TRPM3-related neurodevelopmental disorder

Short description: Rare disease

TRPM3-related neurodevelopmental disorder

Specialty| Neurology

TRPM3-related neurodevelopmental disorder[1] is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system.[2] The broad phenotype includes global developmental delay, intellectual disability, epilepsy, musculoskeletal anomalies, altered pain perception, ataxia, hypotonia, nystagmus, and cerebellar atrophy.[2][3][4]

## Contents

* 1 Signs and Symptoms
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 Epidemiology
* 7 Other Resources
* 8 References

## Signs and Symptoms

The earliest sign for TRPM3-related neurodevelopmental disorder is usually congenital hypotonia. Infant feeding issues including dysphagia and gastroesophageal reflux are also reported.[1] Global developmental delay is nearly always present along with mild-to-severe intellectual disability.[1][2][4] Epilepsy is reported in 50% of cases.[1][2]

Other signs of TRPM3-related neurodevelopmental disorder are dysmorphic facial features, scoliosis, hip dysplasia, exotropia, strabismus, nystagmus, ataxia, and altered pain perception.[1][2]

## Cause

TRPM3-related neurodevelopmental disorder is an autosomal dominant genetic disorder.[1] It is caused by missense mutations in the TRPM3 gene.[1][2] Since the general population has numerous truncating variants and microdeletions throughout TRPM3, the underlying mechanism for neurodevelopmental disorder is not haploinsufficiency.[3]

Research has shown that the disease-associated mutations lead to a gain-of-function. The mutations produce increased basal activity of the TRPM3 ion channel as well as increased response to chemical and noxious heat stimuli. The gain-of-function results in increased intracellular Ca2+. It is possible that this increased channel activity and/or Ca2+ induced nerve damage could be the underlying mechanism of the disease.[5][6][2]

## Diagnosis

Diagnosis is made through genetic testing using an intellectual disability or epilepsy multigene panel that includes TRPM3 or whole exome sequencing.[1] Following identification of a mutation in the TRPM3 gene, alterations in channel activity are evaluated using electrophysiological assays and calcium imaging [2][6][5]

## Treatment

There is currently no known cure or treatment for TRPM3-related neurodevelopmental disorder. Treatment for individual manifestations of symptoms may follow standard of care (anti-epileptic medication for seizures, physical therapy, occupational therapy, speech therapy, etc).[1]

A single study points to the anti-convulsant drug primidone as an off label therapeutic.[7] Primidone is a known TRPM3 antagonist.[8]

## Prognosis

Life span is apparently not impacted by TRPM3-related neurodevelopmental disorder. Not enough data currently exists to understand the disease progression.[1]

## Epidemiology

There are currently >30 reported cases of TRPM3-related neurodevelopmental disorder.[1][4][2] [9] [10][11] It is unknown what the prevalence of this disorder is worldwide.

## Other Resources

TRPM3 Foundation

## References

1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Dyment, David; Lines, Matthew; Innes, A Micheil (2023-02-23). TRPM3-Related Neurodevelopmental Disorder. University of Washington, Seattle. PMID 36821706. https://www.ncbi.nlm.nih.gov/books/NBK589387/.
2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Burglen, Lydie; Van Hoeymissen, Evelien; Qebibo, Leila et al. (2023). "Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders". eLife 12. doi:10.7554/elife.81032. PMID 36648066.
3. ↑ 3.0 3.1 Dyment, David A.; Terhal, Paulien A.; Rustad, Cecilie F. et al. (2019). "De novo substitutions of TRPM3 cause intellectual disability and epilepsy". European Journal of Human Genetics 27 (10): 1611–1618. doi:10.1038/s41431-019-0462-x. PMID 31278393.
4. ↑ 4.0 4.1 4.2 Lines, Matthew A.; Goldenberg, Paula; Wong, Ashley et al. (2022). "Phenotypic spectrum of the recurrent TRPM3 p.( Val837Met ) substitution in seven individuals with global developmental delay and hypotonia". American Journal of Medical Genetics Part A 188 (6): 1667–1675. doi:10.1002/ajmg.a.62673. PMID 35146895. https://portal.findresearcher.sdu.dk/da/publications/29c6a551-d9c8-4cf5-a411-163a5cad88c4.
5. ↑ 5.0 5.1 Zhao, Siyuan; Yudin, Yevgen; Rohacs, Tibor (2020). "Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms". eLife 9. doi:10.7554/elife.55634. PMID 32343227.
6. ↑ 6.0 6.1 Van Hoeymissen, Evelien; Held, Katharina; Nogueira Freitas, Ana Cristina; Janssens, Annelies; Voets, Thomas; Vriens, Joris (19 May 2020). "Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy". eLife 9: e57190. doi:10.7554/eLife.57190. ISSN 2050-084X. PMID 32427099.
7. ↑ Becker, Lena‐Luise; Horn, Denise; Boschann, Felix et al. (2023). "Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep". Epilepsia 64 (5): e61–e68. doi:10.1111/epi.17586. PMID 36929095.
8. ↑ Krügel, Ute; Straub, Isabelle; Beckmann, Holger; Schaefer, Michael (2017). "Primidone inhibits TRPM3 and attenuates thermal nociception in vivo". Pain 158 (5): 856–867. doi:10.1097/j.pain.0000000000000846. PMID 28106668.
9. ↑ Gauthier, LW; Chatron, N; Cabet, S; Labalme, A; Carneiro, M; Poirot, I; Delvert, C; Gleizal, A et al. (November 2021). "Description of a novel patient with the TRPM3 recurrent p.Val837Met variant.". European Journal of Medical Genetics 64 (11): 104320. doi:10.1016/j.ejmg.2021.104320. PMID 34438093.
10. ↑ Kang, Q; Yang, L; Liao, H; Yang, S; Kuang, X; Ning, Z; Liao, C; Chen, B (1 June 2021). "A Chinese patient with developmental and epileptic encephalopathies (DEE) carrying a TRPM3 gene mutation: a paediatric case report.". BMC Pediatrics 21 (1): 256. doi:10.1186/s12887-021-02719-8. PMID 34074259.
11. ↑ Sundaramurthi, JC; Bagley, AM; Blau, H; Carmody, L; Crandall, A; Danis, D; Gargano, M; Gustafson, AG et al. (8 September 2023). "De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy.". Cold Spring Harbor Molecular Case Studies: mcs.a006293. doi:10.1101/mcs.a006293. PMID 37684057.

Classification|

* OMIM: 620224

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External resources|

* GeneReviews: TRPM3-Related Neurodevelopmental Disorder

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