Miller–Dieker syndrome

Overview

Miller–Dieker syndrome (MDS) is a rare genetic disorder characterized by a severe brain malformation known as lissencephaly, which means "smooth brain." In individuals with MDS, the brain lacks the normal folds and grooves (gyri and sulci), leading to profound developmental and neurological impairments. The syndrome is named after Drs. James Q. Miller and H. Dieker, who first described the condition in the 1960s and 1980s, respectively.

MDS is also associated with distinct facial features, growth retardation, feeding difficulties, seizures, and severe intellectual disability. It is typically caused by a deletion of genetic material on chromosome 17p13.3, which includes the LIS1 gene, critical for normal brain development. The condition is usually not inherited and results from a spontaneous (de novo) genetic mutation. Miller–Dieker syndrome is considered one of the most severe forms of lissencephaly.

Causes

Miller–Dieker syndrome is caused by a deletion of a portion of the short arm (p) of chromosome 17 at position 17p13.3. The deletion typically includes multiple genes, but the loss of the LIS1 (also known as PAFAH1B1) gene is primarily responsible for the lissencephaly seen in MDS. In many cases, the YWHAE gene is also deleted, contributing to the severity of the syndrome.

The deletion usually occurs sporadically and is not inherited from the parents. However, in some cases, it may be associated with a chromosomal rearrangement such as a balanced translocation in one of the parents, which can increase the risk of recurrence in future pregnancies. Genetic counseling and chromosomal analysis of the parents are important when a child is diagnosed with MDS.

Symptoms

The signs and symptoms of Miller–Dieker syndrome are apparent early in infancy and result from the structural abnormalities in the brain and the involvement of other systems. Common features include:

Neurological and Developmental Symptoms

• Severe intellectual disability

• Global developmental delay (motor and cognitive)

• Lissencephaly (smooth brain surface)

• Refractory epilepsy or infantile spasms

• Muscle hypotonia (low muscle tone) in early infancy, progressing to spasticity (increased muscle tone)

Facial Features

• Prominent forehead (frontal bossing)

• Bitemporal narrowing (narrowing of the temples)

• Short nose with upturned nostrils

• Thin upper lip and small jaw (micrognathia)

• Abnormal ear placement or shape

Other Symptoms

• Feeding difficulties and failure to thrive

• Growth retardation

• Respiratory complications (frequent infections or apnea)

• Vision and hearing impairments

Due to the complexity and severity of the condition, most affected children require continuous medical care and support throughout their lives.

Diagnosis

Diagnosis of Miller–Dieker syndrome is based on clinical evaluation, brain imaging, and genetic testing. The following methods are commonly used:

• Neuroimaging (MRI): Magnetic resonance imaging of the brain typically reveals classic lissencephaly with a thickened cortex and reduced or absent gyri (agyria or pachygyria)

• Genetic testing:

  • Chromosomal microarray: Detects microdeletions on chromosome 17p13.3

  • FISH (Fluorescence in situ hybridization): Used to identify deletions in the LIS1 gene

  • Whole exome or genome sequencing: May be used in complex or unclear cases

• Prenatal diagnosis: Possible via chorionic villus sampling (CVS) or amniocentesis if a chromosomal deletion is known in the family

Early diagnosis is crucial for initiating supportive care and preparing families for the prognosis and care needs of the child.

Treatment

There is no cure for Miller–Dieker syndrome. Treatment focuses on managing symptoms, improving quality of life, and providing supportive care. A multidisciplinary approach is essential, involving neurologists, pediatricians, therapists, and nutritionists. Common interventions include:

1. Seizure Management

• Antiepileptic medications (e.g., valproic acid, levetiracetam) to control seizures

• Monitoring for refractory epilepsy and considering other options like ketogenic diet or vagus nerve stimulation if seizures are uncontrolled

2. Nutritional Support

• Feeding therapy or use of feeding tubes (gastrostomy) in cases with severe dysphagia

• Dietary support to prevent malnutrition and ensure adequate caloric intake

3. Developmental and Supportive Therapies

• Physical therapy to manage spasticity and support mobility

• Occupational therapy to enhance daily living activities

• Speech therapy, though speech development is often severely limited

• Vision and hearing assessments and support as needed

4. Respiratory and Cardiac Care

• Monitoring for respiratory infections or apnea

• Treatment of any secondary complications such as aspiration pneumonia

Psychological support and counseling are also important for families coping with the challenges of this lifelong condition.

Prognosis

The prognosis for Miller–Dieker syndrome is poor due to the severity of the brain malformation and associated complications. Most affected children have profound developmental delays, severe epilepsy, and require lifelong medical care. Many children with MDS do not survive beyond early childhood, with respiratory complications and seizures being the most common causes of death.

However, with appropriate medical and supportive care, some children may live longer and achieve limited developmental milestones. Early intervention, symptom management, and supportive therapies can help optimize quality of life and ease the burden on families and caregivers.

Genetic counseling is highly recommended for affected families to understand the recurrence risk in future pregnancies and explore reproductive options.