Miller-Dieker syndrome

Miller-Dieker syndrome (MDS), also known as Miller-Dieker lissencephaly, is a rare inherited disease that manifests itself in a brain development disorder and a characteristic face. MDS is an incurable disease and individuals who suffer from it live about two years.

MDS was discovered in the 1960s independently by two doctors: J. Miller and H. Dieker.

Cause
MDS is an autosomal dominant disorder of brain development.

This is microdeletion syndrome on chromosome 17, which is characterized by a hemizygous deletion of 17p13.3 and thus the loss of several neighboring genes. There are more than 50 genes in this area, but the main hallmark (lissencephaly) of MDS is the gene LIS1, which is important for normal brain development. 90% of patients have a deletion in this gene. LIS1 encodes a subunit of the enzyme PAPAF, which is responsible for the organization of microtubules required for neuronal migration.

The phenotype is further affected by the loss of other genes, which probably cause the characteristic facies of affected individuals.



Symptoms and Phenotype
Symptoms of MDS include brain dysgenesis, hypotonia, and 'facial dysmorphia. The brain is smooth (=lissencephaly) and without gyrification. There is type 1 lissencephaly, which is characterized by complete agyria, and type 2, where we can find grooves at the frontal and occipital poles. The cerebral cortex consists of only 4 layers (instead of 6), which is due to the imperfect migration of neurons into the cerebral cortex during the 3rd and 4th months of development.

The fetus may be affected by polyhydramnios, reduced intrauterine growth and reduced movements during development.

Newborns have a characteristic facies characterized by a small nose with anteverted nostrils, a protruding upper lip with a thin red rim, and micrognathia. Other features include a high forehead, small chin and flat eyes. Their development stagnates at the level of 3-6 months and they do not learn to sit or walk independently.

Heredity and Prognosis
Most patients die before the reproductive age and therefore only about 20% of patients inherit the disease from their parents, the majority acquire microdeletions by ``de novo'' mutations. Parents with a balanced rearrangement have a 22% risk of miscarriage and a 26% risk of giving birth to an affected individual.

In the parent of the affected individual, the karyotype and the LIS1 gene are investigated by FISH.

Hypotonia occurs in these individuals early in life, but spasticity and convulsions develop with age. Patients suffer from severe mental retardation, their motor development stagnates and they are only capable of non-specific answers.

Children usually suffer from epilepsy, which manifests itself before the 6th month of life. Furthermore, they have problems with taking in food that they cannot swallow, which puts them at risk of aspiration pneumonia. Patients may present with microcephaly, cryptorchidism, omphaloceles, heart defects, clinodactyly, and renal anomalies.

Most patients do not live more than two years.

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