NORD gratefully acknowledges Jasmine Fung, BBiomedSc, the University of Hong Kong; Christopher Mak, PhD, the University of Hong Kong; Angela Lin, MD, MassGeneral Hospital for Children, Boston, MA; and Brian Chung, MD, the University of Hong Kong for the preparation of this report.
Summary
MN1 C-terminal truncation (MCTT) syndrome is a rare autosomal dominant genetic disorder caused by a genetic change at one end (the C-terminal) of the MN1 gene. The genetic disorder is characterized by intellectual disability with delayed or absent speech, delayed gross motor development, distinctive structural changes in the brain (rhombencephalosynapsis), unique facial features, and hearing loss. This new syndrome was first reported in 2020. There is ongoing research to better understand the spectrum of symptoms, the long-term prognosis, and gather knowledge to provide the most appropriate genetic counseling.
The symptoms and physical findings associated with MCTT syndrome may vary from one person to another (variable expression). Affected individuals or parents of affected children should talk to their physicians and consult with a medical genetics team about their specific case and associated symptoms.
To date, a total of 25 patients have been reported in the medical literature, but other patients are known anecdotally. The majority individuals with MCTT syndrome have mild to moderate intellectual disability and severe expressive language delay or absent speech. Most have gross motor delay but are able to walk independently at a later age. Some individuals have mild to moderate hearing impairment of conductive and/or sensorineural nature. Low muscle strength, also known as floppy baby (hypotonia) and feeding difficulty due to poor ability to suck are also frequently seen during infancy. The height and weight (growth parameters) of affected children are typically normal.
Individuals with MCTT syndrome may have distinctive imaging findings of the brain. Magnetic resonance imaging (MRI) shows abnormal development of the cerebral cortex (perisylvian polymicrogyria and/or cortical dysplasia), fusion of the structures in cerebellum (rhombencephalosynapsis), and the presence of embryonic vessel construction (persistent trigeminal artery) that may be important when considering surgical approaches.
Characteristic features of the head and facial (craniofacial) region include tall forehead, flattened midface, prominent eyes, widely set eyes (hypertelorism), downslanting eyes, low-set ears with abnormal shape, and a short, upturned nose especially in infancy. Skull shape abnormality is also frequently observed. Some will have premature fusion of skull bones (craniosynostosis) which may require surgical intervention. Neurosurgical care should be customized.
Abnormality of the curvature of the spine (scoliosis/lordosis/kyphosis), congenital structural heart defects, seizures, and behavioral problems have been observed in some individuals with MCTT syndrome.
Due to the limited case reports of MCTT syndrome, it is unknown if the life span of individuals with MCTT syndrome is affected. The oldest individual known to the authors is a healthy male in his late 30’s who lives a full life under the care of his family, demonstrating survival into adulthood is probable. It is likely that MCTT syndrome is both underrecognized and underreported in adults.
MCTT syndrome is caused by a disease-causing mutation at the “C-terminal” of the MN1 gene which terminates the protein product prematurely. When such a disease-causing (pathogenic) change occurs, the protein product may absent, insufficient or faulty. Different organ systems could be affected depending on the function and place of action of the affected protein. In MCTT syndrome, the genetic change creates an abnormal protein that is shorter than usual, and this affects its usual dynamic and interaction within the body, in particular the development of the brain. Therefore, the symptoms of the syndrome are largely related to neurodevelopmental issues.
Several disease-causing genetic changes have been reported in the medical literature. These alterations usually occur in de novo fashion, meaning that the change is new and not inherited from either parent. The likelihood of these parents having another child with the same syndrome is low.
MCTT syndrome follows an autosomal dominant inheritance pattern, so one disease-causing genetic change is sufficient to cause the disease. An individual with a disease causing change in the MN1 gene has a 50% chance in each pregnancy of passing the change to his/her offspring. The risk is the same for male and female children.
In very rare cases, a parent with a MN1 pathogenic gene variant in some body and reproductive cells (somatic and germline mosaicism) may be mildly or minimally affected. Only one such case has been ever reported, where the father carried a mosaic mutation, had two affected siblings and presented with mild features of dysplastic ears and a high and narrow palate. In such circumstances, individuals are recommended to seek the advice of a clinical geneticist for genetic evaluation and counseling, and to discuss reproductive options and any concerns regarding potential risks to future children.
MCTT syndrome was first identified by two groups of researchers in 2020, reporting 22 and 3 individuals, respectively. With the increasing availability of genetic testing and recognition of the syndrome, more patients have been identified. However, many individuals may still be undiagnosed. Patients have been identified from various parts of the world and among different ethnic backgrounds. Males and females are affected equally.
MCTT syndrome is usually diagnosed in early childhood or at a later age by the identification of characteristic symptoms, a detailed patient and family history and a thorough clinical evaluation and investigation. The diagnosis of MCTT syndrome is confirmed by identifying a disease-causing genetic change at the C-terminal of the MN1 gene. This could be achieved by performing targeted genetic testing (MN1 sequencing) or comprehensive genomic testing (exome sequencing/ genome sequencing).
Currently, there is no evidenced-based protocol or guidelines for treating MCTT syndrome. However, providers can offer treatment for people with MCTT based on the specific symptoms that are apparent in each individual. For developmental delay, early developmental intervention and educational training may be beneficial. Physiotherapy, occupational therapy and speech therapy are useful for most individuals. The training focus could emphasize alternative non-verbal communication methods (for example, sign language).
Individuals with craniosynostosis should have a formal neurosurgical evaluation and may require surgery. Surgery is performed to improve the appearance of the child’s head. Rarely is it performed to relieve increased intracranial pressure. Surgery may not be necessary for some individuals. Hearing aids may be beneficial for individuals with hearing impairment. Individuals with seizure(s) may benefit from antiepileptic drugs as per neurologist’s assessment.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contacts for additional information about MCTT syndrome:
Dr. Brian H.Y. Chung
Department of Paediatrics and Adolescent Medicine
LKS Faculty of Medicine
The University of Hong Kong
Hong Kong
[email protected]
Dr. Christopher C.Y. Mak
Department of Paediatrics and Adolescent Medicine
LKS Faculty of Medicine
The University of Hong Kong
Hong Kong
[email protected]
Dr. Christopher T. Gordon
Laboratory of Embryology and Genetics of Human Malformation,
Institut National de la Sante´ et de la Recherche Me´dicale
(INSERM) UMR 1163,
Institut Imagine,
75015 Paris
France
[email protected]
Angela E. Lin, MD
Medical Genetics, MassGeneral Hospital for Children
Harvard Medical School
Boston, MA
[email protected]
JOURNAL ARTICLES
Mak C, Doherty D, Lin A et al. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis. Brain. 2020;143(1):55-68. doi:10.1093/brain/awz379
Miyake N, Takahashi H, Nakamura K et al. Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities. The American Journal of Human Genetics. 2020;106(1):13-25. doi:10.1016/j.ajhg.2019.11.011
INTERNET
Human Disease Genes Homepage
https://humandiseasegenes.nl/mn1/
MCTT Syndrome Facebook Group
https://www.facebook.com/groups/1542521759383791
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