Helsmoortel-Van Der Aa syndrome (HVDAS)
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The ADNP (activity-dependent neuroprotective protein) gene is a crucial brain gene that is highly expressed. It affects brain formation, connectivity and development, as well as brain function and acts as protein-protecting nerve cells against electrical blockade (i.e. protection against inability of nerve cells to communicate electrically). Studies have identified ADNP as a regulator of axonal transport, dendritic spine plasticity and autophagy. The ADNP gene also affects many other organs and functions of the body.
The ADNP gene when mutated, causing ADNP Syndrome, which is estimated to be one of the top single gene causes of Autism per the NIH National Library of Medicine Genetics Home Reference, and it is also the only protein significantly decreasing in the serum of Alzheimer's disease (AD)
ADNP SYNDROME SUMMARY
ADNP syndrome, also known as Helsmoortel-VanDerAa syndrome (HVDAS) is a complex neuro-developmental genetic disorder caused by a change (mutation or partial deletion) in the ADNP gene.
ADNP syndrome can affect the neurological, cardiovascular, endocrine, immune, musculoskeletal and gastrointestinal systems, as well as muscle tone (hypotonia), vision, hearing, growth, feeding and sleep. Developmentally, it can cause delays in intelligence, delayed development of speech, speech apraxia or absent speech and global motor planning delays, (including gross motor, fine motor and oral motor). It causes development disorders such as Autism Spectrum Disorder (ASD) in a substantial proportion of cases. In fact, it is estimated: ADNP to be mutated in at least .17% of genetic autism cases, making it one of the most frequent ASD-associated genes known to date.
SIGNS AND SYMPTOMS
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ADNP syndrome is not fully understood. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below.
Many infants present with hypotonia / low or weak muscle tone (78%). Infants may also present with feeding difficulties. Oral motor dysfunction such as poor sucking and chewing and hypotonia are often seen together in children with ADNP syndrome. This contributes to causing the majority of infants to experience feeding difficulties (83%). Swallowing problems may also be seen and there can be a risk of aspiration. Many children who experienced oral motor dysfunction early on develop apraxia of speech and or dyspraxia.
The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), complex motor planning delays (96%), delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%).
Developmental and motor delays are usually seen early on. Missed milestones such as delays in sitting, holding up one’s head, crawling and walking are seen in infancy and children are usually diagnosed with mild to severe global developmental and global motor planning delays. Walking independently is often delayed until a few years later in childhood and children may have an abnormal gait.
Children with ADNP syndrome in their younger years tend to be easily amused with frequent smiling and laughing and have a very happy demeanor similar to Angelman syndrome. This often delays diagnosis for behavior disorders such as autism even when the child displays many autistic features early in life.
Sleep disorders can also develop, including sleep apnea, frequent waking throughout the night as well as early waking. Many children have tonsils and adenoids removed to attempt to remedy some of the sleep issues.
As children age they may exhibit mild to severe intellectual disability. There are often delays in developing speech. Some children with ADNP syndrome may not be able to speak while others speak a few words or in short sentences. Apraxia and other oral motor disorders specifically affecting the motor planning of the tongue appear to cause the most difficulty in the majority of the non-verbal children.
The majority of affected children may meet the criteria for autism spectrum disorder and may exhibit poor social interaction and mild to severe repetitive (stereotypic) behaviors such as repetitive speech, rocking back and forth, hand flapping, hand clapping, rubbing fingers or snapping fingers (93%). They often have an obsession for music and water play. Children with ADNP syndrome often seek direct “adult” interaction but limited to no direct interest in interacting with other children. Specifically, at a very young age they appear to enjoy direct social interactions with adults, and often smile, laugh and make eye contact. This is atypical for autism but it is very typical for ADNP syndrome. This often delays the autism diagnosis even when the child displays many autistic features at a young age.
Sensory processing disorder (both seeking and avoiding) is often seen (67%), with oral sensory seeking being the most prevalent. Because of this, children tend to lick their hands or other objects often, chew on non-edible items, gag, and put objects in their mouth. They also tend to place tablets and other lit objects or devices directly in front of their eyes or ears for stimulation.
In addition to autism and sensory processing disorder, children may have a variety of behavioral issues including attention deficit hyperactivity disorder, obsessive compulsive disorder, temper tantrums and aggression, mood disorders, and anxiety.
Cerebral imaging shows structural brain abnormalities in slightly over half of the patient population (56%). Other neurological problems may exist. Individuals with ADNP syndrome may develop seizures (16%). Many parents report absent like seizures as infants along with breath holding episodes. Reported brain abnormalities include wide ventricles (29%), cerebral atrophy (18%), delayed myelination (9%) and white matter lesions (8%). Approximately 50% of children with ADNP syndrome have had one or more episodes of developmental regression of speech.
Children with ADNP syndrome often have a high pain threshold (64%). Many parents report that their child does not seem to feel pain, some reporting fractures with no sign of uncomfortableness or distress. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain or an injury.
Gastrointestinal symptoms are common. Affected individuals can develop backflow of stomach acids into the esophagus (gastroesophageal reflux). This has been reported as mild to severe. Some children require the placement of a feeding tube due to severe feeding problems. Episodes of chronic constipation and diarrhea are seen in almost all children with ADNP syndrome. Other symptoms include cyclic vomiting, delayed digestion, and irritable or inflammatory bowel conditions.
Some children as they grow past the toddler years have an abnormal increased appetite and have difficulties feeling full (hyperphagia), similar to Prader Willi syndrome. This can lead to excessive weight gain. Some children also develop an abnormally increased desire to drink water.
Some affected individuals may have congenital heart defects (38%). Ventricle or atrial septal defect is a common heart defect in ADNP syndrome. Additional congenital heart defects have been reported in ADNP syndrome.
Affected individuals have distinctive facial features prominent forehead, high hairline, droopy eyelids (ptosis), thin upper lip, broad nasal bridge, malformed ears, eyes that are farther apart than normal (hypertelorism), and crossed eyes (strabismus). Affected individuals may see objects that are farther away clearer than they see objects that are close up (farsightedness or hypermetropia). Cortical Vision Impairment has also been seen in multiple reported cases.
Some infants experience early eruption of their baby (deciduous or primary) teeth, showing a full set of baby teeth by their first birthday, including molars. This is not seen in any other known syndrome making it unique to ADNP syndrome. The teeth may be abnormally small, jagged, and discolored. Because of early tooth eruption, some children develop tooth decay as toddlers due to the decrease in enamel.
Some affected individuals have abnormally small pinkies that are fixed or ‘locked’ in a bent position (clinodactyly). Certain joints of fingers may be abnormally prominent.
Children with ADNP syndrome are prone to immune system dysfunction, including recurring infections, especially upper respiratory, ear and urinary tract. Recurring skin infections with delayed healing have also been reported. These recurrent infections may indicate an underlying problem with the immune system. Repeated upper respiratory tract infections may be related to low muscle tone and subsequent problems with aspiration. Thermoregulatory problems have been reported by parents. Those include report that some children spike fevers extremely fast and have difficulty regulating their body temperature in hot and cold environments. Many children have cold hands and feet.
Some areas of the endocrine system can be affected in ADNP syndrome. There are reports that some children exhibit growth delays and will be shorter than expected for their age and gender (short stature). Hypothyroidism has been reported as well as abnormal cholesterol and iron in numerous cases. Early puberty has also been seen.
Some children have tended to develop truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs. Some have abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity) and abnormal sideways curvature of the spine (scoliosis).
Males and females are both likely to be affected by this neuro-genetic disorder. (59% boys / 41% girls) The exact number of people who have this disorder is unknown. According to one estimate, about 1 in 27,000 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 believed to account for about .17% of individuals with autism, making it one of the most common, single-gene causes of an autism spectrum disorder. Approximately 205 affected children have been identified worldwide in the medical literature and as reported by the ADNP non-profit research organization as of Jan 2019.
ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP) gene. These mutations occur spontaneously in the majority (97%) of reported cases meaning there has been no family history of the disorder (de novo mutations).
ADNP syndrome occurs most frequently as a new (sporadic or de novo) mutation in the activity dependent neuroprotective protein (ADNP) gene. These mutations occur spontaneously in the majority (97%) of reported cases meaning there has been no family history of the disorder (de novo mutations). The disorder is usually not inherited from or “carried” by a healthy parent, however, several (5) hereditary cases have been reported.
Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.
Fragile X syndrome
A diagnosis of ADNP syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. Premature tooth eruption and abnormal tooth development when occurring along with developmental delays or autism symptoms can lead to a suspicion of ADNP syndrome.
CLINICAL TESTING AND EVALUATIONS
Molecular genetic testing can detect mutations in the ADNP gene known to cause ADNP syndrome, but is available only as a diagnostic service at specialized laboratories.
Neurological examinations should be conducted to evaluate areas such as hypotonia, motor milestones, gross motor skills and gait, fine motor coordination, nerves, reflexes and seizure history. Imaging techniques such as magnetic resonance imaging (MRI) or electroencephalography (EEG) may be used to aid in a diagnosis.
A cardiac evaluation should be conducted. An echo-cardiogram may be performed. An echo-cardiogram 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 should conduct a thorough, extensive eye examination to look for eye abnormalities or vision impairments that may be associated with the disorder. Pediatric audiology should also be consulted and hearing assessed.
All patients with ADNP syndrome should be referred to centers with expertise in developmental disorders for comprehensive cognitive, behavior and ASD evaluations. A-typical features should be considered as well as integrating careful clinical evaluation, caregiver reports, and structured direct observation. A diagnosis of ASD may aid in designing individualized educational and related service treatments plans and in justifying services through the board of education and insurance providers.
Referrals for speech and language therapy, physical therapy, and occupational therapy evaluations should also be made. Because of significant learning and attention deficits, increased frequency of treatment may be favorable. Careful assessment of gait is important, as is appropriate referrals for pediatric physiatrist, physical therapy and orthopedics to explore various interventions.
Given the broad array of motor deficits, low muscle tone and related feeding problems, physical, occupational, and feeding therapy should be initiated as early as possible.
Endocrine abnormalities should be considered and assessed when clinically indicated.
In summary, comprehensive assessment and regular monitoring of patients with ADNP syndrome across developmental and organ systems are necessary to clarify the extent and severity of how ADNP develops over time.
The greatest goal of the ADNP Kids Research Foundation (ADNP-KRF) is to increase awareness and scientific understanding and to support research for the discovery of effective clinical therapeutic treatments, drug development and eventually, a cure.
Establishing the natural history of ADNP syndrome is one of the top goals of the ADNP-KRF. It is an important step toward designing effective clinical trials and may support the advancement of multiple therapeutic possibilities in the future.
In 2017 the ADNP-KRF launched a research partnership with the Seaver Center for Autism at Mount Sinai for Research and Treatment. This innovative ADNP Syndrome study works at developing precision approaches to the treatment of individuals of ADNP Syndrome.
Following the launch of the Seaver Center study, the ADNP-KRF announced the advancement toward the clinical trial of CP201/NAP for ADNP Syndrome, partnering with Coronis Neurosciences to support the 1st possible drug treatment for ADNP Syndrome.
In early 2018 the FDA gave Orphan Drug Designation to CP201/NAP.
In fall of 2018 the ADNP-KRF attended the FDA Pre-IND meeting for CP201/NAP and witnessed it’s successful approval to move forward.
The ADNP-KRF also supports the investigation of genetic exome research at the University of Washington (TIGER) and ongoing studies through the University of Tel Aviv, University of Antwerp and Cognitive Genetics Belgium.
ADNP ASSOCIATED RESOURCES
https://ADNPkids.com (informational website with patient stories)
https://www.facebook.com/groups/ADNPkids/ (International parent support group - private)
AUTHOR TO SITE: Sandra Bedrosian-Sermone / ADNP Kids Research Foundation
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