Overview

Miller-Dieker Syndrome (MDS) is an extremely rare genetic disorder characterised by abnormal brain development known as lissencephaly, whereby the surface of the brain appears very smooth, featuring fewer folds and grooves. These malformations are associated with severe intellectual disability, epilepsy, breathing and feeding problems, and impaired muscle strength.¹ 

Physical traits of the disorder include distinct facial features, such as a prominent forehead, a short nose, a thickened upper lip, a small jaw, and an increased distance between the eyes. Children may also have microcephaly, or a smaller head than usual, which is associated with impaired brain development.² 

Understanding the aetiology and genetic basis of MDS is crucial for diagnosis, management, and potential therapeutic interventions. This article will explore the causes, genetic factors and current research related to MDS.

Genetic basis of miller-dieker syndrome

Overview of genetic factors

Genes are specific sequences of DNA that correspond to particular instructions for making proteins involved in all functions and processes in the body. They are passed down from parents to children and determine traits such as height, hair colour, and eye colour. When the instructions stored in a gene change from what they typically would be, whether randomly, or passed on from a parent, it is referred to as a mutation.³ Genetic mutations can lead to many conditions, such as sickle cell disease or birth defects that affect how the body appears and/or functions.

Some genetic conditions are caused by problems in our chromosomes, which are structures found in the nucleus of each of our body’s cells and contain our genes. Humans typically have 46 chromosomes, arranged in 23 pairs, though this can sometimes change, leading to too many or too few chromosomes, or where particular areas of the chromosome may be missing. A common example is Down’s syndrome, where there are three copies of chromosome 21 instead of two. Chromosomes ensure that DNA is accurately copied and distributed during cell division, which is crucial for the growth, development, and repair of all of our body’s cells. Each gene is located at a specific position, or locus, on a chromosome, with some genes having multiple functions. 

Chromosome 17p13.3 deletion

Mutations can be helpful, or they can disrupt the normal function of genes, leading to various genetic disorders like MDS. They can be small changes, such as the alteration of a single base pair, or larger changes, such as insertions, deletions, or duplications of segments of DNA that may have a larger effect on the person.

Deletions involve the loss of a part of DNA from a chromosome. This can range from a small segment to a large portion containing multiple genes. The impact of a deletion mutation depends on its size and location, as well as which genes were lost, as one gene can code for different functions or multiple genes may be required for one specific process.

In MDS, deletion occurs near the end of the short arm of chromosome 17, in the region labelled as 17p13.3. This deletion includes several critical genes, which can be linked to the specific symptoms seen in MDS.¹ For example, the loss of a gene called PAFAH1B1 is responsible for lissencephaly, whilst the loss of another gene, YWHAE, increases the severity of lissencephaly seen in those with MDS.⁴ Many other genes in the deleted area are essential for brain development and likely contribute to the various symptoms.

Mechanisms of genetic mutation

Genetic disorders occur when there are changes in the DNA sequence of a gene, or when there are abnormalities in the chromosome structure or number. There are different ways these disorders can develop.

An inherited mutation is passed down from parents to their children, with many different ways of it being passed on:

• Autosomal dominant means only one copy of the mutated gene is needed to cause the disorder
• Autosomal recessive means two copies of the mutated gene are needed to cause the disorder
• X-linked inheritance means the mutation is located on the X chromosome, affecting people assigned male at birth (AMAB) more severely as they only have one X chromosome, so a mutation in the only copy of the gene is enough to cause a condition
• Y-linked inheritance means the altered gene is located on the Y chromosome, which only people AMAB have, so it can only be passed from the father to a male child
• Balanced translocation is where a piece of one chromosome is transferred to another without the loss or gain of any genetic material. Though the parent may not show symptoms, they can pass on their unbalanced genetic material to their children
  • Inherited cases of MDS are very rare, though when they do occur it is usually due to a parent carrying a balanced translocation that affects chromosome 17⁵

A de novo mutation is a spontaneous change in an individual’s DNA, and is not inherited:

• MDS is not usually inherited, with the deletion event occurring randomly during the formation of eggs or sperm (gametogenesis) or in early foetal development. This is likely due to either a mistake during DNA replication or the effects of different environmental factors, meaning there is typically no family history of the disorder⁵

Mosaicism occurs when an individual has two or more genetically different sets of cells in their body, leading to a mix of normal and mutated cells. The distribution of the mutated cells can vary, leading to a variety of symptoms.⁶

• Mosaicism in MDS can result in less severe symptoms compared to individuals with the deletion in all cells⁷
• Genetic testing may show that some cells have the 17p13.3 deletion whilst others do not 

Genetic testing and diagnosis

Many different techniques can be used to test for disorders like MDS, to provide a diagnosis. One technique, Fluorescence in Situ Hybridisation (FISH), uses fluorescent probes that bind to specific DNA sequences on chromosomes to detect the presence or absence of specific DNA regions, such as the chromosome 17p13.3 deletion seen in MDS.⁸

Early diagnosis of MDS is crucial, allowing for the introduction of interventions and methods for managing symptoms which would significantly improve the quality of life and outcomes for children with the disorder. 

Prenatal ultrasounds can detect abnormal brain development early in pregnancy, although this method is not very reliable as the brain is typically smooth until later on in pregnancy.⁹  

Amniocentesis can be used early in a pregnancy to obtain a small sample of cells from the developing embryo to detect chromosome deletion.

At birth, though facial dysmorphism can be apparent, children can remain underdiagnosed because of the disorder’s rarity and symptom similarity with more common syndromes. Magnetic Resonance Imaging (MRI) can be used for early diagnosis by revealing the lissencephaly seen in those with MDS.¹⁰

Clinical manifestations and diagnosis

Neurological features

Lissencephaly is the most prominent feature of MDS, where the normal folds and grooves of the brain are absent or underdeveloped. This severely affects neural function, resulting in severe intellectual disability and delays in motor skills and language development.

Seizures are very common in those with MDS, and will likely require multiple antiepileptic drugs alongside frequent monitoring and dosage adjustment.

Physical features

Distinct facial features are associated with MDS, including a prominent forehead and narrowing of the temples giving the head a distinctive shape, as well as a small jaw, upturned nostrils, a thin upper lip and a broad nose.

Other features such as structural defects in the heart, kidneys, or intestines are also very common. Severe defects may require surgical intervention, or long-term support, such as the placement of a feeding tube. 

Developmental and behavioural features

Individuals with MDS typically show significant cognitive impairments, with most children being unable to achieve typical milestones like speaking or walking independently, with learning as a whole being severely impacted and children requiring extensive support for any form of education or skill acquisition.

Furthermore, behavioural challenges are frequent in MDS, ranging from feeding difficulties due to poor muscle tone and coordination issues to irritability, sensory processing issues and sleep disturbances.

FAQs

How common is Miller-Dieker syndrome?

MDS is very rare, affecting approximately 1 in every 100,000 babies, meaning roughly 75,000 people worldwide have been diagnosed with it.

Are there any treatments for Miller-Dieker syndrome?

There is currently no cure for MDS, but the symptoms associated with the disorder can be treated. For example, seizures can be managed with antiepileptic drugs, with regular monitoring to minimise side effects. Specialised feeding bottles or the placement of feeding tubes can help those with gastrointestinal issues, and surgical interventions can be considered for physical abnormalities such as heart defects or cleft palates.

What is the prognosis for an individual with Miller-Dieker syndrome?

The majority of individuals with MDS will show significant developmental delays and intellectual disabilities, with symptom severity varying based on the extent of the deletion. Supportive care and family support can improve the child’s quality of life, but most do not survive beyond childhood.

Summary

Miller-Dieker Syndrome is a rare genetic disorder characterised by severe brain abnormalities and distinct facial features. It leads to developmental delays and a wide range of symptoms from seizures to cognitive impairment. It is caused by a random (de novo) deletion of a section of genes on chromosome 17 and is rarely inherited. The deleted region contains genes crucial in brain development, with the loss of these genes resulting in disrupted brain formation and the characteristic traits of MDS. 

Genetic testing can be used to diagnose this rare disorder, and though individuals do not typically live past childhood, their quality of life can be improved through symptom management and supportive care.