TRPM3-related neurodevelopmental disorder

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]

TRPM3-related neurodevelopmental disorder
SpecialtyNeurology

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][4] Epilepsy is reported in 50% of cases.[1]

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

Cause

TRPM3-related neurodevelopmental disorder is an autosomal dominant genetic disorder.[1] It is thought to be caused by a de novo missense mutation in the S4-S5 linker region or the extracellular S6 region of the TRPM3 gene.[3][5] 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 these mutations are gain-of-function mutations. The gain-of-function 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 also 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]

Diagnosis

Diagnosis is made through genetic testing usually an intellectual disability or epilepsy multigene panel that includes TRPM3 or whole exome sequencing.[1]

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]

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 28 reported cases of TRPM3-related neurodevelopmental disorder.[1] It is unknown what the prevalence of this disorder is worldwide.

Research

Little research has been conducted on TRPM3-related neurodevelopmental disorder to date. A single study points to the anti-convulsant drug primidone as an off label therapeutic.[6] Primidone is a known TRPM3 antagonist.[7]

Other Resources

TRPM3 Foundation

References
  1. Dyment, David; Lines, Matthew; Innes, A Micheil (2023-02-23). "TRPM3-Related Neurodevelopmental Disorder". PMID 36821706. {{cite journal}}: Cite journal requires |journal= (help)
  2. 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. 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. 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. 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. 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.
  7. 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.
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