ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome, is a rare neurodevelopmental genetic condition caused by a mutation in the ADNP gene. This gene is important for brain formation and development, and a mutation can affect multiple body systems. Although first identified in 2014, ADNP syndrome is now considered one of the more common single-gene causes of autism spectrum disorder, with symptoms that vary significantly between individuals.
The Genetic Cause of ADNP Syndrome
The Activity-Dependent Neuroprotective Protein (ADNP) gene provides instructions for making the ADNP protein. This protein is a regulator of gene expression, for genes involved in brain development. It functions in a larger protein complex that remodels chromatin, the material that packages DNA into chromosomes. By changing how tightly DNA is packed, this process controls which genes are active, and a disruption can alter the activity of many other genes.
ADNP syndrome is almost always the result of a de novo mutation. This means the genetic variant occurs spontaneously at conception or during early development and is new to the individual, not inherited from either parent. Because the change is not present in the parents’ DNA, the chance of them having another child with the syndrome is very low, though not zero due to the small possibility of germline mosaicism.
Common Characteristics and Symptoms
The signs and symptoms of ADNP syndrome are broad and differ in severity. A primary characteristic is global developmental delay, affecting skill acquisition. This includes significant delays in motor milestones like sitting and walking, and profound impacts on speech, with some individuals remaining nonverbal. Intellectual disability, ranging from mild to severe, is also a common feature. Many individuals exhibit features of Autism Spectrum Disorder (ASD), such as repetitive behaviors and challenges with social interaction.
Despite these challenges, children often have a happy and affectionate demeanor, sometimes marked by unprovoked smiling and laughter. Behavioral issues can also arise, including:
- Anxiety
- Temper tantrums
- Sleep disturbances
- Attention-deficit/hyperactivity disorder (ADHD)
Distinctive facial features are common, including:
- A prominent forehead
- A high hairline
- A broad nasal bridge
- A thin upper lip
A highly characteristic physical sign is the premature eruption of primary (baby) teeth. Vision problems like crossed eyes (strabismus) and farsightedness (hyperopia) are also frequent. Other health issues can be associated, including feeding difficulties and hypotonia (weak muscle tone) in infancy, as well as gastrointestinal problems like constipation and reflux.
The Diagnostic Process
Diagnosis often begins when a clinician observes a combination of developmental delays, autistic characteristics, and specific physical traits. Features such as intellectual disability and particularly the early eruption of baby teeth can lead a doctor to suspect ADNP syndrome, prompting further investigation.
A definitive diagnosis is made through molecular genetic testing, which analyzes a person’s DNA for a pathogenic variant in the ADNP gene. The most common methods are whole exome sequencing or whole genome sequencing, which examine the protein-coding regions of all genes or the entire genetic code, respectively. A multigene panel that targets genes known to be associated with neurodevelopmental disorders may also be used. Identifying the specific mutation confirms the diagnosis and can help rule out other conditions with similar features.
Symptom Management and Therapeutic Support
There is currently no cure for ADNP syndrome, so interventions focus on managing symptoms and supporting the individual’s development. This requires a coordinated, multidisciplinary team of specialists and therapists to address the wide array of challenges. The approach is tailored to the specific needs of each person.
Early and intensive therapy is a primary part of management. Physical therapy helps with gross motor skills and mobility, while occupational therapy focuses on fine motor skills and daily living activities. Speech therapy is important to address the significant language delays, and specialized methods may be used for children with apraxia of speech.
Behavioral interventions, such as Applied Behavior Analysis (ABA), can be beneficial for managing behaviors associated with autism. In a school setting, an Individualized Education Program (IEP) is established to provide tailored educational support and accommodations.
Medical management involves regular monitoring by specialists to address associated health issues. This can include visits with cardiologists for heart anomalies, gastroenterologists for digestive problems, and ophthalmologists for vision issues, ensuring that any complications are treated promptly.