TRPM3-related neurodevelopmental disorder

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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

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

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References

  1. 1 2 3 4 5 6 7 8 9 10 11 Dyment, David; Lines, Matthew; Innes, A Micheil (2023-02-23). "TRPM3-Related Neurodevelopmental Disorder". University of Washington, Seattle. PMID   36821706.{{cite journal}}: Cite journal requires |journal= (help)
  2. 1 2 3 4 5 6 7 8 9 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 . PMC   9886277 . PMID   36648066.
  3. 1 2 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. PMC   6777445 . PMID   31278393. S2CID   195804345.
  4. 1 2 3 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. S2CID   246749002.
  5. 1 2 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 . PMC   7255801 . PMID   32343227.
  6. 1 2 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. PMC   7253177 . 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. S2CID   257581570.
  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. PMC   5402713 . PMID   28106668.
  9. ↑ Gauthier, LW; Chatron, N; Cabet, S; Labalme, A; Carneiro, M; Poirot, I; Delvert, C; Gleizal, A; Lesca, G; Putoux, A (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 . PMC   8167971 . PMID   34074259.
  11. ↑ Sundaramurthi, JC; Bagley, AM; Blau, H; Carmody, L; Crandall, A; Danis, D; Gargano, M; Gustafson, AG; Raney, EM; Shingle, M; Davids, JR; Robinson, PN (8 September 2023). "De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy". Cold Spring Harbor Molecular Case Studies. 9 (4): mcs.a006293. doi: 10.1101/mcs.a006293 . PMC   10815282 . PMID   37684057. S2CID   261620692.
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