Miller-Dieker Lissencephaly

What Causes Miller-Dieker Lissencephaly?

MDS occurs when part of a particular chromosome, called chromosome 17, is missing in a child’s cells. A chromosome is a cellular structure that carries genes, the coded genetic material passed on from parents to their children in the reproductive process. Genes control the normal development and healthy functioning of the body’s cells. Although children inherit their parents’ genes, the abnormal change in chromosome 17 that causes MDS usually happens randomly and spontaneously, rather than because of a trait inherited from the parents.

The loss of genetic material from chromosome 17 causes MDS symptoms, but researchers are not yet sure exactly how the disorder develops.

Is Miller-Dieker Lissencephaly Hereditary?

In most MDS cases, the loss of genetic material from chromosome 17 happens randomly, either in the sperm or egg cells before fertilization or early in the fetus’s development. In these cases, there is no abnormality in the parents’ chromosomes. The child does not inherit the genetic abnormality from the parent. Most sufferers of MDS have no family history of the disorder.

In about 12 percent of cases, MDS occurs because of genetic abnormalities in a parent’s cells. The parent’s abnormality is called a “balanced translocation” in chromosome 17. This means that the chromosome’s genetic material is abnormally rearranged, but none of the material is lost. Because the genetic material is complete, even though it is in the wrong arrangement, the parent usually doesn’t experience MDS symptoms. However, the translocation can cause some genetic material to be lost during fetal development. The loss of genes results in the development of MDS in the child.

How Is Miller-Dieker Lissencephaly Detected?

In some cases, MDS may be detected before birth. Prenatal imaging such as ultrasound exams or magnetic resonance imaging (MRI) may show abnormal brain development. Prenatal analysis of the amniotic fluid may also be able to detect the genetic abnormalities that cause MDS.

After birth, MDS might be suspected if a newborn baby possesses the disorder’s physical features. However, these features may also indicate other conditions; therefore, MDS may go undiagnosed in its early stages.

The manifestation of symptoms may be an early sign of the disorder. Early symptoms may include:

• Problems with feeding
• Slow growth
• Physical developmental delays
• Intellectual developmental delays
• Seizures

How Is Miller-Dieker Lissencephaly Diagnosed?

If parents have no family history of MDS, there may be no reason to suspect that the disorder is present in a developing fetus. This can cause the condition to go undiagnosed before birth. Abnormal brain development may be apparent in routine prenatal ultrasound imaging, but the characteristic smooth cerebral cortex is challenging to spot early in fetal development.

The distinct facial and other physical features often associated with MDS are not necessarily reliable to diagnose the disorder because these features may indicate conditions other than MDS.

DNA testing can reliably identify the genetic abnormalities that cause MDS. These tests can be done via amniocentesis or chorionic villus sampling (CVS) during pregnancy.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Miller-Dieker Lissencephaly Treated?

There is no cure for MDS, and there are no treatments that can directly improve the disorder’s symptoms. Treatment programs typically focus on supportive care such as assistance with feeding and other physical needs.

When seizures are a symptom of the disorder, control of these seizures becomes an essential part of the child’s safety and development. Anti-seizure medications are often prescribed.

Because eating and swallowing difficulties are common and may get progressively worse, using a feeding tube may be necessary.

How Does Miller-Dieker Lissencephaly Progress?

Life expectancy for children with MDS is short, with many sufferers not surviving past the age of 2. It is uncommon for sufferers to reach 10, and survival into the teen years is even rarer.

Children with MDS develop slowly, both physically and mentally. Problems with muscle tone and motor control make it rare for a sufferer to sit or walk. Most children will only reach the developmental level of a 3-5 month-old infant. When seizures are not well controlled, the child’s development may be even more limited.

The most common causes of death in MDS sufferers stem from their difficulties with swallowing and breathing. Aspiration of food or liquid into the lungs can lead to fatal respiratory illnesses such as pneumonia. In some cases, seizures may be so severe that they are life-threatening.

How Is Miller-Dieker Lissencephaly Prevented?

There is no known way to prevent spontaneous cases of MDS caused by chromosome damage during fetal development.

When parents have one child with MDS, the likelihood of another of their children having the disorder depends on whether or not either parent is carrying a balanced chromosome rearrangement. If either parent has a balanced translocation on chromosome 17, the chances of having another child with MDS may be as high as 1 in 3. However, if neither parent has a translocation, the chances of having a second child with MDS are very low.

A genetic counselor can help parents assess the risks for future pregnancies.

Miller-Dieker Lissencephaly Caregiver Tips

Living with MDS is not easy for children or parents. For the sake of your child and your health, keep these essential caregiving tips in mind:

• Get help. Children with MDS face many challenges, and providing for their care is beyond most parents’ abilities alone. Ask your healthcare provider for referrals to support services that can provide physical therapy, occupational therapy, speech therapy, and all the other things your child needs.
• Learn about the disorder. Every child’s experience with MDS is different. Your child’s symptoms and their severity are unique. Learn as much as you can about the condition in general and your own child’s specific challenges. Education can help you feel less overwhelmed, and you’ll feel better knowing that you’re doing everything you can to improve your child’s quality of life.
• Take care of yourself. As is the case with any debilitating illness, caregivers for children with MDS are at risk of mental and emotional health struggles of their own. It is helpful to have a support system to take some of the weight of caregiving from you. Keep your connections with loved ones strong, and don’t be afraid to ask for help when you need a break. Knowing that you’re not alone is also important; support groups, either locally or online, can put you in touch with other parents who are dealing with MDS.

Miller-Dieker Lissencephaly Brain Science

Scientists know that MDS is caused by the loss of one or more genes from chromosome 17. The disorder is likely not caused by the loss of just one particular gene but by the loss of multiple genes. Each of these genes is responsible for some different aspect of the disorder.

Research has suggested that the loss of one specific gene, called PAFAH1B1, is responsible for the disorder’s distinctive abnormal brain development (lissencephaly). The loss of another gene, called  YWHAE, seems to increase the severity of lissencephaly in MDS sufferers. The loss of other genes probably causes the disorder’s other characteristics and symptoms.

Miller-Dieker Lissencephaly Research

Title: Development of Non-invasive Prenatal Test for Microdeletion and Other Genetic Syndromes Based on Cell-Free DNA (Microdel Triad)

Stage: Completed

Principal investigator: Kim Martin, MD

Children’s Hospital Of Philadelphia

Philadelphia, PA

This study’s primary purpose is to collect family triads from families affected by a genetic or microdeletion/duplication (MD/D) syndrome to further develop non-invasive prenatal testing based on fetal DNA isolated from maternal blood. To assist with the development of the test, we will need to collect blood samples from women whose child was diagnosed with a genetic or MD/D syndrome, a blood sample from that child, and a blood sample from their confirmed unaffected siblings. Since the test is based on Natera’s Parental Support™ technology, buccal or blood samples from the biological fathers will also be requested.

A recent abstract from a five-year study on prenatal microarray testing revealed that 1.6% of women who present for routine prenatal indications have a positive microarray test. With the frequency of microdeletions and microduplications (MD/D) now known to be higher than previously thought, the field is likely to move toward offering invasive testing for microarray abnormalities to all pregnant women. Although non-invasive prenatal testing for aneuploidy is now clinically available, it has become clear that non-invasive prenatal testing for MD/D is equally important. However, access to these samples is made difficult as the standard of care for offering microarray analysis to all pregnant women will take time to come to fruition. We would like to develop this non-invasive as the standard of care so that fewer women will have to undergo invasive testing to diagnose microarray abnormalities. Thus, there is an unmet need to develop novel tests that would increase the scope of non-invasive prenatal screening.

Title: Congenital Muscle Disease Study of Patient and Family Reported Medical Information (CMDPROS)

Stage: Unknown

Principal investigators: Gustavo Dziewczapolski, PhD and Anne Rutkowski, MD

Congenital Muscle Disease International Registry

Torrance, CA

The Congenital Muscle Disease Patient and Proxy Reported Outcome Study (CMDPROS) is a longitudinal 10-year observational study to identify care and trend key care parameters and adverse events in the congenital muscle diseases using the Congenital Muscle Disease International Registry (CMDIR). The CMDIR registers individuals with and without genetic confirmation who have been given a clinical diagnosis of congenital muscular dystrophy, congenital myopathy, and congenital myasthenic syndrome, or myofibrillar myopathy, through the limb girdle/late onset spectrum.

Identifying care parameters and adverse events in rare genetic neuromuscular diseases can be difficult. Care is fragmented; genetic confirmation may not be prioritized by the medical community or covered by medical insurance, and patients are scattered globally with potential challenges aggregating data across centers. Natural history studies are currently being launched. However, potential biases to participation include recruiting less severely affected patients given difficulty traveling secondary to a medically fragile condition. There is currently no treatment for these conditions, though optimizing and standardizing care and care delivery can promote significant gains in quality of life and survival. Identifying disease-specific care parameters and correlating those parameters with adverse event rates will not only contribute to the development of evidence-based guidelines but inform clinically meaningful outcomes for future clinical trials.

Study hypothesis:

To use patient and proxy reported survey answers and medical reports to build a longitudinal care and outcomes database across congenital muscle diseases.

To generate congenital muscle disease subtype specific adverse event rates and correlate with key care parameters.

The primary outcome is survival measured from date of birth to date of death. The primary outcome will be analyzed by congenital muscle disease subtype and maximal ambulatory status achieved.

Secondary outcomes include disease-specific adverse event rates, including rates of hospitalization; rates of antibiotic use; rates of pulmonary infections; pneumothorax, atelectasis, aspiration, and adverse complaints including bloating, constipation, chest pain, dyspnea assessed by a validated breathing assessment, vomiting and nausea, and difficulty eating. Patient and proxy hospitalization, pneumothorax, and atelectasis reports will be confirmed by obtaining hospital discharge summaries. Additional secondary outcomes include ejection fraction (relevance subtype-specific), forced vital capacity in liters, weight, Rapid Eye Movement (REM), sleep apnea hypopnea index, and mean oxygen saturation during REM and total sleep study, age, gender, type of treatment center location (national referral center, tertiary care hospital, community hospital), gastrostomy tube, total number of fractures and Tscore/Zscore of hip and spine on DEXA scans.

Preliminary studies may focus on specific congenital muscle disease subtypes and use retrospective data collection through registry, survey monkey, and telephone interviews to assess adverse event rates over the last month and last year to limit recall bias. Prospective enrollment of same study participants over 12 months will assess monthly rates of adverse events and complaints. A preliminary study, CMD PROADE (Patient and Proxy Reported Adverse Event Rates), is planned in 2 congenital muscular dystrophy subtypes: Collagen 6 Myopathy and LAMA 2 Related CMD.

De-identified data from CMDIR will be made available for IRB-approved natural history studies in congenital muscle diseases.