Introduction

Lissencephaly is a congenital condition that causes the foetal brain to develop with a smooth surface, instead of having folds and grooves (gyri and sulci) seen in a typical brain. This condition affects your child’s cognitive ability and is accompanied by other symptoms, including difficulty eating or swallowing and seizures. Lissencephaly can occur as an isolated case, but can also occur within another condition. One condition in which it would occur is called Miller-Dieker syndrome (MDS).¹

MDS is a genetic disorder that affects the brain, causing it to appear smooth. It is otherwise referred to as Classic lissencephaly (Type I). MDS is characterised by the deletion of chromosome 17, which is responsible for neuronal migration that occurs in the brain during development.²

When it comes to the clinical aspects of lissencephaly as part of MDS, understanding them helps in proper diagnosis, especially in differentiating the different types of Lissencephaly. In being able to properly identify the condition and the correct type, management of symptoms will be better targeted, and proper guidance can be given to families according to their needs.^2,3

Lissencephaly: Basic concepts

Lissencephaly is a rare congenital condition which causes the developing brain to appear smooth instead of having the usual bumps and folds. These bumps or folds in the brain are important to increase the surface area of the brain and cognitive ability. There are different types of lissencephaly, most of which are separated into two main categories, Classic Lissencephaly (Type 1) and Cobblestone Lissencephaly (Type 2). These categories share similar symptoms but different genetic mutations. ¹

Classic lissencephaly (Type 1)

In the classical form of lissencephaly, the cerebral cortex (the outer layer of the brain used for cognitive processing) appears abnormally thick and has 4 instead of 6 layers. This happens due to abnormal neuronal migration in the brain, specifically undermigration. It appears to lack either gyri (folds) or have only a few flat gyri. This type can occur on its own or associated with another condition, such as MDS. Children with this type of experience seizures, hypotonia (low muscle tone), difficulty feeding and slow head growth.^4,5,6

Cobblestone lissencephaly (Type 2)

In cobblestone lissencephaly or type II lissencephaly, the brain appears bumpy or pebbled when seen in scans, as the normal arrangement of brain cells is disorganised. This is because neuronal migration is being overdone. More severe patients have intense hypotonia. Some individuals with cobblestone lissencephaly could have Walker-Warburg syndrome or Fukuyama syndrome. They may also experience muscle and eye abnormalities.^4,7

Miller-dieker syndrome (MDS): overview

MDS is a rare genetic disorder which affects the cerebral cortex (outer layer) of your child’s brain, causing it to appear smooth, without the usual bumps or grooves seen in a typical brain. If your child has MDS, the physical symptoms are evident at birth. Severe developmental and neurological problems become more evident at 6 months old after realising your child is not reaching certain milestones, has difficulty feeding or experiencing seizures.

This condition is very rare, affecting every 1 in 100,000 babies. It was first described in the 1960s by James Q. Miller and H. Dieker, whose observations and features are now referred to as MDSe.

When speaking with your healthcare provider, you may be told terms like lissencephaly or classic lissencephaly syndrome, which refer to the smooth pattern of the brain that is associated with MDS.²

Clinical features of MDS

Neurological features

Children with MDS have a history of delay and setbacks in achieving milestones appropriate for their age. They experience intellectual disabilities and developmental delays. Seizures and hypotonia are also observed in children with MDS.

Physical/dysmorphic features

In addition to neurological symptoms, if your child has MDS, some of the physical features you will notice early are:

• Microcephaly, which is a smaller head size than normal
• A prominent forehead
• Small upturned nose
• The middle part of the pace is sunken or flat
• Wide upper lip
• Small jaw (micrognathia)  contributing to feeding or breathing difficulties^2,3

Other system involvement (e.g., cardiac, gastrointestinal)

Along with those neurological and physical features, there are also some other complications of MDS that some children experience. These complications include:

• Congenital heart conditions: structural problems with the heart which are present at birth.
• Kidney problems
• Omphalocele, which is the abdominal organs developing outside of their belly²

Genetic basis of MDS

A random chromosomal change is what causes children to have MDS. For some children, it is inherited. One parent usually has chromosome 17 in the wrong order. It is still intact and so doesn’t cause the parent to have MDS, but it is a loss of genetic material for future children. For other children, chromosome 17 is deleted from the egg or sperm, or during conception as the baby is developing. The size of the deleted segment varies among affected individuals; however, it usually includes the PAFAH1B1 and YWHAE genes. The deleted gene affects your child’s brain development in the uterus, and so the grooves and folds in the brain do not develop and instead appear smooth. ^2,3  

PAFAH1B1 gene

The PAFAH1B1 gene, also called LIS1, has instructions for making a protein a part of a larger group of proteins called PAFAH1B. It helps in guiding nerve cells to the right place during your child’s brain development. This gene helps with normal brain development and function. ⁸

YWHAE gene

The YWHAE gene provides instructions needed to produce a type of protein called 14-3-3 epsilon protein, which is part of a family of proteins responsible for cell signalling. The 14-3-3 epsilon protein has a role in neuronal migration in the brain, which helps to direct the movement of nerve cells by binding to other proteins. It is necessary for your child’s brain to develop normally.⁹

Diagnostic genetic tests

Diagnostic genetic tests can be done to detect signs of MDS. Diagnostic genetic tests involve identifying a deleted gene, often done through the following testing methods:

• Fluorescence In-Situ Hybridisation(FISH): the use of fluorescent probes to detect specific missing DNA segments
• Array Comparative Genomic Hybridisation (CGH): this detects deleted or duplicated chromosomes
• Whole exome/genome sequencing: used to identify genetic variations

Diagnosis and evaluation

MDS can be diagnosed using different methods. One of these is a prenatal ultrasound, which would detect brain development or other signs of MDS during pregnancy. To test the amniotic fluid for genetic changes that show MDS by performing a genetic amniocentesis. A third way to diagnose MDS is through chorionic villus sampling (CVS), which tests cells from the placenta.

After birth, your healthcare provider would be able to notice some facial features or other signs that indicate MDS.²

A magnetic resonance imaging (MRI) scan can also be done to see the brain and determine whether your child has type I lissencephaly.

Management and prognosis

Unfortunately, there isn’t a cure for MDS, and it is fatal. Those who had this condition usually did not survive beyond infancy, most passing by age 2 and some living to age 10. Treatments for MDS are usually focused on alleviating the symptoms, such as seizures or feeding difficulties.

Many children also experience aspiration pneumonia due to weakened throat muscles, causing food to go into their lungs instead of their stomachs. ²

When it comes to treating your child with MDS/Lissencephaly, due to the condition affecting the body in multiple ways, a multidisciplinary approach may be used to help care for your child. This is a team of specialists involved in your child’s care.

In caring for your child with MDS, it can be challenging. It is important for you to find support services for you and your child and talk to a mental health professional, and find ways to cope with the stress experienced. ²

Conclusion

Lissencephaly in Miller-Dieker syndrome (MDS) can delay a child’s development. Your child may experience seizures and hypotonia. Features such as an upturned nose, a smaller head than normal, a wide upper lip, a small jaw, a prominent forehead and others. Some children have complications such as congenital heart disease or kidney problems. Genetic issues either passed down or developed during conception, can lead to your child having MDS. Specifically, chromosome 17 is deleted from the genetic sequence, including the PAFAH1B1 and YWHAE genes, which are responsible for neuronal migration in the brain.

To detect signs of MDS, tests such as FISH (Fluorescence In-Situ Hybridisation), Array CGH (Comparative Genomic Hybridisation), and Whole Exome/Genome Sequencing would be used.

MDS can be diagnosed by testing the amniotic fluid (amniocentesis), testing placenta cells (chorionic villus sampling) and prenatal ultrasound. Also, features and other signs seen after birth can help your healthcare provider to give a diagnosis.

Diagnosing MDS early helps your healthcare provider to help manage your child’s symptoms and keep them comfortable while living with this condition, and can help in your child’s development.