Miller-Dieker syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at September 26, 2016
StartDiseasesMiller-Dieker syndrome

Miller-Dieker syndrome, a type of lissencephaly is one of several well-documented types of disease caused by a brain malformation that occurs during early fetal development. A person affected with Miller-Dieker syndrome is born with a brain that is lacking the folds and ridges normally found on the outside layer of the grey matter known as the cerebral cortex. In some cases the entire brain is hourglass or figure-8 shaped. It is commonly known as lissencephaly Type A or classical lissencephaly.

Contents

Definition & Facts

Named for Dr. J.Q. Miller when he described it in 1963, Miller-Dieker syndrome was added to the growing list of similar diseases by Dr. H. Dieker in 1969. It is similar in presentation to lissencephaly type B or recessive lissencephaly, a condition also known as Norman-Roberts syndrome.

The National Institute of Neurological Disorders reports most children diagnosed with this disorder do not live past the age of two years. For those that do, their lifespan is generally no more than ten years. The cause of death is typically respiratory disease, pulmonary aspiration of food or liquids, or severe seizures.

Symptoms & Complaints

Children diagnosed with classical lissencephaly present with a host of symptoms. Physical characteristics of Miller-Dieker syndrome include several changes to the facial structure such as a prominent forehead, small jaw, low set ears, and a short, upturned nose. The center of the face tends to have a sunken-in appearance.

All of those affected will have intellectual disabilities and developmental delays when it comes to motor skills. Microcephaly or an abnormally small cranium is found in close to 95% of the documented cases. 90% will have poor feeding, stunted growth, respiratory problems, and a reduced lifespan.

Epilepsy affects all of them and only a few ever learn to sit up on their own. They will not meet the same milestones as children without the disease. The majority suffer from both an abnormal muscle stiffness known as spasticity and weak muscle tone known as hyptonia.

According to the National Institute of Neurological Disorders and Stroke the majority of children with Miller-Dieker Syndrome will never progress beyond the three to five month range of learning. A few children diagnosed with this disorder, however, exhibit more mild physical symptoms and grow into nearly normal intelligence and growth. 

Causes

Classical lissencephaly type A is caused by a defect in the process of embryonic development. This syndrome affects the time when nerve cells should move from their origin to the grey matter of the fetal brain. This generally occurs between the third and fourth month of pregnancy.

An interruption of this process leads to a deletion of necessary genetic material from a single chromosome, not the deletion of the chromosome itself. The amount of missing material varies between patients. PAFAH1B1 and YWHAE are two genes that are lost. This "deletion event" occurs at the moment egg meets sperm or slightly later in the earliest development of the fetus; it is thus not typically an inherited condition and there is no family history associated with it.

According to the Genetic and Rare Disease Information Center, a minority of cases are inherited in an autosomal dominant fashion. This means that the parent carrying a single copy of the defect is unaffected by it. Miller-Dieker Syndrome is believed to be passed to the offspring on the X chromosome. This means that affected males will pass the disease onto their daughters but not their sons.

Genetic testing shows that the carrier parent may have an abnormal arrangement of genetic material on one chromosome known as a "balanced translocation." This is passed to the offspring as an "unbalanced translocation." It is unbalanced due to the missing genetic material that is normally found in a specific place on band 13 of the short arm of chromosome 17. If a child with Miller-Dieker syndrome is born to a carrier parent the chance of its siblings being affected are 25%. 

Diagnosis & Tests

The medically unusual wide range of symptoms associated with this disease makes it one of the hardest to diagnose. One way to confirm Miller-Dieker syndrome before birth is through a cytogenetic test known as fluorescence in situ hybridization, or FISH. Fluorescent probes are introduced into the body of the embryo to allow the doctors performing the test to see the chromosomes. These probes bind to specific amino acids on the chromosomes.

A second commonly used diagnostic tool is obstetric ultrasonography or prenatal ultrasound imaging in which the outline of the brain of the fetus is clearly visible. After the baby is born a magnetic resonance imaging (MRI) will also show clearly the tell-tale signs of a smooth cerebral cortex. Early recognition of this disease has improved with modern imaging techniques as well as with genetic tests.

Treatment & Therapy

A therapeutic plan for a child with Miller-Dieker syndrome is based on treating the current symptoms. It is generally aimed at seizure control and preventing further complications; however, epilepsy that presents in conjunction with lissencephaly is difficult to treat using modern methods. Some babies may have a feeding tube so they receive adequate nutrition.

A small percentage of children eventually show some progress, such as being able to sit up or roll over on their own. Sadly, the majority of those diagnosed with Miller-Dieker syndrome only live to about age two, while some live to be 10 years old and it is reported that at least one lived to be a teenager. 

Prevention & Prophylaxis

Miller-Dieker syndrome cannot be prevented. Certain genetic experiments that cause or reverse the expression of certain amino acids in the genetic code of mice have proved successful in slowing down or stopping the deletion event that causes the disease.

So far there is not a way to translate these experiments for human use, yet that day is coming closer, giving hope that eventually this disease will be reversed prior to neural migration in the brain of the human fetus.