What are WDR45-related disorders?

Pathogenic variants (“mutations”) in the WDR45 gene cause a range of different neurodevelopmental and neurodegenerative conditions, including a rare iron storage condition called beta-propeller protein-associated neurodegeneration (BPAN). Features of WDR45-related disorders include intellectual disability, seizures, loss of developmental skills over time, problems with muscle tone and movement, and behavioral differences. The WDR45 gene is on the X chromosome, which means that females have two copies of this gene while males only have one. Because of this, males tend to have more severe features compared to females.

WDR45is not the name of a medical condition but is rather the name of the gene that is affected. When a disorder is traced back to a disease-causing (pathogenic) variant in the WDR45 gene, it is called a WDR45-related disorder.

Signs and Symptoms of WDR45-Related Disorders

WDR45-related disorders fall into three broad categories, although some children have presentations that may overlap between these categories:

• Beta-propeller protein-associated neurodegeneration (BPAN)
• WDR45-related epileptic encephalopathy
• Intellectual disability only

Beta-Propeller Protein-Associated Neurodegeneration (BPAN)

The most common form of WDR45-related disorders is beta-propeller protein-associated neurodegeneration (BPAN), which is classified as a form of neurodegeneration with brain iron accumulation (NBIA). This condition most commonly affects girls, although boys may rarely be affected as well. In many children with BPAN, delays in achieving developmental milestones during infancy or early childhood may be the first sign of the condition. In other children, seizures are the first symptom.

Core features of BPAN include:

• Epilepsy: Seizures are a common feature during early childhood. Children with BPAN often develop multiple generalized and focal seizure types, which are often difficult to control in childhood. The frequency and intensity of epilepsy often lessens as the child becomes older.
• Developmental delays: All children with BPAN have some degree of developmental delay and ongoing cognitive impairment, which is especially noted in speech and language. Many children have limited or absent expressive speech. Loss of developmental skills and cognitive function is typically observed beginning in adolescence or early adulthood.
• Movement dysfunction: Although most children with BPAN are able to walk independently, they typically have a clumsy gait, often with ataxia. Many children may have fine motor difficulties as well. In adolescence or young adulthood, other movement disorders including dystonia and Parkinsonism begin to emerge.
• Behavioral issues: Features of autism spectrum disorder, repetitive movements and bruxism are seen in many children with BPAN.
• Abnormal brain imaging: Early in childhood, brain MRI typically shows thinning of the corpus callosum and nonspecific hypomyelination. As children get older, global atrophy, abnormal myelination and iron deposition may become apparent on brain imaging.

Many children with BPAN also have:

• Sleeping problems, including difficulties initiating and maintaining sleep
• Feeding difficulties
• Ophthalmological and vision findings

WDR45-related Epileptic Encephalopathy

Encephalopathy refers to a disease that affects the functioning of the brain. WDR45-related epileptic encephalopathy usually affects boys who have a mutation in the WDR45 gene. Boys with this form of WDR45-related disorder typically experience seizures that start in early infancy, often epileptic spasms, that are difficult to control with anti-seizure medication. Developmental delays are often more severe in boys.

Diagnosis of WDR45-related Disorders

Delays in reaching developmental milestones in infancy or early childhood, combined with seizures and delayed myelination is not specific but consistent with a diagnosis of a WDR45-related disorder. However, there are no typical signs or diagnostic criteria that enable a diagnosis based on clinical features alone.

Genetic testing is required to confirm a diagnosis.

Additional tests may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI)to look for structural brain abnormalities

Some children with a WDR45-related disorder are diagnosed with specific epilepsy syndromes based on the types of seizures they have experienced and the features of their EEG. Some of these syndromes include:

• West syndrome
• Lennox-Gastaut syndrome

In these cases, the epilepsy syndrome diagnosis is a description of the types of seizures the child is having, but the genetic diagnosis of BPAN/WDR45-related disorder is the primary diagnosis that explains why a child has developed epilepsy.

Genetics of WDR45-related Disorders

All children with WDR45-related disorders have a pathogenic variant (“mutation”) in the gene WDR45, which encodes the instructions to make a protein called the WD repeat-containing protein 45 (abbreviated WDR45). The “WD family” of proteins play many important biological functions in the body. The WDR45 protein is found in high levels in the brain and is believed to play a critical role in a process called autophagy, a regulated process within the cell that removes unnecessary and dysfunctional cellular components.

In most children with WDR45-related disorders, the WDR45 mutation occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic WDR45 variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the WDR45 mutation. However, a small proportion of cells do carry the WDR45 mutation in very low levels that may be difficult or impossible to detect.

Treatment for WDR45-related Disorders

Treatment for WDR45-related disorders will depend on the type and severity of the seizures and other related features.

• A combination of seizure medications is typically used to control the different seizure types. No particular anti-seizure medication has been shown to be more effective than others.
• A different set of medications, known as rescue therapies, may be given to help stop or shorten clusters of seizures when they occur.
• Implantable devices such as vagus nerve stimulation (VNS) may be considered when medications are not effective in controlling seizures.
• Deep brain stimulation (DBS) may be considered for management of dystonia in older individuals.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.

Problems with movement or motility are best addressed by physical and occupational therapy. Early physical therapy to increase mobility can reduce the risk for later complications, such as contractures or scoliosis. For those with feeding problems, feeding therapy may also be considered.

Cognitive and developmental delays or autism spectrum disorder associated with WDR45-related disorders are treated with physical, occupational, speech and applied behavioral analysis (ABA) therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Resources 

• Don’t Forget Morgan
• NBIA Disorders Association
• BPAN Warriors
• NBIA Alliance
• NBIAcure
• Medline Plus (Genetics Home Reference)
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission