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Last updated: 7/31/2024
Years published: 2024
NORD gratefully acknowledges Juliana Rodegheri Brito, BBmedSc, BS, Evan Lewis, BS, and Michelle Nguyen, BS, Stanford University MS Program in Human Genetics and Genetic Counseling, MaryAnn Campion, EdD, MS, CGC, Professor, Department of Genetics, Stanford University School of Medicine, and Suha Bachir, MD, MS, FACMG, Clinical Assistant Professor, Division of Human Genetics, Department of Pediatrics, Stanford University School of Medicine, for the preparation of this report.
Summary
TRPM3-related neurodevelopmental disorder (TRPM3-NDD) is a rare neurological disorder. There are a wide range of symptoms that affected children can have, including low muscle tone (hypotonia) at birth, developmental delay, intellectual disability, seizures, musculoskeletal findings and eye (ophthalmological) findings. Associated musculoskeletal findings include displacement of hip bones (hip dysplasia) or abnormal curvature of the spine (scoliosis) and a common eye finding is crossed eyes (strabismus). Additional findings include poor muscle control (ataxia), repeated seizures (epilepsy) and decreased muscular activity. Treatment is specific for symptoms and may include early interventional therapies to improve developmental potential, educational support, anti-seizure medications for seizures and other tailored therapies for eye, ataxia and musculoskeletal problems. TRPM3-NDD is caused by a change (variant) in the TRPM3 gene. In most patients, the disease-causing gene variant is not inherited from a parent.
Introduction
TRPM3-NDD is a spectrum of neurological disorders with a variety of features. People with this disorder have hypotonia, skeletal anomalies, developmental delay, intellectual disability and may or may not have seizures. The identification of a TRPM3 gene variant associated with a neurodevelopmental disorder was first reported by Dyment et al., in 2019. Onset of symptoms typically occur at birth, so early diagnosis of TRPM3-related neurodevelopmental disorder is crucial for timely intervention and management.
There are not many reports about TRMP3-NDD in the medical literature, but the signs and symptoms may include:
Based on current knowledge, TRPM3-related neurodevelopmental disorder does not typically limit lifespan. However, information about the long-term progression of behavioral or neurological symptoms remains limited.
TRPM3-NDD is caused by a change (variant) in the TRPM3 gene. Genes provide instructions for our cells to create proteins that play a variety of different roles in how our bodies grow and function. The TRPM3 gene provides the instructions for our bodies to make a protein called an ion channel that allows important molecules to enter nerve and brain cells (neurons). The TRPM3 channel allows calcium and other positively charged atoms called cations to enter the nerve cells. Calcium plays an important role in our brains by allowing neurons to send signals to each other. When calcium and other cations canโt enter cells through TRPM3 channels, it disrupts the way neurons in the brain and body communicate.
There is still a lot left to learn about what the TRPM3 gene does, but researchers are working to figure it out. Researchers used to think the gene was mostly involved in determining how the nerve cells in our bodies detect heat and pressure, but more recent research has shown that TRPM3 also plays an important role in the way the brain develops in the womb. TRPM3 channels are found in cells all over the body, so changes in the gene that affect these channels have a wide range of impacts that vary from person to person. When changes in the TRPM3 gene are passed down, they follow what is known as a dominant inheritance pattern, making TRPM3-NDD a dominant genetic disorder.
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 that is not inherited. Most changes in the TRPM3 gene are de novo. 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.
The number of people with TRPM3-NDD isnโt known but it is thought to be very rare. Between 2019 and 2023, there were 28 new reports of people with TRPM3-NDD. People of any age or ethnicity can be diagnosed with TRPM3-NDD.
Diagnosing TRPM3-related neurodevelopmental disorder starts with a careful clinical evaluation based on observed symptoms. These symptoms range widely and can vary in severity and pattern for each individual. Nevertheless, there is a common set of symptoms typically present in patients. These often manifest as developmental challenges where the child may reach milestones such as sitting, walking, or talking at a slower pace compared to their peers. Lower than usual muscle tone (hypotonia), which may influence movement, could be a feature. Some children may have visual challenges like uncoordinated eye movements (nystagmus) or a misalignment of the eyes (strabismus). Altered sensitivity to heat or pain, certain bone-related issues (musculoskeletal issues) and unique facial features like a wide forehead, deep-set eyes, and a downturned mouth have also been reported.
Doctors might use a special test called an electroencephalogram (EEG) to check if a person has seizures. This test tracks the electrical activity in the brain and can help figure out what type of seizures a person is having. Seizures could look like uncontrolled movements or moments where someone appears to โspace out.โ In addition, a magnetic resonance imaging (MRI) scan can be part of the diagnostic process. This provides a detailed picture of the brain which allows for identification of brain atrophy. Some individuals might show a decrease in the size of the cerebellum, a part of the brain responsible for coordinating movements and maintaining balance.
Diagnosis of TRPM3-NDD is confirmed with genetic testing that identifies a disease-causing variant in the TRPM3 gene.
Genetic testing often begins with a technique known as chromosomal microarray analysis (CMA). This test checks to see if there are any parts of the chromosomes โ the structures that hold our genes โ that have extra or missing pieces. These anomalies can often be associated with symptoms such as intellectual disability or global developmental delay. The diagnostic process may also use multi-gene panels, which examine several specific genes at once, including the TRPM3 gene. Lastly, more comprehensive genetic testing such as whole exome sequencing or whole genome sequencing may be conducted. These wider ranging tests check for changes in most, or even all, of a personโs DNA, which can be especially valuable when symptoms are consistent with many different conditions.
Genetic counseling is recommended as part of the testing process to help families understand the results and possible implications for the affected individual and their family.
Clinical Testing and Work-Up
Once the diagnosis is made, regular check-ups and evaluations are very important for managing the disorder and making sure the individual is developing and staying as healthy as possible. These follow-up visits might include:
There is no known cure for TRPM3-NDD. Treatment focuses on managing symptoms and supporting the individualโs development to improve quality of life.
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:
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For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Becker LL, Horn D, Boschann F, et al. Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep. Epilepsia. 2023;64(5):e61-e68. doi:10.1111/epi.17586
Dyment D, Lines M, Innes AM. TRPM3-Related Neurodevelopmental Disorder. 2023 Feb 23. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK589387/ Accessed July 22, 2024.
Burglen L, Van Hoeymissen E, Qebibo L, et al. Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders. eLife. 12:e81032.(2023) doi:10.7554/eLife.81032
Behrendt M. TRPM3 in the eye and in the nervous system โ from new findings to novel mechanisms. Biol Chem. 2022;403(8-9):859-868. doi:10.1515/hsz-2021-0403
Lines MA, Goldenberg P, Wong A, et al. Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia. Am J Med Genet A. 2022;188(6):1667-1675. doi:10.1002/ajmg.a.62673
Maia N, Nabais Sรก MJ, Melo-Pires M, De Brouwer APM, Jorge P. Intellectual disability genomics: current state, pitfalls and future challenges. BMC Genomics. 2021;22(1):909. doi:10.1186/s12864-021-08227-4
de Sainte Agathe JM, Van-Gils J, Lasseaux E, et al. Confirmation and expansion of the phenotype associated with the recurrent p.Val837 met variant in TRPM3. Eur J Med Genet. 2020;63(8):103942. doi:10.1016/j.ejmg.2020.103942
Dyment DA, Terhal PA, Rustad CF, et al. De novo substitutions of TRPM3 cause intellectual disability and epilepsy. Eur J Hum Genet. 2019;27(10):1611-1618. doi:10.1038/s41431-019-0462-x
Miclea D, Peca L, Cuzmici Z, Pop IV. Genetic testing in patients with global developmental delay/intellectual disabilities. A review. Med Pharm Rep. 2015;88(3):288-292. doi:10.15386/cjmed-461
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