What is MORC2-Related Disorder?
MORC2 Related Disorder (M2RD) is a genetic disorder that causes problems with the nervous system. A genetic disorder is a condition that is due to a mutation of a particular gene. The nervous system includes the brain, spinal cord and nerves. Problems with the nervous system can cause abnormal sensory (sensation), motor (movement), sensorimotor (mixed loss of sensation and movement of the muscles) function or changes in the brain that affect cognition (knowledge and understanding). The gene that is affected in M2RD is called MORC2 and impacts the nervous system among other things. As such, M2RD can also be called a neurogenetic disorder.
M2RD is the exact same disorder as CMT2Z, DIGFAN, SMA-like disorder or, in some cases, Cockayne Syndrome. Regardless of the name, all of these genetic disorders are caused by a problem with the MORC2 gene. In M2RD, there is a mutation (called a point mutation) on the MORC2 gene, which means that the gene is not normal and does not work properly. M2RD results in harm to healthy nerves which causes a loss of function of the connected muscle group so that the muscle cannot work normally. For instance, harm to the long nerves which go to the legs can result in a patient not being able to walk well or even at all. Over time, a muscle that does not get used wastes (shrinks), causing further loss of function or making it even harder for the muscle to work. M2RD causes polyneuropathy which means that more than one nerve and muscle group is affected. In some patients, M2RD may affect parts of the brain which are involved in cognition and thinking (cerebral cortex), or balance (cerebellum).
There are many symptoms associated with M2RD and not all patients have all symptoms. Furthermore, not all symptoms appear at the same stage of a person’s life. Because of this, M2RD resembles a spectrum disorder in that patients experience a variation of severity with different symptoms. While it is not fully understood why there is such variation of symptoms between individuals with M2RD, what is clear is that the specific location of the mutation within the gene, along with other factors, plays a key role in the severity of symptoms [1]. In general, the younger a person is, the more severe the symptoms.
For researchers studying M2RD, gaining a better understanding of its presenting symptoms is vital for patient care and for developing future treatments. Because M2RD is rare and only first discovered in 1994 [2], not enough patients have participated in research yet to accurately describe the spectrum of symptoms or to know how best to treat them.
Why not CMT2Z?
Many people will know MORC2-Related Disorder (M2RD) as CMT2Z or ‘Charcot Marie Tooth Disease type 2Z’. You may have received the diagnosis of CMT2Z and have visited a CMT website for answers. As we noted above, M2RD has many names, including CMT2Z, DIGFAN, SMA-like disorder and Cockayne Syndrome. Having many names for the same disorder is a problem for patients and doctors alike because it makes it harder to find information on the disorder. This creates a misunderstanding of what symptoms may be associated with a disorder, and makes it harder to connect patients with support groups and research opportunities to study treatments.
Why are there multiple names for M2RD and why were you told that you or your child had CMT2Z?
When a disorder is newly discovered, it is common to see many names appear for the same condition. This happens because different doctors around the world will publish medical articles that each claim to have discovered the disorder and each name it something different. Sometimes, a doctor will name the disorder after themselves, such as in the case of ‘Charcot’-’Marie’-’Tooth’ or ‘Cockayne’ Syndrome; all 4 of these words being the last names of the people who published the first medical articles on the disorder. The practice of using last names for disorders is changing and scientists and medical doctors now advocate for names that represent the causes of the diseases or disorders.
Other times, as in the case with CMT2Z, the disorder will be named based on symptoms that look similar to symptoms from another disorder. All the different types of CMT disorders are based on neurological symptoms, they do not describe how the symptoms occur or even what to do about them. CMT2Z has some symptoms (or clinical features) that are similar to other CMT disorders but it also has symptoms that are different from CMT disorders. When we name a disorder based on only some of the similarities it may share with other disorders, such as in the case of CMT2Z, we risk missing other symptoms that are actually caused by the disorder but do not neatly match what we think CMT should look like. For instance, some patients with M2RD or CMT2Z will develop facial abnormalities but since this feature does not fit with what 'CMT’ disorders should look like, these patients have been misdiagnosed which both lengthens the “diagnostic odyssey”, taking a toll on patients and caregivers and prevents these patients from gaining relevant and appropriate medical support.
Lastly, the classification and name ‘CMT’ does not give us any information on the origin of the disorder. M2RD or CMT2Z is due to a mutation on the MORC2 gene. By using the name MORC2-Related Disorder or M2RD for short, it reminds us that the disorder is connected to the MORC2 gene. All other CMT types have genetic mutations on different genes unrelated to MORC2. Calling many disorders by one name can make people think that they are connected when they are not. Because CMT2Z is due to a mutation in the MORC2 gene, MORC2-Related Disorder is a more scientifically appropriate name.
Calling a genetic disorder by its scientific name is better for patients because it:
Helps us focus treatments which target the origin of the problem
Helps us ensure that a patient is diagnosed correctly via genetic testing and not just by looking at symptoms
Opens us up to noticing what other symptoms may exist besides just the most common ones
Helps connect patients and caregivers together for support
When scientists look for medical cures, they try to target the origin of the disorder, not the symptoms. Targeting the origin of a problem is the only way to truly fix it. In the case of CMT2Z, the origin is a mutation in the MORC2 gene. The name MORC2-Related Disorder or M2RD should be used because it describes the gene and how the location of the mutation on the gene can result in very different symptoms depending on where on the piece of DNA the mutation is found. But more on that below!
What are the symptoms of M2RD?
The ‘presentation’ or symptoms of M2RD vary greatly from one patient to another. The reason for this is not fully understood and the pattern of severity and progression is unpredictable [1], however, the differences may have to do with where the mutation is located on the MORC2 gene, amongst other factors. There are many known symptoms of M2RD and likely some unknown symptoms. Symptoms have been seen to appear already in infancy whilst some patients present first signs showing up in adulthood [3]. The hallmark symptom in M2RD is neurodevelopmental impairment which causes abnormal brain function and is present in all individuals with M2RD [4].
Other symptoms that are associated with M2RD may include:
Global developmental delay (this occurs when a person does not meet the age milestones as expected which can include intellectual, physical or mixed missed milestones) [5, 6]
Difficulty standing and/or walking (inability to walk without aids) [3, 9]
Hearing loss [7]
Visual problems [5]
Scoliosis (curvature of the spine) [1]
Muscle contractures, causing foot deformity [1]
Facial dysmorphia (abnormality in the shape and/or size of the face) [5, 6]
Short stature [1]
Tremor [5, 1]
Chronic constipation [1]
Early onset of puberty [7]
Frequent dental caries (cavities) [1]
Thyroid dysfunction [1]
Cerebellar ataxia (difficulties with co-ordination, walking, speech) [7-8]
There is currently little information about the disease progression of M2RD. Some symptoms of M2RD have been reported to progress while others remain stable for at least a period of time. Individuals who develop symptoms later in life may experience progressive weakness of the arms and legs, leading to diagnosis [9].
What causes M2RD?
M2RD is caused by a mutation within the MORC2 gene (called a point mutation) [10]. It has an autosomal dominant inheritance pattern which means that a patient will have one abnormal copy of the MORC2 gene and one normal or working copy or MORC2. One abnormal copy is enough to cause the disorder. An individual with M2RD is born with the genetic mutation on the MORC2 gene so all M2RD patients will have one bad copy of the gene even though not everyone experiences symptoms at the same stage in life. Mutations on the MORC2 gene are almost exclusively de novo, meaning that the mutation is new and was not inherited from parent to child. It is important to note that M2RD is not the fault of a parent; nothing a parent has done before, during or after a pregnancy causes M2RD.
Mutations on the MORC2 gene may be linked to severity where if the mutation is at the beginning of the gene, the symptoms can potentially be worse than if the mutation is at the end of the gene. We still don’t completely understand how the location of the mutation affects the severity of symptoms for a patient with MORC2-Related Disorder. What we can say for certain though is that individuals with M2RD can look very different from one another with the exception of the common feature or symptom which is neurodevelopmental impairment or simply neural impairment in older patients. These differences can be so great that without a genetic test to confirm M2RD, a misdiagnosis is likely. It is for this reason that obtaining a genetic diagnosis is so critical. Without understanding how M2RD looks in all patients, scientists will not be able to investigate potential treatments or a cure.
How is M2RD diagnosed?
Unfortunately, like most rare disorders, obtaining a diagnosis of M2RD often ends up taking longer than it should. Although M2RD can be easily diagnosed with a simple blood test, most patients end up enduring complex and sometimes invasive testing before whole genome sequencing or whole exome sequencing is used to obtain the correct diagnosis. The reasons for this are complex but are rooted in access to testing and an old way of thinking about disorders which is biased towards symptoms as the only way to make a diagnosis.
Because many doctors will not be familiar with M2RD, a patient’s symptoms are often used to make a diagnosis instead of also using genetic testing. Looking at symptoms alone can lead to an incorrect diagnosis; genetic testing must be obtained to confirm the diagnosis of M2RD. Importantly, finding M2RD through genetic testing can currently only be achieved with a specific kind of genetic testing called ‘whole exome sequencing’ (WES) or ‘whole genome sequencing’ (WGS). Both of these genetic tests are now widely available, although cost can often be a barrier to accessing them [3]. This is because the M2RD is not currently included in the list of neuromuscular genetic disorders that are screened (called a panel).
Electrodiagnostic studies are often used in the clinical assessment of M2RD. These studies test the function of nerve and muscle, and include nerve conduction studies and electromyography (EMG).
Electrodiagnostic studies may confirm the presence of a motor and/or sensory neuropathy, which means a problem with the muscles and or nerves, respectively.
MRI brain scans are also sometimes performed. Some M2RD patients may show abnormalities on an MRI brain scan in specific parts of the brain (e.g. cerebellar lesion). An MRI may also reveal a smaller than expected brain (microcephaly) or particular parts of the brain which are smaller than expected for the age of the patient (e.g. cerebellum and vermian) [1]. This finding is variable from patient to patient and more research is needed to understand how a brain change in M2RD affects a patient.
Because modern technology has allowed the diagnosis of M2RD with a simple blood test (whole exome sequencing or whole genome sequencing) and clinical symptoms are not sufficient to obtain a M2RD diagnosis, invasive tests such as nerve biopsy should be carefully considered in terms of how this information will help a patient.
How many people are affected by M2RD?
M2RD is classified as a rare genetic disorder. It is unclear how rare M2RD actually is because many people may be undiagnosed or misdiagnosed as they do not have access to whole genome or whole exome genetic testing. While less than 100 cases of M2RD have been reported in medical journals to date, the number of patients with M2RD is likely to be much higher.
What is the treatment of M2RD?
Treatment of M2RD is currently supportive and specific to the symptoms of each individual patient. Because treatments have not been studied, it is not clear which existing options may be the most effective for each individual. Importantly, as each patient has different symptoms due to the location of their mutation on the MORC2 gene, proposed treatments may be very different from person to person. More research is needed to understand which treatments help a patient, which provide no benefit, and which treatments may actually cause harm. The lack of knowledge around effective treatments can feel frightening which is why it is important to seek medical care from a team of specialists who have some knowledge of M2RD.
Within the M2RD community, many patients or caregivers will report a particular treatment that they feel is working for them. It is important to understand that because of how MORC2 functions and where each patient’s mutation is on the gene, what seems to help one person may not help another. While it may feel natural to assume that one treatment in one patient ‘causes’ that patient to improve, caution is advised against this thinking as some patients in some cases may naturally overcome some symptoms as they grow and develop and improvement is not actually associated with what a patient is doing or taking. As more M2RD patients agree to participate in research, more will be learned on how to effectively treat or even cure M2RD.
Specialists on your medical team
Depending on the needs of the individual patient, specialists who can help manage M2RD either before or after diagnosis could include a combination of a paediatrician, paediatric neurologist, geneticist, genetic counsellor, gastroenterologist, dietician, speech therapist, rehabilitation physician, orthopaedic surgeon, physiotherapist, occupational therapist, and/or psychologist.
When available and when eligibility criteria are met, early developmental intervention programs are helpful in optimising an affected individual’s developmental potential during early childhood. Additional social and/or vocational services including individualised education programs are often helpful during school-age years and adolescence. Psycho-social support such as attending mental health and wellness counselling for the entire family is imperative.
Physiotherapists, physical medicine and rehabilitation physicians, and/or orthopaedic surgeons can offer individualised care of contractures. This may include exercises (administered directly or at the home by parents), orthotic devices and, typically as a last resort, surgical interventions. The risks and benefits of invasive surgical procedures should be considered in the context of the long-term course of M2RD. For example, the beneficial effects of heel cord release procedures may attenuate, or become less effective, over time. It is important to understand that surgical interventions for M2RD symptoms have not been studied and no long-term data exists on whether such interventions are needed or help a patient as they grow. Especially for paediatric patients, invasive treatments should be thoughtfully determined.
Pain management should be considered given the impactful experience of cramps and contractures. This is especially important in a non-verbal and/or younger patient where communication may be difficult. When possible, conservative pain management such as massage therapy could additionally be pursued. Pain management should be regularly discussed with your medical team.
Looking Ahead
There is currently no disease modifying treatment or cure for M2RD. However, through supporting research and by helping M2RD patients find research opportunities, MORCure aims to rapidly drive medical progress for M2RD. First, M2RD needs to be described in more detail before research can be done to find safe and effective treatments. This means that scientists and medical doctors must classify all the different symptoms that patients may have. They must also find adults who are living with M2RD and understand how their symptoms have changed over time. The more patients who obtain a diagnosis and connect with research, the quicker scientists and medical doctors will be able to learn how best to treat patients with this rare disorder.
References
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