Clinical Features And Symptoms Of Miller-Dieker Syndrome

Introduction

Miller-Dieker Syndrome (MDS) is a rare genetic disorder characterised by smooth brain formation (lissencephaly), distinctive facial features, severe intellectual disabilities, and seizures. Caused by a random change in chromosome 17, MDS can be inherited or acquired spontaneously.^1,2

Affecting approximately 1 in 100,000 babies, symptoms of MDS may appear in newborns and infants as early as four weeks to 23 months after birth, with severity varying widely among individuals.^1,2 Tragically, many children with MDS do not survive past early childhood, with most passing away by age two.

Understanding the clinical features and symptoms of MDS is crucial for early diagnosis and intervention, significantly improving patient outcomes and quality of life. Tailored treatments targeting specific symptoms can enhance the management of the condition. Additionally, genetic counselling plays an essential role in family planning, particularly regarding risks in future pregnancies.

This article will explore the symptoms and clinical features of Miller-Dieker Syndrome.

Genetic basis

MDS is a genetic disease, meaning that there is a chromosomal abnormality in the random deletion of chromosome 17.² Chromosomes are structures within the cell that contain DNA, a molecule that holds all the genetic information required for life. Humans have 23 pairs of chromosomes inherited from both biological parents during fertilisation.³ Chromosomes can be divided into two sections, (q), which is the long arm, and (p), which is the short arm. It is this short arm on chromosome 17 where genetic information is deleted, resulting in the symptoms of MDS.²

Gene deletion of chromosomal segments can occur randomly in:²

• The egg
• The sperm
• Within the womb after conception

Inheritance pattern

The gene mutation responsible for MDS, often a deletion, can occur randomly, which is why most children with MDS have no family history of the condition.² However, in about 1 in 10 cases, a genetic mutation on chromosome 17 may be present in one of the biological parents, resulting in an abnormal rearrangement. Although the parent may not exhibit any symptoms of MDS due to the absence of a deletion, this mutation can be inherited by their child.¹ 

MDS follows an autosomal dominant inheritance pattern, meaning that a child needs to inherit only one copy of the mutated gene from either biological parent to develop the condition. This also implies that parents carrying the mutated gene have a 50% chance of passing it on to their offspring.¹

Neurological features

Lissencephaly (smooth brain)

Lissencephaly is a rare brain disorder characterised by a smooth surface on the brain, resulting in developmental delays and cognitive impairments in children. This condition arises during embryonic development, specifically between 12 to 24 weeks of gestation, when there is an abnormal formation of the brain’s ridges (gyri) and grooves (sulci) in the outer layers of the brain.⁴

Lissencephaly has different levels of severity and can classified into two main groups:

• Type 1: classic lissencephaly
• Type 2: cobblestone lissencephaly

Lissencephaly associated with MDS is classified into type 1 lissencephaly, meaning that the outer layer of the brain (cerebral cortex) only has four layers instead of the normal 6 found in healthy patients. This differs from type 2 lissencephaly, where there is no organisation of the cerebral cortex and it is pebbled, resembling cobblestones.⁴

Lissencephaly’s impact on brain function depends on the severity of the disorder. It can cause:

• Mental disability
• Developmental delays 
• Feeding difficulty
• Seizures

Seizures

Seizures are characterised by abnormal, uncontrollable electrical signals in the brain, leading to various physical and cognitive effects. In MDS, seizures are a common symptom, with 80-99% of patients experiencing them.¹ There are three types of seizures associated with MDS:

Infantile spasms

• A seizure that occurs early on in infancy, occurring mostly when the baby is between 5 to 7 months old
• There is an abnormal brain wave that causes damage to the developing brain, leading to slower development and can delay skills like sitting or crawling⁵ 

Generalised tonic-clonic

• A type of seizure where the muscles become stiff and jerk and the patient loses consciousness
• The seizures start on both sides of the brain and can last between 1 to 3 minutes long⁶

Myoclonic

• A type of seizure where there is quick uncontrolled muscle movement but the patient does not fall unconscious similar to a generalised tonic-clonic seizure 
• Myoclonic seizures are unpainful and quick⁷

Intellectual disability 

Intellectual disability is a common symptom in patients with MDS and can range from severe to profound, depending on the extent of brain abnormalities and the severity and frequency of seizures.⁴ This term refers to a neurodevelopmental condition characterized by impaired cognitive and adaptive abilities, affecting a person's capacity to learn, solve problems, and make judgments. It can also impact communication skills and social behaviour.

Hypotonia

Hypotonia is a medical condition describing a loss in muscle tone and motor function. This causes a child’s muscles to feel soft and can seem floppy like a rag doll when they are held.⁸ 

Hypotonia can cause child developmental delays such as:⁸

• Inability to hold their heads up when placed on their stomach
• Difficulty in balancing
• Difficulty in sitting up and remaining seated without falling over
• Trouble in feeding as they are unable to chew or swallow for a long time
• Speech impairments
• Breathing difficulties

Craniofacial dysmorphisms

Facial features

Facial dysmorphia is a very frequent symptom of MDS with 80-99% of patients experiencing these features.¹ Dysmorphia in facial features can include:

• High forehead
• Bitemporal narrowing (when the side of the foreheads are narrower than normal)
• Prominent nasal bridge (when the base of the nose is wide)
• Small upturned nose
• Thin upper lips
• Micrognathia (when the lower jaw is smaller and underdeveloped than normal)

Skull and scalp anomalies

Anomalies within the skull and scalp are another craniofacial dysmorphism common in MDS patients.¹ 

• Cutis aplasia is a medical term used to describe when the skin section of the scalp is missing
• Midface hypoplasia is a term used to describe when the upper jaw, cheekbones and eye sockets are underdeveloped, causing the middle part of the face to appear sunken²

Growth and development

Several growth and developmental delays can affect MDS patients. Growth delay is very frequent, where the slowing down of growth after birth is experienced in 80-99% of MDS patients.¹ This can be split into pre and postnatal growth retardation and developmental milestones. 

Pre- and postnatal growth retardation 

• Refers to when the foetus doesn’t grow and develop at the usual rate 
• This can lead to babies being born early and at a lower birth weight than usual, which could lead to failure to thrive if the baby is unable to gain weight

Developmental milestones 

• These are important achievements that are expected for children to do at a certain stage, i.e. walking and talking at a certain stage
• MDS patients can have developmental delays in their motor milestones (walking and sitting up by themselves) and in their talking and speech development 

Other physical abnormalities

MDS patients can also experience the following abnormalities:¹

Abnormalities in the cardiac system

• ventricular and atrial septal defects (holes within the heart)

Abnormalities within the gastrointestinal system

• difficulties in eating, chewing and swallowing

Renal anomalies 

• where there is damage to the kidney systems

Diagnosis and tests

MDS is diagnosed when a prenatal ultrasound detects abnormalities in the brain development of the foetus, such as lissencephaly or craniofacial dysmorphia.² 

Genetic testing is also performed via genetic amniocentesis which uses amniotic fluid to detect genetic mutation that can lead to MDS.² Other genetic tests can also be used such as: 

• Fluorescence in situ hybridization (FISH) 
• Comparative genomic hybridisation (CGH), where changes in the genome and chromosome number can be detected post-birth to clinically determine if a patient has MDS 
• MRI scans, where images of the brain are taken to determine if it is smooth

Management and prognosis

Currently, there is no cure for MDS, and the prognosis is generally poor, as the condition is often fatal. Management primarily focuses on alleviating and controlling symptoms, utilizing antiepileptic drugs to manage seizures and tube feeding to address feeding difficulties.² 

Caring for a child with a life-threatening condition can be incredibly challenging. Parents must prioritize their mental and physical health while supporting their children, and it is essential to seek out supportive therapies and groups for both parents and children, along with guidance from healthcare professionals.

Unfortunately, children with MDS have low life expectancies, with many not surviving beyond age 2, while a few may live up to age 10. It is exceedingly rare for children with MDS to reach their teenage years.² 

Ongoing clinical research aims to deepen our understanding of MDS, focusing on identifying its genetic basis and developing non-invasive genetic testing methods using blood samples. Continued research may lead to valuable insights and potential treatments for future patients with MDS.

Summary

• Miller-Dieker Syndrome (MDS) is a rare genetic condition that causes a brain abnormality, where the brain is formed smoothly (lissencephaly)
• It is accompanied by specific facial deformities, severe intellectual disabilities and seizures
• MDS is a genetic disease caused by a random change in chromosome 17, which can be random or inherited from their parents
• Symptoms of MDS can range from neurological features to physical features and growth and developmental delays
• MDS is a life-threatening fatal condition with a very poor prognosis as most children diagnosed with MDS pass away at the age of two 
• Clinical research in MDS is ongoing to provide potential future treatment for MDS patients