Last updated:
3/14/2024
Years published: 2020, 2024
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 28 patients have been reported in the medical literature, but other patients are known anecdotally. Most individuals with MCTT syndrome have mild to moderate intellectual disability and severe expressive language delay or absent speech. Most have gross motor delay but can walk independently at a later age. Some individuals have mild to moderate hearing impairment (conductive and/or sensorineural). Low muscle tone (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. An abnormal skull shape is also frequently observed. Some patients have premature fusion of skull bones (craniosynostosis) which may require surgery. 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 of this report is a 46-year-old healthy male who lives a full life under the care of his family, so 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 variant 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 be absent, insufficient or faulty. Different organ systems can 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, particularly the development of the brain. Therefore, the symptoms of the syndrome are mostly related to neurodevelopmental issues.
Several disease-causing variants have been reported in the medical literature. These variants 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. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In very rare cases, a parent with a disease-causing MN1 gene variant in some of their body and reproductive cells (somatic and germline mosaicism) may be mildly or minimally affected. Only one such case has ever been reported, where the father carried a mosaic variant, had two affected siblings and presented with mild features of dysplastic ears and a high and narrow palate. These 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 variant 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 seizures may benefit from antiepileptic drugs.
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/living-with-a-rare-disease/find-clinical-trials/
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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