Miller-Dieker syndrome

Definition

Miller-Dieker syndrome (MDS) is a rare genetic disorder. Its signs and symptoms include severe abnormalities in brain development as well as characteristic facial features. Additional birth defects may also be present.

Description

MDS was named for the two physicians, J. Miller and H. Dieker who independently described the condition in the 1960s. The hallmark of MDS is lissencephaly (smooth brain), a condition in which the outer layer of the brain, the cerebral cortex, is abnormally thick and lacks the normal convolutions (gyri). In some areas of the brain, gyri are fewer in number but wider than normal (pachygyri). Other areas lack gyri entirely (agyri). Normally, during the third and fourth months of pregnancy, the brain cells in the baby multiply and move to the surface of the brain to form the cortex. Lissencephaly is caused by a failure of this nerve cell migration. MDS is often called Miller-Dieker lissencephaly syndrome.

Genetic profile

When MDS was first described, geneticists thought it followed an autosomal recessive pattern of inheritance . However, in the early 1990s, several patients with MDS were found to be missing a small portion of the short arm of chromosome 17 (17p13.3). This is called a partial deletion of chromosome 17. MDS is now classified as a "micro-deletion syndrome" because it is the result of the absence of genes that are normally located in this region of chromosome 17. In 1993, research scientists identified one of the genes in this region. They named it LIS1 for "first lissencephaly gene" because it appeared to be important in normal brain formation. The main evidence for this was that the LIS1 gene was missing in a number of individuals with isolated lissencephaly; that is, lissencephaly without the additional characteristics found in MDS. Researchers then studied a number of patients with MDS and found over 90% of them were missing the LIS1 gene as well as other, as yet unidentified genes, on the short arm of chromosome 17. Geneticists now think that the characteristic facial appearance and other abnormalities seen in MDS are due to the deletion of these other genes. For this reason, MDS has also been described as a "contiguous gene syndrome".

Most genes, including all genes on the autosomes (non-sex chromosomes ), are normally present in pairs. Individuals with MDS who have a micro-deletion of a small region of the short arm of one copy of their chromosome 17 still have one normal copy of this chromosome region on their other chromosome 17. For this reason, MDS is said to be due to "haploinsufficiency," the term for a genetic condition caused by the lack of function of only one of the two copies of a gene. As with other haploinsufficiency syndromes, MDS has also been described as having an autosomal dominant pattern of inheritance.

Individuals with MDS usually die in infancy. Because they do not live to the age where they can reproduce, they cannot transmit MDS to their offspring. Eighty percent of individuals with MDS have it as the result of a new (de novo) deletion of a small part of the short arm of one chromosome 17 in just the one egg or sperm that formed that individual. The parents of these affected individuals have normal chromosomes without deletions. This means that their risk of having another child with MDS is very low (probably less than 1%). However, the other 20% of those with MDS have the syndrome because one of their parents carries a rearrangement of one copy of their own chromosome 17. The rearrangement can be an inversion or a balanced translocation between chromosome 17 and one of the other chromosomes. Since the rearrangement is balanced; that is, all the chromosome material is present but in a rearranged form, the parent is normal. However, when that parent produces an egg or a sperm, the balanced chromosome rearrangement can go through a further rearrangement. This results in a portion of the short arm of chromosome 17 being deleted. The individual who develops from that egg or sperm will have MDS.

Demographics

MDS is present in fewer than one in 100,000 births. There is no information to suggest that the syndrome is more common in any particular ethnic or racial group.

Signs and symptoms

Infants with MDS are usually small at birth. Characteristic facial features may include a high forehead with furrows and vertical ridges, indentation of the temples, a small, upturned nose, up-slanting eyes, a small mouth, a thick, broad upper lip with a thin border, low-set ears, and occasionally, a cleft palate. Some infants with MDS also have birth defects involving the heart and kidneys. Signs and symptoms can vary among MDS patients. This may relate to the actual size or exact location of the chromosome 17 deletion in that individual.

MDS infants have a very limited capacity for development due to the lissencephaly and associated brain abnormalities. Mental retardation is severe to profound. Infants with MDS may be able to do little more than roll over. Convulsions (seizures) develop within a few weeks of birth and can be severe. Most newborns with MDS have low muscle tone (hypotonia), but later develop stiffness (spasticity) and an arching of the body (opisthotonos). Poor feeding leads to a failure to thrive and increases the risk of pneumonia because the infants can accidentally inhale baby formula into their lungs. Head size is usually in the normal range at birth, but poor brain growth means that, by the age of one year, the children have a smaller-than-normal head size (microcephaly).

Diagnosis

MDS is not the only disorder associated with lissencephaly. Autosomal dominant, autosomal recessive, and X-linked patterns of inheritance have been described among the more than two dozen genetic syndromes featuring this brain abnormality. Less commonly, lissencephaly can also be the result of fetal infections such as prenatal cytolomegalovirus (CMV). An accurate diagnosis of MDS is important not only because it can provide a prognosis for the affected child, but because it can give parents an estimate of their risk for having another child with MDS.

MDS may be suspected in the newborn period if an infant has the characteristic facial features along with low muscle tone. Studies of the infant's brain by CAT scan or MRI will show the smooth brain surface. After the diagnosis of MDS is made on the basis of these signs and symptoms, it is very important to study the infant's chromosomes to check for the characteristic chromosome 17 deletion. This is done by sending a small sample of the infant's blood to a cytogenetics laboratory. Trained laboratory personnel (cytogeneticists) first examine the infant's chromosomes through the microscope using traditional techniques. If no deletion or other chromosome rearrangement is detected in this step, newer methods can be used to search for deletions that are too small to see by ordinary means (micro-deletions). A special technique called FISH (fluorescent in situ hybridization) can detect chromosome regions where very small pieces of DNA are missing. This test is usually done on the same blood sample.

Carrier detection

When a chromosome deletion is found in an infant, both parents' chromosomes should also be studied to determine if one of them carries a chromosome rearrangement such as a balanced translocation. Although most parents of infants with MDS have normal chromosomes, in approximately 20% of children, one parent will have a chromosome rearrangement, which can increase the risk for having another child with MDS. Other family members should also be offered chromosome studies because these balanced chromosome rearrangements can be passed down through a family undetected, and, thus, other family members may be carriers. The first step in studying other family members is for a geneticist or genetic counselor to obtain a detailed family history and construct a pedigree (family tree) to determine which family members should be offered testing.

Prenatal diagnosis

If a couple has had one child with MDS, they can be offered prenatal diagnosis in future pregnancies. This option is particularly important for the 20% of MDS families where one parent carries a balanced chromosome rearrangement. The risk for these couples to have another affected child depends on the exact type of chromosome rearrangement present and may be as high as 25-33%. For families in which both parents' chromosomes are normal, the risk of having another child with MDS is low (1% or less). Either chorionic villus sampling (CVS) or amniocentesis can be used early in a pregnancy to obtain a small sample of cells from the developing embryo for chromosome studies. Early prenatal diagnosis by ultrasound is not reliable because the brain is normally smooth until later in pregnancy. Couples who are considering prenatal diagnosis should discuss the risks and benefits of this type of testing with a geneticist or genetic counselor.

Treatment and management

There is no cure for MDS and treatment is usually directed toward comfort measures. Because of the feeding problems and risk of pneumonia, surgeons often place a tube between the stomach and the outside of the abdomen (gastrostomy tube). Feedings can be made through the tube. Seizures are often difficult to control even with medication.

Prognosis

Death often occurs in the first three months of life and most infants with MDS die by two years of age, although there have been reports of individuals living for several years.

Resources

BOOKS

Jones, Kenneth Lyons. Smith's Recognizable Patterns of Human Malformations, 5th ed. Philadelphia, W. B. Saunders, 1997.

ORGANIZATIONS

Lissencephaly Network, Inc. 716 Autumn Ridge Lane, Fort Wayne, IN 46804-6402. (219) 432-4310. Fax: (219) 432-4310. lissennet@lissencephaly.org. <http://www.lissencephaly.org>.

WEBSITES

"Entry 247200: Miller-Dieker Lissencephaly Syndrome." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim>.

Dobyns, W. B. "Lissencephaly and subcortical band heterotopia (Agyria-pachygyria-band spectrum) Overview." (updated October 4, 1999). GeneClinics: Clinical genetic information resource. University of Washington, Seattle. <http://www.geneclinics.org>.

"Lissencephaly, Information for Parents." <http://www.lissencephaly.org/about/lissen.htm>.

The Lissencephaly Network, Inc.<http://www.kumc.edu/gec/support/lissence.html>.

Sallie Boineau Freeman, PhD