ADNP Syndrome

Disease Overview

Summary

ADNP syndrome, also called Helsmoortel-Van Der Aa syndrome, is a genetic disorder that affects brain development and can lead to a wide range of challenges.

The symptoms can vary greatly from one child to another, but almost all affected children have developmental and intellectual delays, difficulties with motor function, delayed or absent speech and features of autism.

The disorder can potentially affect multiple systems of the body including the brain, heart, immune system, gastrointestinal system, endocrine system and musculoskeletal system.

Feeding and gastrointestinal issues are common, and many infants have low muscle tone (hypotonia) that can make them appear floppy. These children might also have sensory processing disorders, sleep problems and a high tolerance for pain, making it hard for parents to know when they are hurt.

Most of the affected children have distinctive facial features, and many develop early primary tooth eruption and often have a happy disposition and unprovoked episodes of laughter and smiling.

About half of the children develop breathing irregularities (breath holding episodes) and episodes of developmental regression of speech that are usually regained over time with intensive therapy.

ADNP syndrome is caused by changes (variants) in the ADNP gene, which typically happen spontaneously, meaning they are not inherited from parents. This syndrome is one of the more common single-gene causes of autism.

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Synonyms

• ADNP-related intellectual disability, autism-related spectrum disorder
• Helsmoortel-Van Der Aa syndrome (HVDAS)

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Signs & Symptoms

ADNP syndrome is complex and not fully understood, even though certain key symptoms are commonly associated with it.

The disorder is rare, with a small number of diagnosed cases, making it difficult to fully grasp all symptoms and the progression of the condition. The most common characteristics found in those with ADNP syndrome are developmental delays (in all patients), intellectual delays (in all patients), motor planning delays (96%) of varying degrees, delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%).

Each child’s experience with ADNP syndrome can vary, and not all children will have every symptom described below. Signs and symptoms may include:

Neurological and developmental symptoms:

• • Low muscle tone (hypotonia): Seen in 78% of infants, making them appear “floppy”
  • Brain abnormalities: Present in 56% of children, including wide ventricles (29%), cerebral atrophy (18%), delayed myelination (9%) and white matter lesions (8%)
  • Seizures: About 16% may develop seizures, with some infants showing absent-like seizures and breath-holding episodes.
  • Developmental regression: Approximately 50% of children may experience temporary loss of skills, particularly in speech.
  • Missed milestones: Delays in sitting, holding up the head and walking are common.
  • Motor planning delays: Most children have mild to severe difficulties in coordinating movements.
  • Speech delays: Children may have trouble speaking; some may remain non-verbal due to oral motor disorders affecting the tongue.

Behavioral and psychological symptoms:

• Happy disposition: Children often appear happy and easily amused, having unprovoked episodes of laughter and smiling which can delay the diagnosis of behavioral disorders like autism.
• Autism spectrum traits: Many children show poor social interaction and repetitive behaviors, meeting criteria for autism spectrum disorder.
• Unusual social interactions: Unlike typical autism, children with ADNP syndrome may seek out and enjoy interactions with adults.
• Sensory sensitivities: About 67% of children have strong preferences or aversions to sensory experiences.
• Oral sensory seeking: Common behaviors include licking, chewing non-food items and putting objects in their mouth.
• Other behavioral issues: Other behavioral problems include attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), temper tantrums, aggression, mood disorders and anxiety.

Feeding and gastrointestinal symptoms:

• Oral motor issues: 83% of infants may have difficulties with sucking, chewing, and swallowing.
• Risk of aspiration: Food or liquids may enter the lungs, increasing the risk of complications.
• Nutritional support: Some children may need thickened liquids or a feeding tube.
• Digestive problems: Many children experience acid reflux, constipation, diarrhea, cyclic vomiting, delayed digestion and irritable bowel conditions.
• Feeding tubes: Severe feeding difficulties may necessitate the use of a feeding tube.
• Hyperphagia: Some children, as they grow, develop an increased appetite and may struggle with feeling full, leading to excessive weight gain.

Heart problems:

• Congenital heart defects: Present in 38% of children, including ventricle or atrial septal defects, right aortic arch, tachycardia, mitral valve prolapse, patent ductus arteriosus, pulmonary artery stenosis and tetralogy of Fallot

Facial, vision and dental features:

• Distinctive facial features: These include a prominent forehead, high hairline, droopy eyelids (ptosis), a thin upper lip, a broad nasal bridge, malformed ears, widely spaced eyes (hypertelorism) and crossed eyes (strabismus).
• Vision problems: Farsightedness (hypermetropia), crossed eyes (strabismus), nearsightedness (myopia), abnormal eye movements (nystagmus), dropped eyelid (ptosis) and cortical vision impairment have been reported.
• Early tooth eruption: Some children have a full set of baby teeth by their first birthday, which may be small, jagged and discolored, potentially leading to early tooth decay.

Musculoskeletal symptoms:

• Joint and bone abnormalities: These may include underdeveloped fingernails and toenails, extra fingers or toes (polydactyly), small pinkies fixed in a bent position (clinodactyly), hip problems, chest deformities, skull deformities and prominent finger joints.
• Hand and feet anomalies: Finger abnormalities, single palmar crease, nail anomalies and a wide space between the first toe and second toe (sandal gap)

High pain threshold:

• About 64% of children may not show signs of pain, even with injuries like fractures, making it difficult to detect pain or discomfort.

Hearing loss that may be due to:

• Narrow auditory canal, frequent ear infections (otitis media)

Additional symptoms may include:

• Abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity)
• Abnormal sideways curvature of the spine (scoliosis)
• Recurrent infections, especially upper respiratory and urinary tract that may indicate an underlying problem with the immune system
• Growth delays that may result in children who are shorter than expected for their age and gender (short stature)
• Truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs
• Difficulty regulating body temperature, and many have cold feet and hands, and some parents report that children spike fevers extremely fast
• Early puberty, thyroid hormone problems, growth hormone deficiency
• Urinary tract anomalies such as narrow ureters (tubes that connect the kidney with the bladder) and bilateral vesicoureteral reflux (urine flows backward from the bladder to one or both ureters and sometimes to the kidneys)

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Causes

ADNP syndrome is caused by a change (variant) in the activity-dependent neuroprotective protein (ADNP) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.

The ADNP gene is responsible for producing a protein that plays a crucial role in controlling how other genes function. It does this through a process called chromatin remodeling. Chromatin is a complex of DNA and proteins that help organize DNA into chromosomes. By altering the structure of chromatin, the ADNP protein can change how tightly the DNA is packed. When DNA is tightly packed, the activity of certain genes is reduced and when it is loosely packed, gene activity increases. This process is essential for regulating gene activity during development.

The ADNP protein is particularly important for normal brain development, but it also influences genes that control the development and function of other body systems. Although researchers are still trying to understand exactly how variants in the ADNP gene affect the function of the ADNP protein, it is thought that these variants cause abnormal chromatin remodeling. This disruption in the process can alter the activity of many genes, leading to problems in the development and function of various tissues and organs, including the brain. These changes are likely responsible for intellectual disability, autism spectrum disorder and other symptoms associated with ADNP syndrome.

ADNP syndrome occurs most frequently because of a new (sporadic or de novo) variant which means that in most reported patients, the gene variant has occurred at the time of the formation of the egg or sperm during embryonic development for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent; however, several hereditary cases have been reported.

If a person with ADNP syndrome were to have a child, they could pass the ADNP gene variant on to their children through autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

ADNP syndrome affects females and males in equal numbers. The exact number of people who have this disorder is unknown. According to one estimate, about 1 in 20,000 people in the general population in the United States and Europe have the disorder. Rare disorders like ADNP syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. ADNP syndrome is thought to account for about 0.17% of individuals with autism, making it one of the most common, single-gene causes of an autism spectrum disorder.

As of January 2022, over 400 affected children have been identified worldwide in the medical literature.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.

Phelan-McDermid Syndrome (PMS) is a rare genetic condition often characterized by low muscle tone at birth, normal growth, severely delayed or absent speech, moderate to profound developmental delays and minor differences in facial features. Heart defects and behaviors associated with autism are also common. PMS is caused by a deletion or structural change in chromosome 22 or a variant in the SHANK3 gene.

Angelman Syndrome is a rare genetic and neurological disorder marked by severe developmental delays, significant learning disabilities and little to no speech. People with Angelman syndrome often have trouble coordinating voluntary movements (ataxia), experience tremors and have a distinctive behavior characterized by a happy demeanor with frequent laughing and smiling. They may also have seizures, sleep disorders and feeding challenges. This syndrome is caused by a deletion or abnormal expression of the UBE3A gene.

Smith-Magenis Syndrome (SMS) is a complex developmental disorder that affects multiple organ systems. It is typically identified by distinctive facial features, skeletal malformations, intellectual disability, speech and motor delays, sleep disturbances and self-injurious behaviors. About 90% of patients have a deletion of a portion of chromosome 17, including the RAI1 gene. In other patients, variants in the RAI1 gene are the cause. The symptoms of SMS can vary greatly among individuals.

Coffin-Siris Syndrome (CSS) is a rare genetic disorder noticeable at birth, often characterized by distinctive facial features, such as a small head, wide nose, thick lips and sparse scalp hair. Affected individuals may also have short fifth fingers and toes with underdeveloped or absent nails, feeding difficulties, frequent respiratory infections and developmental delays. CSS is caused by variants in several genes, including ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. The disorder can vary in severity among those affected.

Other disorders that share symptoms with ADNP syndrome, such as developmental delays, intellectual disability and seizures include Rett syndrome, FOXG1 syndrome, FOXP1 syndrome, Fragile X syndrome, Prader-Willi syndrome, Pitt-Hopkins syndrome, Kleefstra syndrome, MECP2 duplication syndrome, CH2D-related neurodevelopmental disorders and 15q duplication syndrome.

For more detailed information on each of these disorders, you can search for them individually in the Rare Disease Database.

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Diagnosis

The syndrome is diagnosed through genetic testing that looks for variants in the ADNP gene.

Imaging techniques like MRI may be used to identify brain abnormalities and other specialized tests may be done to check for heart defects or eye problems.

An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with the disorder.

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Standard Therapies

Treatment

There is no cure for ADNP syndrome and treatment focuses on managing the specific symptoms each child has. A team of specialists, including pediatricians, neurologists, cardiologists and therapists is often needed to provide comprehensive care. Treatments may include:

• Occupational, physical and speech therapy can help with developmental delays and motor difficulties. Some children may benefit from water or music therapy.
• Medication, including anti-seizure medication and medication for sleep problems or behavioral issues
• Surgery when needed for heart defects or other complications
• Assistive devices such as communication devices for children with speech delays

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Ongoing research is being conducted to better understand ADNP syndrome and develop more effective treatments. The ADNP Kids Research Foundation is actively involved in supporting research and clinical trials, including studies on new medications that could help manage symptoms.

The drug NAP, also known as davunetide, has shown promise in improving some of the cognitive issues seen in a specific mouse model where the ADNP gene is partially disabled. In studies, it has been found to help with learning and memory and to reduce brain cell damage in these mice. Davunetide has been explored as a possible treatment for several neurological conditions. It can be delivered through the nose (intranasally) or by injection into a vein (intravenously) and it has been shown to reach the brain effectively. Clinical trials have shown that davunetide is well-tolerated in humans with no major side effects reported.

Although researchers are not yet certain whether ADNP syndrome is caused by a complete or partial loss of ADNP function, and while the mouse model used in the studies has not been evaluated for autism-like behaviors, the results from these studies provide hope that davunetide could be a potential treatment.

The drug ketamine is also being studied as a possible treatment for children with ADNP syndrome.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Sragovich S, Malishkevich A, Piontkewitz Y, et al. The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse. Transl Psychiatry 2019 Jan 15;9(1):2. https://www.nature.com/articles/s41398-018-0357-6

Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, et al. Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP. Biological Psychiatry 2019; Feb. 85:287–297. https://www.ncbi.nlm.nih.gov/pubmed/29724491

Arnett AB, Rhoads CL, Hoekzema K, Bedrosian-Sermone S, et al. The autism spectrum phenotype in ADNP syndrome. Autism Research. 2018; 11, 1300–1310. https://www.ncbi.nlm.nih.gov/pubmed/30107084

Hacohen-Kleiman G, Sragovich S, Karmon G, et al. Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. J Clin Invest. 2018 Nov 1;128(11):4956-4969. https://www.ncbi.nlm.nih.gov/pubmed/30106381

Pascolini G, Agolini E, Majore S, et al. Helsmoortel-Van der Aa syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement. Eur J Paediatr Neurol. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29475819

Gozes I, Van Dijck A, Hacohen-Kleiman G, Bedrosian-Sermone S, et al. Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children. Transl Psychiatry. 2017;7:e1166. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538113/

Gozes I, Patterson MC, Van Dijck A, Downing A, Bedrosian-Sermone S, et al. The eight and a half year journey of undiagnosed AD: gene sequencing and funding of advanced genetic testing has led to hope and new beginnings. Front Endocrinol (Lausanne). 2017;8:107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437153/

Helsmoortel C, Vulto-van Silfhout AT, Coe BP, et al. A SWI/SNF related autism syndrome caused by de novo mutations in ADNP. Nat Genet. 2014;46:380-384. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990853/

Vandeweyer G, Helsmoortel C, Van Dijck A, et al. The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism. Am J Med Genet C Semin Med Genet. 2014;166C:315-326. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195434/

De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional, and chromatin genes disrupted in autism. Nature. 2014;515:209–215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723/

Gozes I, Helsmoortel C, Vanderweyer G, Van der Aa N, Kooy F, Bedrosian-Sermone S. The compassionate side of neuroscience: Tony Sermone’s undiagnosed genetic journey – ADNP mutation. https://www.ncbi.nlm.nih.gov/pubmed/26168855

INTERNET
Van Dijck A, Vandeweyer G, Kooy F. ADNP-Related Disorder. 2016 Apr 7 [Updated 2022 Oct 6]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355518/ Accessed Aug 19, 2024.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:615873; Last Update: 09/17/2021. Available at: https://www.omim.org/entry/615873 Accessed Aug 19, 2024.

ADNP-related syndrome. Unique. 2022. Available at: ADNP syndrome FTNW.pdf (rarechromo.org) Accessed Aug 19, 2024.

ADNP Syndrome. MedlinePlus. March 2017. Available at: https://ghr.nlm.nih.gov/condition/adnp-syndrome Accessed Aug 19, 2024.

ADNP syndrome. Orphanet. Last update: January 2019. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=404448. Accessed Aug 19, 2024.

ADNP syndrome. Genetic and Rare Diseases Information Center. Last updated: 2/18/2016. https://rarediseases.info.nih.gov/diseases/12931/adnp-syndrome Accessed Aug 19, 2024.

Human Disease Genes. ADNP https://humandiseasegenes.nl/adnp/ Accessed Aug 19, 2024.

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