Miller-Dieker syndrome is a rare disorder with unknown prevalence.

Genetic information is stored in all human cells in the form of molecules called DNA. DNA molecules arrange themselves in structures called chromosomes. Human cells have 23 pairs of chromosomes where one copy of each chromosome is inherited from the father and one copy is inherited from the mother. Chromosomes consist of smaller DNA segments called genes. Each gene is involved in specific cellular and biological functions.  MDS is caused by the deletion of a segment of chromosome 17. This deletion typically involves multiple genes and depending on the size of the deletion, more or fewer genes will be affected. 

Typically, there are many folds and grooves on the surface of the brain which increase the available surface area of the brain to accomodate for the many complex tasks performed by the human brain. The deletion of the PAFAH1B1 gene has been associated with the loss of the folds and the grooves of the surface of the brain (lissencephaly). YWHAE is another gene in the same region that, if deleted, will increase the severity of lissencephaly. Deletion of other genes probably contributes to other variable features of MDS.

MDS is not typically inherited, meaning that neither of the parents have a chromosomal abnormality. Instead, the deletion occurs as a random event either during the time that sex cells are formed or during early stages of pregnancy. Sometimes, MDS might be inherited from healthy parents. This occurs when a parent carries what is known as a balanced translocation. A chromosomal translocation occurs when two chromosomes in a cell exchange (translocate) segments of their DNA. A translocation is balanced when the exchange does not change the overall genetic content of the cell; the individual still has all the genes they need, however, the translocated genes are in chromosomes other than what is normally expected. Individuals with a balanced translocation are healthy as they are not missing any genes. However, when they have children, they may pass on a chromosome with a misplaced gene such that it is missing a segment or has an extra piece. In this case, the child has inherited an unbalanced translocation. MDS can occur if an individual inherits an unbalanced translocation in chromosome 17, in the region associated with MDS.

Newborns affected by MDS may appear normal at birth or have mild symptoms such as difficulty feeding and low muscle tone (hypotonia) which presents as “floppy” limbs. Their head circumference tends to be normal at birth, however, due to slow growth, they develop microcephaly (small head) within the first year of life. Neurological symptoms appear in the first few months and include seizures, developmental delay and intellectual delay. Seizures may be present shortly after birth but in most cases start between six months to one year of age. Feeding may improve after birth but usually worsens again after the onset of seizures. Airways control may also be affected which increases the risk of respiratory infections such as pneumonia. Some infants may have low muscle tone in their core muscles (core muscles may feel abnormally soft) and stiff limbs (limb spasticity). The severity of these symptoms depends on the severity of lissencephaly. 

Individuals affected by MDS often have a prominent, high forehead, a sunken middle face, a broad nasal bridge, and a small nose that is turned upwards. Ears tend to be placed lower than expected and abnormally shaped. A small jaw and a large upper lip is also common. 

Furthermore, heart defects, kidney abnormalities, and malformation of the fingers such as excessive curvature have been reported. Some infants are born with a condition where their internal organs such as intestines, liver, and the stomach, stick outside the belly enclosed in a transparent sac through a hole in the belly (omphalocele).

Diagnosis is suspected based on the presence of the distinctive facial features, and the observation that the child is failing to meet the expected developmental milestones. Diagnosis is confirmed by the analysis of the chromosomal structure and brain Magnetic Resonance Imaging (MRI)

Genetic tests that analyze chromosomal structures can identify chromosome 17 deletions in regions associated with MDS. In addition, a brain MRI can show an abnormally smooth brain and other brain malformations that are characteristic of MDS. An MRI is a medical imaging technique that uses strong magnetic fields to visualize the internal organs of the body. An MRI machine is a long tube-shaped magnet with both ends open. The individual is asked to lie still in the tube while images are being taken. The machine might make loud noises and individuals are often given earplugs. Taking an MRI might take anywhere from 10 minutes to more than an hour.

There is no cure for MSD, but specific symptoms can be treated. Newborns may require a tube that carries food from the nose to the stomach called a nasogastric tube as they may have difficulty swallowing. Many infants affected by MSD will eventually require a gastronomy tube, a tube inserted into the stomach through an incision in the belly which brings nutrients directly to the stomach. In addition, seizures need to be managed based on the specific type and the frequency of the seizures. Since infants are at an increased risk of pneumonia which is the most common cause of death in infants affected by MSD, they must be monitored for infections.

The developmental outlook and the life expectancy of individuals affected by MSD is poor. Most affected children do not live beyond childhood, and many die in the first two years of life. The oldest individual with MSD known to date died at 17. Life expectancy varies slightly and depends on the severity of an individual’s brain abnormalities.

The developmental outlook of children affected by MSD also depends on the severity of brain abnormalities, as well as how well-controlled the seizures are. Developmentally, affected children may reach milestones equivalent to 3-5 months of age and they might be able to sit in rare cases.

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