The Role of Maf2c Gene Mutation in Maf2c Deficiency Syndrome in Children and Cognitive Neurobehavioral Disorders

MEF2C deficiency is a very rare genetic disorder caused by a change (mutation) in the MEF2C gene. The mutation, which is often a deletion, results in a loss of function of the MEF2C protein, which is essential for the proper functioning of the musculoskeletal, cardiovascular, nervous, craniofacial, and immune systems. A deletion mutation occurs when part of a chromosome is missing. Signs and symptoms vary widely and usually first appear when the patient is between one and two years of age. Some of the most common presenting symptoms include decreased muscle tone (hypotonia), general developmental delay, seizures, and brain abnormalities. Children with MEF2C deficiency usually have a variety of brain abnormalities. MRI of the brain of patients with MEF2C deficiency may show loss of brain cells, enlarged ventricles, or an abnormal corpus callosum. MEF2C deficiency is caused by mutations in the MEF2C gene, located on the long arm of chromosome 5 at 5q14.3, or in the promoter and enhancer regions of the gene, which result in a deficiency or complete absence of functional MEF2C protein. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in the DNA sequence and is not inherited from the affected parent. There are currently no approved treatments that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is needed that includes the following specialists, treatments, and tests: An ophthalmologist and audiologist for annual vision and hearing evaluation.

Overview of MEF2C Deficiency Syndrome

MEF2C deficiency is a very rare genetic disorder caused by a change (mutation) in the MEF2C gene. The mutation, which is often a deletion, results in a loss of function of the MEF2C protein, which is essential for the proper functioning of the musculoskeletal, cardiovascular, nervous, craniofacial, and immune systems. A deletion mutation occurs when part of a chromosome is missing. Signs and symptoms vary widely and usually first appear when the patient is between one and two years of age. Some of the most common presenting symptoms include decreased muscle tone (hypotonia), general developmental delay, seizures, and brain abnormalities. Currently, there is no cure for MEF2C deficiency, and care is based on individual symptoms. Anticonvulsant medications are prescribed for seizures, melatonin for sleep problems, and physical, occupational, and speech therapy for developmental delays [1]. The MEF2C gene was discovered in 2008 by Dr. Stuart Lipton and his research team at the Burnham Institute. Initially, Dr. Lipton's study showed that disruption of the MEF2C gene resulted in smaller brains, reduced neuron numbers, and severe autism-like abnormalities in mice. Mutations in the MEF2C gene are included in the list of mutations associated with Rett-like phenotypes, such as Rett syndrome, Angelman syndrome, Pitt-Hopkins syndrome, CDKL5 deficiency disorder, and many genes associated with autism [1].

Clinical Signs and Symptoms of MEF2C Deficiency Syndrome

Normally, there are no specific symptoms during pregnancy or delivery of a child with MEF2C deficiency. The individual appears to develop normally during infancy and by infancy or early childhood, symptoms such as hypotonia, feeding difficulties, and poor eye contact may appear. Seizures may occur, especially when the infant is ill or has a fever. Global developmental delay is seen in almost all patients with MEF2C deficiency. There is variability in these developmental delays, particularly in speech, gait, cognitive abilities, and social skills. These patients also present with some distinctive facial features ranging from mild to severe [1,2]. Children with MEF2C deficiency usually have a variety of brain abnormalities. MRI of the brain of patients with MEF2C deficiency may show loss of brain cells, enlarged ventricles, or an abnormal corpus callosum. MEF2C protein has been shown to play a role in reduced forebrain growth both dorsally and ventrally [1,2].

Figure 1: Images of children with MEF2C deficiency syndrome with distinctive facial features [1].

MEF2C patients are likely to have epilepsy, but the age of onset and type of seizures vary. Most often, the patient develops seizures during infancy. Some of the seizures that patients experience includes infantile spasms, febrile, partial, absence, tonic-clonic, and myoclonic seizures. It has been found that the severity of the phenotypic (symptoms) may be related to the location of the mutation in the MEF2C gene [1,2].

Summary of symptoms

Neurological: Brain abnormalities (MRI), abnormal corpus callosum, loss of brain cells (frontal cortical atrophy), enlarged or asymmetrical ventricle [1,2]. Less common: Cerebral or cortical abnormalities, white matter abnormalities, delayed myelination or hypomyelination, underdeveloped cerebellum (mild cerebellar vermis hypoplasia), abnormal forebrain development [1,2]. Epilepsy may include the following types and is often accompanied by fever: Brief muscle jerks (myoclonic seizures). Generalized tonic-clonic seizures involving loss of consciousness and muscle contractions. Absence seizures involving a brief, sudden interruption of consciousness. Atonic seizures involving sudden loss of tone [1,2].

Figure 2: Other images of children with MEF2C deficiency syndrome with dysmorphic faces [1].

The EEG of patients may show bilateral temporal slow waves, bilateral parietal spike waves, or other generalized spike wave discharges [1,2]. Behavioral: A wide range of stereotyped movements, non-purposeful use of the hands such as clapping, pressing, biting and sucking, head shaking, clenching of teeth (bruxism), rocking the chair, pressing the tongue, staring at the ceiling. [1,2]. Other behavioral signs include: inappropriate laughter, excessive enjoyment of running water, short attention span, poor eye contact, social withdrawal, feeding problems such as overfilling the mouth with food or sleep problems such as insomnia and nighttime laughter, delayed behavioral development, speech delay, severe speech disorders, loss of expressive language skills, gross motor delays, sitting and walking skills absent or delayed by two to three years of age, unsteady and wide gait, poor coordination [1,2]. Musculoskeletal: Decreased muscle tone (hypotonia) which is more severe in women, muscle spasms (hyperkinesis), abnormal hand shape, increased range of motion (hypermobility), abnormal reflexes [1,2]. Prognosis: Myopia (nearsightedness), pale blue eyes, crossed eyes (strabismus), blindness, respiratory, episodic respiratory abnormalities (apnea, hyperpnea or hyperventilation), frequent upper respiratory tract infections [1,2].

Gastrointestinal: Severe GERD (gastroesophageal reflux disease), constipation [1,2]. Craniofacial: Broad forehead, depressed nasal bridge, large mouth with full lips, distinct pharyngeal pillars (space between upper lip and nose), tented upper lip, short columella (space separating nostrils), down-turned corners of mouth, upper eyelid skin folds (epicanthic folds), small chin, short nose, underdeveloped ears, prominent eyebrows, upward slant of the space between the eyelids (palmateric cleft) [1,3]. Cardiovascular: Possible associations between MEF2C mutations and heart disorders, patent ductus arteriosus (abnormal blood flow), double-outlet right ventricle (both aorta and pulmonary artery exit from the right ventricle), ventricular septal defect (hole in the heart) [1,3]. Dermatologic: Red birthmarks (hemangiomas), thinning of the skin (atrophic skin) [1,3]. Other less common symptoms: high pain tolerance, jugular fossa (empty space near the neck/throat), floppy larynx, cold hands and feet, cleft palate, duplex left kidney (two ureters from one kidney [1,3].

Etiology of MEF2C Deficiency Syndrome

MEF2C deficiency is caused by mutations in the MEF2C gene, located on the long arm of chromosome 5 at 5q14.3, or in the promoter and enhancer regions of the gene, which result in a deficiency or complete absence of functional MEF2C protein. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in the DNA sequence and is not inherited from the affected parent. The MEF2C gene encodes a transcription factor that is involved in the normal development of the heart, brain, craniofacial region, vasculature (blood flow), and immune system. The MEF2C enhancer region is widely expressed in glial cells, which are cells that support the cells of the brain and nervous system [1,4].

Figure 3: Schematic of the physical map of chromosome number 5, where the MEF2C gene is located on the long arm of this chromosome as 5q14.3 [1].

The MEF2C gene can have these mutations within the gene or upstream in the enhancer or promoter regions. The enhancer and promoter regions of the gene are called regulatory elements. These are DNA elements that help to "turn on" the gene so that more MEF2C protein can be transcribed and translated. MEF2C deficiency can also be called haploinsufficient MEF2C, which is a characteristic of an autosomal dominant disorder. This means that one functional copy of the gene is not enough to ensure that the child does not have the disease. The MEF2C protein is a transcription factor, meaning that it helps activate the transcription of other genes. When the MEF2C protein is missing or malfunctioning, the genes that promote transcription for them are also affected. These genes include MECP2 and CDKL5, which are also involved in Rett syndrome and the disorder CDKL5 deficiency. Therefore, loss of MEF2C function leads to reduced activation of these genes, resulting in symptoms similar to Rett or CDKL5 deficiency. The severity of symptoms of MEF2C deficiency depends on the number of gene affected by the mutation, with larger abnormalities reflecting more severe symptoms of the syndrome [1,4].

Figure 4: Schematic of the molecular mechanism of the MEF2C gene in pulmonary endothelium of PAH disease versus normal pulmonary endothelium [1].

Frequency of MEF2C Deficiency Syndrome

MEF2C deficiency appears to affect males and females equally and does not appear to have an ethnic predisposition. The age of onset is most often in infancy or early childhood. MEF2C deficiency is often misdiagnosed as Rett syndrome because of its Rett-like phenotype. Approximately 50 patients with MEF2C deficiency have been identified, but this number is likely higher due to misdiagnosis of subtle symptoms that mimic other, more well-known disorders [1,5].

Figure 5: Schematic of the biochemical mechanism of the MEF2C gene in the calcium channel of nerve cells from the control group and patients with autism [1].

Disorders Associated with MEF2C Deficiency Syndrome

MEF2C deficiency has clinical overlap with Rett syndrome, Angelman syndrome, Pitt Hopkins syndrome, and CDKL5 deficiency disorder. Often, these syndromes are grouped under the term "Rett-like," but the use of this term has recently been discouraged because these syndromes are now clinically distinct. The symptoms of the following disorders can be similar to those of MEF2C deficiency. Comparisons may be helpful in making a differential diagnosis [1,5].

Rett syndrome is a rare neurodevelopmental disorder that affects mostly females. Babies with Rett syndrome develop normally for about 7 to 18 months after birth. Then, they begin to miss some developmental milestones, such as language production and purposeful hand movements. They also have other symptoms, such as uncontrolled hand movements, ataxia, microcephaly, and many features of autism spectrum disorder. Rett syndrome is caused by mutations in the MECP2 gene and results in a wide range of disabilities. Symptoms of MEF2C deficiency are similar to those of Rett syndrome, such as motor delays and stereotyped behavior, but unlike Rett syndrome, there is typically no microcephaly or growth retardation. Also, seizures tend to start later and are less severe in MEF2C deficiency than in Rett syndrome [1,5].

Figure 6: Schematic of the role of the MEF2C gene in the synapse [1].

Angelman syndrome is a rare neurological disorder characterized by developmental delay, learning disabilities, speech problems, ataxia, jerky movements of the limbs, cheerful disposition, and unexpected laughter. The most common symptoms include seizures and sleep problems. Angelman syndrome is caused by a mutation in the UBE3A gene. The symptoms of MEF2C deficiency are similar to those of Angelman syndrome, but unlike Angelman syndrome, microcephaly is typically not present. Neither syndrome involves neurodevelopmental regression [1,6]. Pitt-Hopkins syndrome (PTHS) is a rare neurological disorder. Common symptoms of the disorder include speech problems, seizures, abnormal breathing patterns, ataxia, distinctive facial features, intellectual disability, and other delays in reaching developmental milestones. People with PTHS are often very social and cheerful. Pitt-Hopkins syndrome is caused by a mutation in the TCF4 gene. Pitt-Hopkins syndrome presents with motor and cognitive delays similar to those seen in patients with MEF2C deficiency. However, they can be distinguished because patients with Pitt Hopkins usually experience more severe respiratory symptoms, such as gasping for air or breath-holding spells, which may lead to loss of consciousness [1,6].

Figure 7: Schematic of the autosomal dominant inheritance pattern that MEF2C deficiency syndrome can follow [1].

CDKL5 deficiency is a rare X-linked disorder that causes neurodevelopmental disorders. People with this disorder are likely to have seizures in the first few months of life. They have severe motor and language disabilities. In addition, these patients will have cognitive disabilities and stereotyped hand movements. CDKL5 deficiency is caused by a mutation in the CDKL5 gene. Many of the symptoms that these patients experience is similar to those of MEF2C deficiency [1,6].

Diagnosis of MEF2C Deficiency Syndrome

One of the only ways to test for MEF2C deficiency is with a chromosome microarray test to test for chromosome number 5. To see small chromosomal abnormalities, a fluorescence in situ hybridization (FISH) test may be used. For even smaller chromosomal abnormalities, a multiplex probe ligation-dependent amplification (MPLA) test may be used to identify genetic abnormalities. Hypotonia and epilepsy are early symptoms that appear in the first few years after birth and may lead to the diagnosis of MEF2C deficiency [1,6].

Treatment Pathways for MEF2C Deficiency Syndrome

There are currently no approved treatments that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is needed that includes the following specialists, treatments, and tests: An ophthalmologist and audiologist for annual vision and hearing evaluation [1,6]. A cardiologist for annual checkups to assess blood pressure and heart rate. The patient should also have an electrocardiogram (EKG) or echocardiogram (ECHO) to evaluate for heart disease [1,6]. Electroencephalography (EEG) and MRI of the brain to monitor seizure activity and other neurological signs [1,6]. A psychiatrist to evaluate behavioral symptoms [1,6]. Physical therapy, occupational therapy, and speech therapy. Developmental/behavioral therapy or music therapy may also be helpful [1,6]. A dermatologist may be referred for hemangiomas [1,6]. An immunologist may be needed if the patient has recurrent infections [1,6]. Many of the other treatments these patients receive are similar to those given to children with autism spectrum disorder or other neurodevelopmental disorders. Seizures are usually well controlled with various medications. Melatonin may be used for sleep problems. Genetic counseling is recommended for families with affected children [1,6].

Normally, there are no specific symptoms during pregnancy or delivery of a child with MEF2C deficiency. The individual appears to develop normally during infancy and by infancy or early childhood, symptoms such as hypotonia, feeding difficulties, and poor eye contact may appear. Seizures may occur, especially when the infant is ill or has a fever. Global developmental delay is seen in almost all patients with MEF2C deficiency. There is variability in these developmental delays, particularly in speech, gait, cognitive abilities, and social skills. These patients also present with some distinctive facial features ranging from mild to severe. MEF2C patients are likely to have epilepsy, but the age of onset and type of seizures vary. Most often, the patient develops seizures during infancy. Some of the seizures that patients experience includes infantile spasms, febrile, partial, absence, tonic-clonic, and myoclonic seizures. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in the DNA sequence and is not inherited from the affected parent. The MEF2C gene encodes a transcription factor that is involved in the normal development of the heart, brain, craniofacial region, vasculature (blood flow), and immune system. One of the only ways to test for MEF2C deficiency is with a chromosome microarray test to test for chromosome number 5. To see small chromosomal abnormalities, a fluorescence in situ hybridization (FISH) test may be used. There are currently no approved treatments that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is needed that includes the following specialists, treatments, and tests: An ophthalmologist and audiologist for annual vision and hearing evaluation [1,6].