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