Pseudo-Angelman Syndrome

This is article no. 2 in a series on Rare Diseases. Next article coming soon. Previous article- Apocrine carcinoma.

An overview

Name of the disease: Pseudo-Angelman Syndrome

Other names the disease is known by:

-        2q23.1 microdeletion syndrome

-        Del(2)(q23.1)

-        monosomy 2q23.1

Prevalence rate in the US: <1000

Average life expectancy: mid-50s – early 70s for severe to moderate intellectual disabilities

Mortality rate: <10% in individuals with severe to moderate intellectual disabilities (this rate is more than double the general population)

Pseudo-Angelman syndrome is a neurological disease, which is classified as Rare since it affects fewer than 1000 people in the US (as reported by the National Institute of Health). However, the information on this disease, like other rare diseases, is incomplete. This article aims to raise awareness of rare neurological diseases such as Pseudo-Angelman syndrome.

Onset of symptoms: the symptoms of the disorder can appear early as a newborn and an infant

Its symptoms include:

-        Seizures

-        Moderate-severe learning difficulties- mental retardation (MR)- and behaviour issues (the roles of the frontal and parietal lobes in the brain are planning and executing actions, as well as proprioception)

-        Speech and developmental delays (one of the functions the temporal lobe in the brain is responsible for is audio processing and speech)

-        Trouble sleeping

-        Repetitive movements of the fingers, wrists, etc. or motor stereotypy

Hypotonia, slow weight gain, and shorter height may also be present in children affected by the disease.

Symptoms help diagnose the diagnosis, but only genetic testing confirms it.

The genetic mechanism of the disease

Genetic cause of the disease: a microdeletion on 2q23.1

A chromosomal deletion occurs when a region of a chromosome is removed, resulting in the loss of genetic material within that specific segment. A microdeletion affects an even smaller part on the chromosome.

Hence, in Pseudo-Angelman syndrome, the 2q23.1 microdeletion involves the loss of a small section of DNA on chromosome no. 2. More specifically, the DNA is lost from position 23.1 on chromosome 2. The exact role of chromosome 2 is not yet known (there is active research in this field), but chromosome 2 likely contains protein-coding genes. The chances are that key proteins that genes in chromosome 2 code for, are not made when there is a 2q23.1 microdeletion i.e. the microdeletion removes these crucial genes, and so cells cannot produce the proteins. Thus, giving rise to Pseudo-Angelman syndrome in the individual.

Indeed, research has shown that usually the MBD5 gene is deleted in patients with the syndrome (in one study, all 15 patients had lost this gene from the removed region). The next prominent gene that is deleted is EPC2, which is a gene that is thought to be involved in causing MR.

Inheritance of the disease: mostly de novo

A study by van Bon et. al (2009) depicted that 10 out of 11 patients were shown to have de novo inheritance of 2q23.1 microdeletion.

Comparison to Angelman syndrome

See Table 1

The syndrome is called Pseudo-Angelman, so where does the Angelman part of the name come from? (The disease is named after Dr. Harry Angelman, who had first described and reported the syndrome in 1965).

Angelman syndrome (AS) is also a rare disease, however, it has a higher prevalence rate than Pseudo-Angelman. One possibility could be in the way these different conditions come about in the first place.

Loss of function (rather than a deletion) of the UBE3A gene in chromosome 15 from the mother, gives rise to AS. It is an example of an imprinting disorder. (Two copies of each chromosome are normally inherited, but in genomic imprinting, only one copy of a particular chromosome is passed on i.e. either the copy from the mother is inherited, or from the father- not both. Deletion, loss of function etc. may cause the other copy to not be inherited. Imprinting disorders lead to developmental and growth problems in the affected individual).

In contrast, Pseudo-Angelman syndrome is often de novo, and not inherited. It is not an imprinting disorder like Angelman’s, because Pseudo-Angelman is caused by a microdeletion in 2q23.1.

However, AS presents severe physical, learning, and intellectual problems. The syndrome causes seizures and developmental delays. The similarity in patients with Pseudo-Angelman can be seen here; therefore, it may be why Pseudo-Angelman is named so.

Table 1: a comparison of AS and Pseudo-Angelman syndrome

Are there any treatments for Pseudo-Angelman syndrome?

Cure available: none

There is no one cure to help patients with the disease, but depending on symptoms, treatment may be offered accordingly.

Current treatments based on symptoms:

-        Seizures--> anti-seizure medicines

-        Behaviour issues--> behaviour therapy

-        Speech and developmental delays--> speech therapy

-        Difficulty sleeping--> medicine, sleep training     

Potential future treatments or cures: targeted therapy in chromosome 2

Research is ongoing for a cure, and it is considering targeting particular genes of chromosome 2 in therapy- perhaps the MBD5 and ECP2 genes.

The outlook for research into this disease

Aside from discerning the exact roles and functions of the genes on chromosome 2, there is active research in targeted therapy for Pseudo-Angelman syndrome. Likely, once the rest of the roles of the genes on chromosome 2 are elucidated, efforts can be invested towards modifying or even inserting these genes (e.g. MBD5 and ECP2) back into the chromosome, which would lead to better protein expression. This could be a possible treatment for the rare neurological disease.

Outside the molecular and genetic front, there should be increased awareness about this disease: this helps in reporting and diagnosing the syndrome, in addition to providing care and treatment to patients and their families.

Summary

In conclusion, Pseudo-Angelman Syndrome is a rare 2q23.1 microdeletion syndrome, which gets its name from the imprinting disorder AS. Pseudo-Angelman is characterised by seizures, moderate to severe learning difficulties, and developmental delays. Hence, making it a neurological disease as well. Treatments are available according to symptoms; but efforts are ongoing to ascertain the roles of other chromosome 2 genes, leading to potential targeted therapy.

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Patient organisations specifically for this disease:

-        Chromsome Disorder Outreach

-        Unique

The information in this article does not substitute professional medical advice. For any concerns, please refer to your doctor or local genetic centre.

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Written by Manisha Halkhoree

REFERENCES

van Bon, B., Koolen, D., Brueton, L. et al. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet 18, 163–170 (2010). https://doi.org/10.1038/ejhg.2009.152

Mayo Clinic, 2024.  Angelman syndrome. Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseases-conditions/angelman syndrome/diagnosis-treatment/drc-20355627#:~:text=Depending%20on%20your%20child's%20symptoms,sign%20language%20and%20picture%20communication.

Medline Plus, 2024. Angelman syndrome. Retrieved from Medline Plus Gov: https://medlineplus.gov/genetics/condition/angelman-syndrome/#:~:text=Angelman%20syndrome%20affects%20an%20estimated%201%20in%2012%2C000%20to%2020%2C000%20people.

National Institute of Health, 2024. 2q23.1 microdeletion syndrome. Retrieved from National Institute of Health: https://rarediseases.info.nih.gov/diseases/10998/2q231-microdeletion-syndrome