develop a non-invasive prenatal screening test based on fetal DNA isolated from maternal blood.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02109770
Contact: Melissa Schirmer, MS 650-249-9090 ext 696 [email protected]

Contact: Melissa Stosic, MS, CGC 650-249-9090 ext 411 [email protected]

Contact: Melissa Savage 650-249-9090 ext x411 [email protected]

There is no cure for Miller-Dieker lissencephaly syndrome. It is not possible to replace missing pieces of chromosomes. Treatment is limited to management, surveillance, and targeted therapies of medical concerns.

If someone has Miller-Dieker lissencephaly syndrome, their primary care provider should know/do the following:

• The prognosis is typically poor and life expectancy is low
• Monitor their growth (weight, length, head circumference)
• Monitor their development, and make sure the child is receiving the proper supportive services
• Monitor respiratory status especially during periods of illness
• Refer to a child neurologist if seizures or developmental regression is not
If a primary care provider would like more specific information regarding this condition and the management considerations, reference the genereview’s:LIS1 associated Lissencephaly article

If a child is found to have Miller-Dieker lissencephaly syndrome and parental genetic testing is normal, the chance to have another child with Miller-Dieker lissencephaly syndrome is very low, likely less than 1%. There is the rare chance of gonadal mosaicism where some of the mother’s egg cells or some of the father’s sperm cells have the chromosome difference. This usually cannot be detected through a blood test. Even if this is the case, the recurrence risk for future pregnancies is likely very low.

Diagnosing someone with Miller-Dieker lissencephaly syndrome can help guide their medical management and surveillance. It can help the primary care provider better recognize and treat medical concerns. This diagnosis can also assist with getting educational, developmental, and supportive services.

In terms of family members, this genetic diagnosis can help provide reproductive risks to other family members and may influence reproductive decision-making. A genetic diagnosis can also help parents and other family members connect with supportive services and other families if they are interested.

Genetic testing for Miller-Dieker lissencephaly syndrome is typically ordered by a geneticist and genetic counselor after seeing them for an appointment. A clinic appointment typically involves a complete review of the patient’s medical history, a three generation family history that documents health problems and genetic conditions, a detailed physical examination, discussion of recommended testing, and consent for genetic testing if the patient/guardian is interested. Sometimes this happens in one clinic visit, and sometimes this happens over the span of a few clinic visits. Each clinic is different. In terms of insurance, sometimes the clinic checks with your insurance, and sometimes it is your responsibility to call your insurance. As stated earlier, each clinic operates differently. If genetic testing is pursued, a blood sample and signed paperwork is sent to a laboratory that performs the testing. Results are then sent back to the geneticist and genetic counselor who contact the patient/guardian with results.

As of January 21, 2016, over 20 laboratories in the United States offer genetic testing for Miller-Dieker lissencephaly syndrome. This may also be an underestimate. A genetic counselor can help you find the best lab to have this testing performed. Some laboratories participate with and are the preferred laboratory of specific insurance companies.

Two great websites that list the different labs are the following:

1) https://www.genetests.org/
2) https://www.nextgxdx.com/

About 80% of cases of Miller-Dieker lissencephaly syndrome are not inherited. These are called “de novo” cases. In these cases, there is no family history and the chromosome 17p13.3 deletion occurs randomly during the formation of the sperm cells or egg cells, or in early development in the womb. There is nothing parents can do to cause or prevent a chromosome 17p13.3 deletion in a child if it happens randomly. This does not commonly happen twice within a family.

About 20% of the time, deletions of chromosome 17p13.3 are due to an unbalanced chromosome rearrangement. An unbalanced chromosome rearrangement is the medical term for pieces of chromosomes which are attached to a different chromosome; this can cause missing (deletion) or extra (duplication) genetic material. Sometimes, a parent has a balanced chromosome rearrangement that can cause a chromosome 17p13.3 deletion in their child. When a parent has a balanced chromosome rearrangement, they have all of the chromosomal material, but it is just rearranged. The parent does not show signs or symptoms because all of the chromosomal material is present. However, when a parent goes to have a child, this parent is at an increased risk to have a child with an unbalanced amount of chromosomal material [too much (duplication) and/or too little (deletion)].

When this happens with chromosome 17p13.3, the child would be at increased chance to have a deletion of this region, and thus have Miller-Dieker syndrome.

The best person to explain this concept is a genetic counselor. If your child does not have a genetic counselor, ask your main doctor or use the Find a Genetic Counselor tool on the National Society of Genetic Counselors website.

Each chromosome is made up of genes. Genes are genetic instructions that tell our bodies how to grow and develop. Because everyone has two copies of chromosome 17 (one inherited from mother and one inherited from father), everyone has two copies of every gene located on chromosome 17. When someone has Miller-Dieker lissencephaly syndrome, they are missing genetic material at chromosome region p13.3 on one copy of chromosome 17. Therefore they only have one copy of each gene at this region instead of the normal two. Genes in this specific region on chromosome 17 have many important roles in the body, especially for brain development.The two most important genes in this region are LIS1 (also called PAFAH1B1) and YWHAE When someone is missing one copy, the gene can no longer do its job and the person has health problems.

There are several way to find out information about clinical research for Miller-Dieker Lissencephaly syndrome:

1. Contact Dr. William Dobyns of the University of Washington and Dr. Joseph Gleeson at the University of California, San Diego whom are conducting genetic research on lissencephaly and related brain malformations.
For more information about the lissencephaly project and related research, contact:
Joseph G. Gleeson, M.D.
University of California, San Diego
E-mail: [email protected]
Web: http://www.cbd.ucsd.edu
William B. Dobyns, M.D
University of Washington
E-mail: [email protected]
Web: http://www.seattlechildrens.org/research/integrative-brain-research/

2) https://clinicaltrials.gov/ These are studies receive US government funding. Some studies are supported by private industries.
3) Clinical trials are conduct at the National Institute of Health Clinical Center in Bethesda, MD. One can contact the recruitment office at (800)411-1222, (866)411-1010, or [link url="[email protected]” target=”_blank”>[email protected]
4) To learn about clinical trials sponsored by private sources, you can contact [link url="www.centerwatch.com ” target=”_blank”>www.centerwatch.com

Most people with Miller-Dieker lissencephaly syndrome have severe developmental delay and intellectual disability. The best developmental level achieved is comparable to an infant of 3-5 months of age. Developmental achievements may include rolling over, tracking with the eyes, and sometimes, though rarely, sitting.

The exact prevalence of Miller-Dieker lissencephaly syndrome is unknown, but it is thought to be a rare condition. The specific brain difference called lissencephaly (smooth brain) is thought to be seen in 11.7-40 per million birth. This number may not capture all people who have this type of brain difference.

Most babies with Miller-Dieker lissencephaly syndrome have a normal head size at birth. After birth, head growth slows down and by age one, the head size is usually smaller than normal (microcephaly).

Babies affected with Miller-Dieker syndrome (MDS) may appear normal at birth. Some may have mild-moderate low muscle tone and poor feeding. Other signs and symptoms of MDS such as seizures, small head size and developmental delay present within the first year of life.

Features of Miller-Dieker lissencephaly syndrome are present in all individuals who have a chromosome 17p13.3 deletion that includes the critical genes in all of their cells. Every person is an individual so features and medical concerns may be more severe in some people than in others. The severity may not be able to be determined at birth and is not always predictable by the specific genetic testing result.

There can be ultrasound findings if a baby has Miller-Dieker lissencephaly syndrome. These can include:

• Slow growth (intrauterine growth restriction)
• Brain abnormalities such as: ventriculomegaly (increase in size in ventricles of the brain), lissencephaly (smooth brain), abnormalities of the corpus callosum, and microcephaly (small head size)
• Congenital heart defects
• Kidney abnormalities
• Omphalocele (intestines or other organs in the abdomen are outside of the body in a sac because of a hole in the belly button)

If a mother is pregnant with a baby who has Miller-Dieker lissencephaly syndrome, the pregnancy may be complicated by polyhydramnios (too much amniotic fluid). There may be decreased fetal movement as well. If polyhydraminos is detected during a pregnancy, the woman may be followed more closely by their doctor and may need to see a high-risk pregnancy doctor called a perinatologist.

The development of Infants with Miller-Dieker lissencephaly (MDS) syndrome is typically poor and people are typically never able to talk. Often people with MDS do not achieve developmental milestones above that of a 3-5 month old infant. This is due to the severity of the brain difference, lissencephaly, which is the main feature in this condition. If the level of lissencephaly is milder, a person may achieve higher developmental milestones such as sitting, though this is rare.

There has not been a reported case of a person with Miller-Dieker lissencephaly syndrome having a child. People with Miller-Dieker lissencephaly syndrome are severely affected developmentally and many do not survive past two years of age.

There is an available technology called preimplantation genetic diagnosis (PGD). This is available if a known balanced chromosome rearrangement runs in the family. If some embryos are made in the laboratory using mother’s egg cells and father’s sperm cells, genetic testing can be performed to see if a chromosome 17p13.3 deletion is present. The embryos that don’t have the chromosome 17p13.3 deletion can then be implanted in the mother. If one is interested in pursuing this, they can speak with a genetic counselor who specializes in preimplantation genetic diagnosis and/or assisted reproductive technology. Genetic counselors can be found using the website http://nsgc.org

There are other names for Miller-Dieker lissencephaly syndrome. They are the following:

• Chromosome 17p13.3 deletion syndrome
• LIS1-associated lissencephaly

If you have questions about whether an abbreviation or name of condition is similar to Miller-Dieker syndrome, ask your main doctor or genetics doctor.

There are several support groups for Miller-Dieker lissencephaly syndrome. They are the following:
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
o Website: http://rarediseases.info.nih.gov/GARD/

NIH/National Institute of Neurological Disorders and Stroke
P.O. Box 5801
Bethesda, MD 20824
Phone: (301) 496-5751
Toll-free: (800) 352-9424
Website: http://www.ninds.nih.gov/

We Are R.A.R.E.
4208 Chateau Rd.
Orlando, FL 32808 USA
Phone: (407) 617-4111
Email: [email protected]
Website: http://www.WeAreRARE.org

The Cortical Foundation
The Cortical Foundation is dedicated to providing services to educate, advocate, support, and improve
awareness of cortical malformations.
http://cortfoundation.org/cms/

Lissencephaly Network, Inc.
716 Autumn Ridge
Fort Wayne, IN 46804-6402
Phone: (219) 432-4310 Contact: Dianna Fitzgerald
Fax: (219) 749-6337
Web site: http://www.lissencephaly.org
E-mail: [email protected] or [email protected]

Facebook
Miller Dieker Syndrome Support
https://www.facebook.com/Miller-Dieker-Syndrome-Support-Families-197564453638203/

There are other genetic conditions that include lissencephaly (smooth brain). Similar conditions to Miller-Dieker lissencephaly syndrome include:

– LIS1-related malformations. Classic lissencephaly is caused by mutations in the LIS1 gene.
– DCX-¬related malformations. Classic lissencephaly is caused by mutations in the DCX gene.
– TUBA1A-related malformations. Classic lissencephaly is caused by mutations in the TUBA1A gene. Mutations in this gene can also cause a small and underdeveloped cerebellum (Norman-Roberts syndromes).
– Baraitser-Winter syndrome. Features include lissencephaly, a characteristic head shape, and eye malformations (shallow orbits, droopy eyelids, holes in the iris, choroid, or both).
– Walker-Warburg syndrome. Features include “cobblestone” lissencephaly, severe developmental delay and intellectual disability, muscle weakness and wasting early in life, and eye abnormalities.

Not all chromosome 17p13.3 deletions are the same. Chromosome 17p13.3 deletions can be different sizes. Some deletions of this region are smaller than typically seen in Miller-Dieker syndrome and thus may not involve the critical genes to give the signs and symptoms of MDS. Also some deletions can be much larger than the typical region for MDS, and therefore, may contain other important genes necessary for proper development.

Sometimes, a child can have another chromosome difference in addition to a chromosome 17p13.3 deletion.

If you are unsure the size of your child’s deletion or what genes are specifically involved, speaking with a genetic counselor may be best. If your child does not have a genetic counselor, ask your main doctor who they would recommend or use the Find a Genetic counselor tool on the National Society of Genetic Counselor’s website.