Overview

Miller-Dieker syndrome, also known as MDS, is a very rare genetic disorder characterised by several neurological symptoms. These include seizures, breathing difficulties and lissencephaly, among other health consequences. Lissencephaly describes the appearance of the brain. Typically, the brain has many grooves, which are vital for how it functions.

However, when lissencephaly occurs, there are either no grooves present or the grooves are not present in sufficient numbers. This loss of grooves explains some of the symptoms experienced by MDS sufferers. MDS is caused by a small deletion of an area on chromosome 17.¹ Chromosomes are important as they carry all the genetic information inherited from our parents. Each human has 46 chromosomes, 23 from their mother and 23 from their father.²

Causes of Miller-Dieker syndrome

MDS is caused by a small deletion of an area in chromosome 17, specifically 17p13.3. Although it is known which part of the chromosome is deleted, it is unknown why this occurs. Deleting this region causes a loss of several genes, most importantly two genes called PAFAH1B1 and YWHAE.¹ 

The loss of this area on the chromosome results in partial monosomy, which means one chromosome does not have information due to changes in structure or deletions. The other chromosome remains unaffected and has the information present.³ 

MDS is not typically inherited from a parent and occurs by chance. However, there is a potential that one parent has a rearrangement on chromosome 17. This means that the chromosome has all the information it needs to function, leaving the parent is unaffected. But, the information is in the wrong order.⁴ 

If you have a child with MDS, it is recommended that you and your partner get genetic counselling to determine whether either parent has a rearranged chromosome. If this is the case, a genetic counsellor can help determine the risk of having another child with MDS. 

If a parent has a rearranged chromosome, there is an increased risk that they will have another child with MDS. However, if neither parent has a rearranged chromosome, there is no increased risk of another child having MDS.⁵

PAFAH1B1 gene

The PAFAH1B1 gene is responsible for cortical development and movement of cells called neurons in the brain. Two working copies of the PAFAH1B1 are needed for these processes to be achieved. In patients with Miller-Dieker syndrome, there are not two copies present.⁶

The brain has many different regions, including the cerebral cortex, which is essential for cognition and plays a role in many other things, such as attention, thinking, memory and language.⁷ Therefore, when this PAFAH1B1 gene is lost due to the deletion of the 17p13.3 area on the chromosome, deficits in these processes are caused.

YWHAE gene

While it is known that the YWHAE gene is lost, it is not exactly known how it affects MDS symptoms, as there has been more focus on the PAFAH1B1 gene. However, studies have shown that loss of YWHAE causes a higher risk of epilepsy and changes in facial features. Typically, these are prominent foreheads and short noses, which are features also observed in patients with MDS.⁸ 

Diagnosis of MDS

Because of how rare MDS is and because the symptoms overlap with several other disorders, it is unlikely that an MDS diagnosis will occur before birth. However, it is not impossible. If there are concerns for the baby due to scans or tests, a doctor can recommend several methods to attempt to diagnose MDS before birth. The procedures can be split into two categories:

Amniocentesis

Amniocentesis is a procedure typically performed between 15 and 20 weeks of pregnancy. It involves a doctor using an ultrasound to guide the insertion of a needle into the belly to reach the amniotic sac, a structure that surrounds the baby. Once the needle is in the amniotic sac, some fluid is removed. 

Researchers then test this fluid in a laboratory, which can determine whether there are any chromosome changes using a technique called fluorescence in-situ hybridisation (FISH) to determine if genes are missing on chromosome 17.⁹

Chorionic villus sampling (CVS)

Chorionic villus sampling is a procedure performed approximately between 11 and 14 weeks of pregnancy. It can involve injecting a needle into the placenta through the belly, similar to amniocentesis, or a small tube can be inserted into the cervix.¹⁰

Doctors can recommend these procedures and they will discuss the potential risks such as a miscarriage or infection. Therefore, you are not required to undergo these procedures if you are not comfortable.

After birth

Diagnosis after birth can occur when the child does not reach certain milestones, indicating that there are some developmental delays. Some children also have seizures starting at birth or very early after birth. These symptoms overlap with several other disorders. 

However, children with MDS have distinct facial characteristics, which include low-set rotated ears, the middle of the face being sunken in, and a small jaw, which may help doctors diagnose patients with MDS.¹¹

Symptoms of MDS

The main characteristics of MDS include lissencephaly and seizures. Lissencephaly means that the brain is smooth, which causes mental and physical developmental delays. 

Developmental delays

Children with MDS will usually only achieve developmental milestones typically associated with babies 3 to 5 months old. These include rolling over, tracking with eyes, and sometimes sitting, although uncommon. This also means that MDS patients are usually unable to speak.

Microcephaly

Babies with MDS usually have microcephaly, which means that their head is smaller than would be expected. However, this is not commonly seen until the baby is approximately one year old, as the head is a typical size you would expect for an infant.¹²

Seizures

Seizures are also very common in patients with MDS. They are caused by an imbalance of excitatory and inhibitory signals in the brain, which can cause too much activity and therefore result in a seizure. Seizures can also occur when the activity in the brain which should not happen at the same time, occurs simultaneously. Seizures in patients with MDS typically begin very early on after birth.¹³ 

Most children with MDS develop intractable epilepsy – which is a type of epilepsy that does not react to medication, making it difficult to alleviate seizures. If seizures occur frequently, there is a high chance that they will cause further brain damage.¹²

Dysphagia

Children with MDS often have dysphagia, which means that they have issues with swallowing. Many brain regions are involved in the process of swallowing, and one of them is the cerebral cortex, which is responsible for beginning the voluntary process of swallowing but also coordinating the movement. 

Therefore, due to the lack of folds in this brain region, affected individuals will have problems swallowing.¹⁴ Because of the difficulty swallowing, feeding trouble often results. This can lead to failure to thrive, i.e., difficulty growing or gaining weight. 

Breathing

Individuals with Miller-Dieker syndrome also have problems with breathing. The brainstem controls breathing. However, there is evidence that the cerebral cortex is also involved in breathing, explaining why this symptom is also present in children with MDS.¹⁵

Hypotonia

Individuals with MDS commonly have hypotonia, which means that they have poor muscle tone, which can make their movements appear floppy. Muscle tone is controlled by signals that begin in the brain and are connected to nerves in the muscle. This could also explain why some developmental milestones, such as sitting, are not achieved.¹⁶

Additional symptoms of MDS

Although MDS symptoms are primarily linked to the brain, other areas of the body can be affected by MDS, which include:¹⁷

• The heart - development of heart conditions
• Limbs - development of clinodactyly (fingers or toes are curved)
• Kidneys - development of kidney problems
• Organ organisation - omphalocele (the organs in the belly are on the outside instead of the inside)¹⁸ 

Although these can also occur, they are less frequent. However, if your child is diagnosed with this condition, it is essential to ensure that these symptoms are not also present.¹⁷

Treatment of MDS

Because of how uncommon MDS is and because it occurs before birth and is difficult to predict, there is currently no way to prevent MDS from occurring. There is also no treatment currently available. However, if your child is diagnosed with MDS, there are several ways to help alleviate symptoms and ensure a reasonable quality of life. These include:^19,20

• Anti-seizure medication
• Feeding tube
• Breathing tube

Summary

MDS is a rare genetic condition caused by a small deletion of an area on chromosome 17. MDS is not typically inherited but occurs randomly. The two genes usually lost include the PAFAH1B1 and YWHAE genes. This deletion causes the common features of MDS, including lissencephaly, developmental delays and seizures. MDS can be diagnosed before birth via amniocentesis or chorionic villus sampling, or after birth. Because MDS develops before birth and is difficult to predict, MDS cannot be prevented. The management of MDS is symptomatic, as no cure is currently available.