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Angelman Syndrome

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Description: Angelman syndrome is a rare genetic disorder characterized by intellectual disability, severe speech impairment, balance issues, and a happy, excitable demeanor.
Type: Angelman syndrome is a genetic disorder. The type of genetic transmission is typically a deletion or mutation of the maternal copy of the UBE3A gene on chromosome 15, or, less commonly, paternal uniparental disomy (UPD) which means both copies of chromosome 15 are inherited from the father.
Signs And Symptoms: Signs and symptoms of Angelman syndrome and their relative frequency in affected individuals are:
Prognosis: The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. Some speech and a greater degree of self-care are possible among the least profoundly affected. Walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to significantly improve the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent Angelman syndrome girls, but do not seem to affect long-term health.The facial features remain recognizable with age, but many adults with AS look remarkably youthful for their age.Puberty and menstruation begin at around the average age. Sexual development is thought to be unaffected, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.The majority of those with AS achieve continence by day and some by night. Angelman syndrome is not a degenerative syndrome, and thus people with AS may improve their living skills with support.Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults can eat with a knife or spoon and fork, and can learn to perform simple household tasks. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis if it is present. The affectionate nature may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable. People with Angelman syndrome appear to have a reduced but near-normal life expectancy, dying on average 10 to 15 years earlier than the general population.
Onset: Angelman syndrome typically presents its symptoms within the first year of life, usually noticeable between 6 to 12 months of age. However, clear diagnostic features often become more apparent by the time the child is 2 to 3 years old.
Prevalence: Angelman syndrome is a rare genetic disorder, with an estimated prevalence of approximately 1 in 12,000 to 20,000 individuals.
Epidemiology: Though the prevalence of Angelman syndrome is not precisely known, there are some estimates. The best data available are from studies of school age children, ages 6–13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8-year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/20,000 and the Danish study showed a minimum AS prevalence of about 1/10,000.
Intractability: Angelman syndrome is a genetic disorder, and while it is not "curable," it can be managed with supportive care to improve quality of life. Treatment focuses on managing symptoms through therapies such as physical therapy, occupational therapy, communication therapy, and medications for related issues like seizures. Nonetheless, due to its genetic basis, the syndrome itself remains intractable.
Disease Severity: Angelman syndrome is a complex genetic disorder that affects the nervous system. The severity of the disease can vary, but it typically includes severe developmental delays, speech impairments, movement and balance problems, and distinct behavioral traits such as frequent laughter and a happy demeanor. Individuals often require lifelong care and support. The condition does not directly affect life expectancy, but associated complications can impact overall health.
Healthcare Professionals: Disease Ontology ID - DOID:1932
Pathophysiology: Angelman syndrome is a genetic disorder primarily affecting the nervous system. It is caused by a loss of function in the UBE3A gene located on chromosome 15. In most cases, this is due to a deletion of a segment of the maternal chromosome 15, paternal uniparental disomy (both copies of chromosome 15 are inherited from the father), or mutations in the UBE3A gene itself. The UBE3A gene is critical for normal neurological development, and its loss leads to symptoms such as severe developmental delays, lack of speech, seizures, and distinctive behaviors like frequent laughter and happy demeanor. The UBE3A gene is normally expressed from the maternal allele in neurons, and its absence disrupts normal brain function, leading to the characteristic features of Angelman syndrome.
Carrier Status: Angelman syndrome is typically not inherited in a traditional manner and does not have a "carrier status" like some other genetic disorders. Instead, it is primarily caused by an issue on chromosome 15, such as a deletion of a segment of the maternal chromosome, mutations in the UBE3A gene, paternal uniparental disomy, or imprinting defects. These genetic alterations usually occur sporadically, meaning they are random events rather than inherited from a parent's carrier status.
Mechanism: Angelman syndrome is a genetic disorder primarily characterized by severe developmental delays, intellectual disability, speech impairment, and problems with movement and balance.

### Mechanism:
Angelman syndrome results from the loss of function of the UBE3A gene on chromosome 15. Normally, the UBE3A gene is active on the maternal chromosome and silent on the paternal one in certain areas of the brain. The disorder occurs when the maternal copy of the gene is deleted, mutated, or otherwise inactivated.

### Molecular Mechanisms:
The UBE3A gene encodes an enzyme called ubiquitin-protein ligase E3A, which plays a role in targeting proteins for degradation within cells. The lack of functional UBE3A enzyme disrupts normal protein degradation, leading to an accumulation of certain proteins that can interfere with neuronal function. This molecular defect specifically affects brain regions involved in cognition, motor function, and behavior, leading to the characteristic symptoms of Angelman syndrome.
Treatment: There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because people with AS often have multiple types of seizures. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Mild laxatives are also used frequently to encourage regular bowel movements. Additionally, among a cohort of 163 individuals with AS, ranitidine was shown to be the most frequently prescribed medication for treating gastroesophageal reflux disease (GERD). Early intervention with physiotherapy is sometimes used to encourage joint mobility and prevent stiffening of the joints.Occupational therapists can contribute to the development and augmentation of non-verbal communication skills by addressing the foundational skills such as finger isolation, motor planning, hand-eye coordination, spatial awareness, and refining gestures. This is important because individuals with Angelman Syndrome who already possess some form of non-verbal communication have a much harder time adapting to changes in a new or existing AAC device because they can communicate their needs much faster nonverbally.Occupational therapists can assist individuals with Angelman syndrome with many other skills as well. Many individuals with Angelman syndrome also have difficulty processing sensory information and responding appropriately to sensory stimuli. Occupational therapists can work together with these individuals to improve their visual perceptual skills and increase their sensory awareness.Expressive verbal communication is limited by AS, but many people with the disorder are able to learn non-verbal communication skills to express their needs. Deictic gesturing (i.e, pointing to an object) is the most commonly used form of non-symbolic communication in AS, followed by physically manipulating others (such as moving a caregiver's hand to a specific object or guiding a person to a new location) and non-speech vocalizations. Some are able to use symbolic communication such as signing, though the prevalence of this ability is related to both genetic etiology and epilepsy status, with non-deletion etiologies without epilepsy showing the highest prevalence of symbolic communication skills. People with AS tend to have much higher receptive language abilities than expressive; recent studies have shown that patients with AS have typical auditory brain region responses to speech but atypical memory responses, suggesting that word meaning recall is delayed or processed differently in AS. This may be caused by the altered cortical morphology seen in AS in the precuneus, a region of the brain involved in self-reflection and memory. Similarly, both adults and children with AS show a delay in processing speed in speech processing, and this should be accounted for during communication.
Compassionate Use Treatment: Angelman syndrome currently lacks a cure, but several compassionate use, off-label, and experimental treatments are being explored:

1. **Compassionate Use Treatments**:
- These treatments are accessed when standard treatments are not effective or available. They are typically provided under regulatory frameworks that allow patients to access investigational drugs. Specific examples include investigational therapies still in clinical trial phases.

2. **Off-Label Treatments**:
- **Antiepileptic Drugs**: Used to manage seizures, which are common in Angelman syndrome. Medications such as valproic acid or clonazepam might be prescribed off-label.
- **Melatonin**: Often used off-label to treat sleep disturbances, which are frequent in individuals with Angelman syndrome.

3. **Experimental Treatments**:
- **Gene Therapy**: Research is ongoing to explore gene therapy approaches that could potentially correct the underlying genetic defect.
- **UBE3A Reactivation**: Scientists are investigating methods to activate the paternal copy of the UBE3A gene, which is typically silenced in individuals with Angelman syndrome.
- **Gaboxadol (OV101)**: A drug initially developed for sleep disorders is being studied for its potential benefits in improving symptoms of Angelman syndrome.
- **Levodopa**: Being evaluated in clinical studies to address motor function deficits.

These treatments are still under investigation and may not be widely available. It's essential for patients to consult healthcare professionals for the most appropriate and up-to-date advice.
Lifestyle Recommendations: Lifestyle recommendations for individuals with Angelman syndrome focus on improving quality of life and managing symptoms. They generally include:

1. **Physical Therapy**: To improve motor skills and coordination.
2. **Speech Therapy**: Since communication can be challenging, alternative methods like sign language or communication devices may be beneficial.
3. **Behavioral Therapy**: To address hyperactivity and other behavioral issues.
4. **Educational Support**: Tailored education plans to meet individual learning needs.
5. **Regular Medical Follow-ups**: To monitor and manage associated health issues such as seizures.
6. **Balanced Diet and Regular Exercise**: To maintain overall health.
7. **Sleep Management**: Strategies to improve sleep patterns, which are often disrupted in individuals with Angelman syndrome.
8. **Social and Recreational Activities**: To promote social skills and engagement.

Close collaboration with healthcare providers is essential to develop a comprehensive care plan tailored to the individual's needs.
Medication: There is no cure for Angelman syndrome, so treatment focuses on managing symptoms and improving quality of life. Medications may be prescribed to address specific issues such as seizures, sleep disorders, or hyperactivity, but no specific medications target the syndrome itself.
Repurposable Drugs: Research into repurposable drugs for Angelman syndrome is ongoing. Several drugs have shown potential in preclinical studies, including:

1. **Gaboxadol (OV101)**: A tonic GABAA receptor agonist being investigated for its ability to modulate GABAergic signaling.
2. **Levodopa**: Typically used in Parkinson's disease, it's being explored for its effects on motor and cognitive symptoms.
3. **Minocycline**: An antibiotic with neuroprotective properties that may improve neuronal function.
4. **Ketogenic diet**: Not a drug, but shows potential in reducing seizure frequency and improving neurodevelopmental outcomes.

These and other potential treatments are in various stages of study. Clinical trials are essential to establish their efficacy and safety.
Metabolites: Angelman syndrome is primarily linked to genetic mutations rather than specific abnormalities in metabolites. It is caused by a loss of function of the UBE3A gene on chromosome 15. However, the condition is not typically associated with a distinct metabolic profile or specific metabolite abnormalities. Metabolite levels in individuals with Angelman syndrome generally do not show unique patterns that are used for diagnosis or treatment. The focus in managing Angelman syndrome is usually on addressing neurological and developmental symptoms.
Nutraceuticals: Nutraceuticals are food-derived products that offer health benefits, including the prevention and treatment of diseases. In the context of Angelman syndrome, there is limited research specifically addressing the efficacy of nutraceuticals. It is essential to consult with healthcare providers for personalized guidance on diet and supplementation.

Regarding nanotechnology (abbreviated as "nan."), there is emerging interest in using nanotechnology for drug delivery and treatment of genetic disorders, including Angelman syndrome. However, this is still largely in the experimental stages and not yet widely available as a treatment option. Further research and clinical trials are necessary to establish its safety and effectiveness.
Peptides: Angelman syndrome is a genetic disorder that primarily affects the nervous system. Currently, there are no specific peptide treatments for Angelman syndrome. Research is ongoing to explore various therapeutic approaches, including gene therapy, to address the underlying genetic cause. For now, management of the condition focuses on alleviating symptoms and improving quality of life through physical therapy, communication therapy, and other supportive measures.