Overview of MBD5 Genetic Disorders

The MBD5 gene is thought to be involved in the production of certain proteins that are necessary for proper neurological development and function. When part of this gene is missing or duplicated (there are extra copies), the expression of these necessary proteins is altered and can greatly hinder the proper development of the neurological system.

Inherited neurodevelopmental disorders involving the MBD5 gene include MBD5 haploinsufficiency, 2q23.1 microdeletion syndrome, and 2q23.1 duplication syndrome. In all cases, part of the gene is missing; or, in the case of duplication, an extra copy of the gene is present.

Conditions like haploinsufficiency, microdeletion, or duplication all cause a cluster of symptoms that may include intellectual disability, impaired speech, or absence of speech, seizures, autism spectrum disorder, disrupted sleep patterns, and/or specific physical features.

Disorders involving the MBD5 gene are thought to be rare, but this may not be the case. Only recent developments in the field of genetics and DNA research have made a diagnosis of this condition possible and more prevalent. Many people may have MBD5 genetic disorders but have not been specifically diagnosed.

Prior to about 2003 (when the capability to diagnose MBD5 genetic disorders became more prevalent), many individuals may have been diagnosed with pseudo-Angelman's syndrome.

It is not currently believed that race or gender increases or affects the prevalence of MBD5 genetic disorders.

Symptoms

Despite the underlying cause (haploinsufficiency, duplication, or deletion) all MBD5 associated neurodevelopmental disorders include common features including:

• intellectual disability (usually moderate or severe) and global developmental delays
• speech difficulty ranging from absence of speech to single words or short sentences
• hypotonia (poor muscle tone)
• gross motor delays
• seizures
• infants with feeding difficulties related to hypotonia
• severe constipation related to hypotonia
• autism spectrum disorder
• short attention span
• self-injury
• aggressive behaviors
• repetitive movements or behaviors
• anxiety
• obsessive-compulsive disorder
• bipolar disorder
• sleep disturbances (may include night terrors or waking frequently during the night)

In addition, symptoms may include altered physical features including small hands and feet, short stature, ear anomalies, prominent nose, a broad forehead, small chin, arched eyebrows, a thin or "tented" upper lip, prominent front teeth, scoliosis, microcephaly, sandal toe (a large gap between the first and second toe), and fifth finger clinodactyly (abnormal development of the pinky finger).

A very small percentage of individuals with this disorder may experience heart problems (specifically atrial septal defect, ventricular septal defect, and pulmonary valve stenosis).

Some individuals with 2q.23.1 microdeletion have been documented with very few symptoms at all. Others may have severe neurological manifestations but lack the physical features associated with this disorder. Every individual with an MBD5 genetic anomaly is unique.

Causes

MBD5 genetic disorders can be passed on from the parent to a child. It is inherited in an autosomal dominant manner, meaning that a parent with one abnormal copy of the gene can pass it on to their child.

However, the majority of MBD5 genetic disorders are what is called de novo. A de novo genetic mutation is a spontaneous genetic mutation. In this case, both parents have normal copies of the gene, but something alters the DNA either before or shortly after conception.

It is very rare but possible for a child to inherit the condition from a parent who also has an MBD5 genetic disorder. This accounts for only a minority of cases.

Diagnosis

The majority of individuals are diagnosed using a test called chromosomal microarray analysis (CMA). This is a simple blood test that looks at a person's entire genome examining individual chromosomes for any alterations.

Chromosomal microarray analysis is a relatively new test and can be expensive so other tests may be ordered first when a genetic disorder is suspected. However, simple karyotyping or screening for individual genetic disorders that can cause similar symptoms (such as fragile X syndrome) will not identify MBD5 genetic disorders.

In addition to fragile x syndrome, similar genetic disorders include Smith-Magenis syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Rett syndrome, Koolen-De Vries syndrome, and Kleefstra syndrome.

Your healthcare provider can help to identify the best testing to use based on symptoms as well as your financial and health insurance situation.

If testing is positive for an MBD5 genetic disorder, a logical next step is genetic counseling. Genetic counseling can identify any other family members who may have an MBD5 genetic disorder or if any future children are at risk of inheriting it. Some key things we know include the following:

• Each child born to an individual who has an MBD5 genetic disorder has a 50% chance of inheriting it.
• Most MBD5 genetic disorders (approximately 90%) are de novo. Siblings of these individuals have an extremely small risk (less than 1%), but still a slightly higher risk than the rest of the population for having an MBD5 genetic disorder.
• If the genetic disorder was inherited from a parent (not de novo) siblings of an individual with an MBD5 genetic disorder have a higher risk of inheriting the condition.

After an MBD5 genetic disorder has been identified other tests may be indicated to look for related conditions or symptoms. For example, an electroencephalogram (EEG) can identify underlying seizures or epilepsy and help guide treatment for this specific feature. Another example would be a cardiac evaluation to look for any possible heart abnormalities.

Treatment

There is no cure or specific treatment for the underlying cause of MBD5 genetic disorders at this time. Treatments are aimed at alleviating or minimizing the symptoms and manifestations of this disorder. A multidisciplinary approach is necessary meaning that multiple specialists from different areas may be needed to address specific symptoms.

Even though there is no cure for this disorder, treatment can help individuals with MBD5 genetic disorders to be happier, more functional, and more independent.

Early Intervention

Symptoms may be evident from a very early age and infant feeding problems should be addressed. Work closely with your pediatrician to make sure your baby is gaining weight properly and is always well hydrated.

Infants usually have hypotonia (low muscle tone) and may be floppy and unable to hold their heads up on time. Enrolling in an early intervention program (usually offered through your school district) can be very beneficial and may provide things like physical therapy or speech therapy.

Physical Therapy

Hypotonia causes gross motor delays and may result in missed milestones such as rolling over, sitting up, crawling, and walking. Early physical therapy to improve muscle tone can help to improve functionality, strength, and mobility so that individuals can reach these goals.

Speech Therapy

Speech problems are significant in individuals with MBD5 genetic disorders. Speech therapy, especially when instituted early on, can greatly improve communication skills. Consider sign language and other forms of non-verbal communication as well.

Occupational Therapy

Fine motor skills may also be delayed in children with MBD5 genetic disorders. Occupational therapy can help with functional skills such as helping your child learn to feed themselves, dress themselves, or brush their hair or teeth.

Addressing Behavior

Individuals with MBD5 genetic disorders often have behavioral problems similar to people on the autism spectrum. They may have problems with repetitive behavior, acting out, and poor social skills. Consulting a specialist in this area for strategies in modifying behavior and improving social skills can improve functionality.

Some have been reported to pick at their skin or engage in other self-harm.

Since autism is a common symptom of MBD5 genetic disorders behavioral programs and therapies that are effective for children with autism may also be helpful, for example, applied behavioral analysis (ABA) therapy. It can be noted that while many kids with autism have an aversion to social settings, some children with MBD5 genetic disorders have been reported to seek out and enjoy social interaction.

Other symptoms may include hyperactivity or anxiety. If these symptoms are particularly severe you may wish to discuss medications to control these symptoms with your healthcare provider.

Individualized Education Plan (IEP)

Children with an MBD5 genetic disorder can benefit from an IEP. This will protect your child legally and help them to have the best educational experience possible. The therapies listed above are often available as part of the public school program and an IEP can help to ensure that your child has access to these therapies at school. An IEP helps to ensure they are given adequate accommodations for learning in a safe environment.

Constipation

Constipation is caused by hypotonia in approximately 80% of individuals who have MBD5 genetic disorders. Consult with your healthcare provider on dietary modifications, adequate fluid intake, and medications such as magnesium supplements, fiber supplements, stool softeners, or suppositories. These may be used alone or in combination to control symptoms of constipation.

Addressing Sleep Issues

Sleep disruptions can be significant and debilitating for people with MBD5 genetic disorders. Some common sleep issues include night terrors, nighttime seizures, and waking up frequently throughout the night and very early in the morning. Daytime sleepiness can be a problem as a result of poor sleep. Behavior problems may also be exacerbated by poor sleep.

Night terrors are episodes of waking up briefly during the night confused and disoriented. Sometimes a child might cry or get up and walk around but then suddenly will fall back asleep as though nothing happened.

Some medications that are frequently used to address sleep problems include melatonin and trazodone. Practicing good sleep hygiene such as bedtime routines, going to bed at a set time each night, and maintaining a proper sleep environment may also be helpful.

Seizures

About 80% of people with an MBD5 genetic disorder suffer from seizures. The typical time of onset is about two years of age. Anyone diagnosed with an MBD5 genetic disorder should undergo an evaluation with a neurologist and subsequent EEG testing.

Even though seizures are so prevalent, there is not one specific type of seizure that individuals with MBD5 genetic disorders typically exhibit. Multiple different types of seizures have been observed including seizures that come from the frontal lobe, absence spells, generalized tonic-clonic seizures, nocturnal (sleep-related) seizures, and startle-induced atonic seizures.

Medications used to control seizures may include acetazolamide, carbamazepine, clonazepam, levetiracetam, and lamotrigine. Rescue medications such as diazepam are also sometimes prescribed to have on hand in the case of an emergency (a prolonged or severe seizure).

Heart Abnormalities

While cardiac abnormalities have been documented in individuals with 5MBD genetic disorders current research shows this symptom to be rare (less than 11%). The following are heart abnormalities that have been known to occur:

• Atrial Septal Defect (ASD): This is a hole in the septum that divides the upper chambers (atrium) of the heart. The defect is present at birth and is usually surgically repaired if it fails to close on its own.
• Ventricular Septal Defect (VSD): This is a hole in the septum dividing the lower chambers of the heart (ventricles) and is present at birth. This is a common congenital heart defect. Symptoms depend on the size of the hole (small holes may not cause any symptoms). May close on its own or need to be surgically repaired.
• Pulmonary Valve Stenosis: The pulmonary valve opens and closes to allow blood to flow out of the heart and to the lungs. In pulmonary valve stenosis, the valve is thicker and stiffer than normal and doesn't open as well as it should. In most cases, a cardiac catheterization procedure to stretch the valve will relieve symptoms. More rarely, surgery is necessary.

Prognosis

Current research indicates that people with MBD5 should have a normal life expectancy with treatment and care. While the sheer volume of symptoms associated with this genetic disorder can seem overwhelming, many people with MBD5 genetic disorders are noted to be able to live happy and fulfilling lives.