Clinical characteristics.

TRPM3-related neurodevelopmental disorder (TRPM3-NDD) is characterized by congenital hypotonia, developmental delay affecting motor and speech/language skills, mild-to-severe intellectual disability, seizures, ophthalmologic manifestations including strabismus, nystagmus, and refractive errors, and musculoskeletal manifestations (e.g., talipes equinovarus, hip dysplasia, scoliosis). Reported seizure types include febrile, absence, generalized tonic-clonic, infantile spasms, and atonic drops. Cerebellar atrophy may be seen on brain MRI.

Diagnosis/testing.

The diagnosis of TRPM3-NDD is established in a proband with a heterozygous pathogenic variant in TRPM3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; physical medicine and therapies for ataxia as needed; anti-seizure medications for epilepsy as needed; standard treatments for ophthalmologic manifestations, musculoskeletal manifestations, and hearing impairment; social work support and care coordination as needed.

Surveillance: Monitor developmental progress, educational needs, changes in neurologic manifestations, growth, feeding, behavioral issues, and family needs at each visit; ophthalmologic and hearing evaluation annually.

Genetic counseling.

TRPM3-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Vertical transmission of a TRPM3 pathogenic variant from an affected father to an affected son has been reported in one family to date. Each child of an individual with TRPM3-NDD has a 50% chance of inheriting the pathogenic variant. Once the TRPM3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

TRPM3-related neurodevelopmental disorder (TRPM3-NDD) should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings

• Congenital hypotonia
• Developmental delay (DD)
• Intellectual disability (ID) of varying degrees of severity (mild to severe)
• Seizures (febrile, absence, generalized tonic-clonic, infantile spasms, atonic drops)
• Ophthalmologic findings (strabismus, nystagmus, refractive errors)
• Musculoskeletal features (talipes equinovarus, hip dysplasia and/or subluxation, scoliosis)

Imaging findings on brain MRI. Cerebellar atrophy

Family history is consistent with autosomal dominant inheritance. Absence of a known family history does not preclude the diagnosis, as vertical transmission of a TRPM3 pathogenic variant (from an affected father to an affected son) has only been reported in one family to date [Burglen et al 2023].

Establishing the Diagnosis

The diagnosis of TRPM3-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in TRPM3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variant. (2) Identification of a heterozygous TRPM3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with DD or an older individual with ID may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of TRPM3) is rarely useful and typically NOT recommended.

• An ID or epilepsy multigene panel that includes TRPM3 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of TRPM3-NDD, some panels for ID or epilepsy may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

TRPM3-related neurodevelopmental disorder (TRPM3-NDD) is characterized by congenital hypotonia, developmental delay, intellectual disability, seizures, and ophthalmologic and musculoskeletal manifestations. To date, 28 individuals have been reported in the literature with a pathogenic variant in TRPM3 [Dyment et al 2019, de Sainte Agathe et al 2020, Gauthier et al 2021, Kang et al 2021, Burglen et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). DD is near universal in those with a pathogenic variant in TRPM3.

Infant feeding difficulties have been reported (four individuals) that included dysphagia and gastroesophageal reflux.

A significant proportion of individuals assessed at age two years and older had not attained independent steps (11/26; this includes two adults older than age 18 years). For those that are able to walk independently, the average age of first steps is three years (range: age 1-5 years).

Speech is often severely affected and approximately half of affected individuals do not have single words (13/24). For those using at least single words, first words were used at an average age of three years (range: age 1-5 years). Some individuals can use signs or aids to help with communication, and a minority of individuals can speak in short sentences.

ID is also common. When the extent of disability was assessed and reported, the majority had ID in the severe or moderate-to-severe range. Moderate and mild ID was reported in 4/22 and 1/22 individuals, respectively. Two individuals were reported to have cognitive ability in the "low-normal" range.

Other neurologic features

• Congenital hypotonia is often the first manifestation observed in a neonate, though it is often considered mild. The results of a muscle biopsy have been reported in one individual with TRPM3-NDD and was described as nondiagnostic [Lines et al 2022].
• Increased pain tolerance has been reported, anecdotally, by the parents of individuals with TRPM3-NDD [Dyment et al 2019]. Similarly, some individuals have an increased tolerance to heat (e.g., a preference for hot baths and no physical reaction to burns).
• Athetoid or choreoathetoid movements have been reported in 4/28 (14%) affected individuals and typically occur in infancy and resolve spontaneously.
• Ataxia has been reported in four individuals with subsequent neuroimaging showing cerebellar atrophy.

Epilepsy. Several seizure types have been reported (febrile, absence, generalized tonic-clonic, tonic, electrical status epilepticus during slow-wave sleep, and infantile spasms) with no single type being characteristic for the disorder. When reported, seizure onset varied from age nine months to seven years (average: age 3.4 years). Most individuals required one anti-seizure medication or no medication to attain seizure control. To date, one individual has been reported with a history of infantile spasms and Lennox-Gastaut syndrome refractory to treatment [Kang et al 2021]. EEG abnormalities are seen in 17/26 individuals.

Neurobehavioral and psychiatric manifestations. Features of autism spectrum disorder have been reported in 8/28 individuals including stereotypies, poor eye contact, and sensitivities to touch and taste. Some children with TRPM3-NDD have also been reported to have frequent aggressive outbursts.

Ophthalmologic involvement. Strabismus is common and has been reported in 15/28 individuals. Nystagmus has been reported in a minority (6/28). Refractive errors are also rarely reported (2/28).

Musculoskeletal manifestations are common. Talipes equinovarus has been reported in 7/28 and hip dysplasia and/or hip subluxation in 7/28. Scoliosis has been reported in 6/28 individuals. Patellar dislocations have also been reported.

Growth. Height, weight, and head circumference are typically in the normal range. One child with height less than the 3rd centile was reported, although this person had a significant scoliosis impacting height [Lines et al 2022].

Neuroimaging (MRI). Cerebellar atrophy has been reported in 6/26 individuals. Nonspecific MRI findings such as mild cortical volume loss (6/26) and periventricular white matter hyperintensities (2/26) have also been reported. Heterotopias have been seen in one individual.

Other

• Hearing impairment. Only one individual has been reported to date with a unilateral hearing deficit [Dyment et al 2019].
• Facial features. Broad forehead, deep-set eyes, prominent nasal root, bulbous nasal tip, large ear lobes, short philtrum, and micrognathia comprise the facial gestalt of those with TRPM3-NDD. However, the features are relatively nonspecific and do not constitute a recognizable syndrome.

Prognosis. Based on current data, life span is not limited by this condition, as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance is complete though clinical expression is variable.

Prevalence

There is no known prevalence estimate to date; 28 individuals with TRPM3-NDD have been reported since 2019.

Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with TRPM3-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TRPM3-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, orthopedics, rehabilitation medicine, physical therapy, occupational therapy, speech-language pathology, ophthalmology, developmental pediatrics, and clinical genetics (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

TRPM3-related neurodevelopmental disorder (TRPM3-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most individuals reported to date with TRPM3-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo TRPM3 pathogenic variant.
• Vertical transmission of a TRPM3 pathogenic variant from an affected father to an affected son has been reported in one family to date [Burglen et al 2023].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. To date, this has not been reported.
    * A parent with somatic and germline mosaicism for a TRPM3 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the TRPM3 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the TRPM3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with TRPM3-NDD has a 50% chance of inheriting the TRPM3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRPM3 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the TRPM3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TRPM3 encodes a temperature- and neurosteroid-sensitive cation channel. The protein is comprised of six transmembrane domains, and the channel itself has a tetrameric structure with a central pore and four alternative pores. The channel has a voltage-sensing domain as well as the central pore domains. The gene is expressed in neuronal as well as non-neuronal tissues (kidney, eye, pancreas). Missense variants associated with TRPM3-related neurodevelopmental disorder (TRPM3-NDD) lead to increased basal activity of the cation channel, which results in an increased calcium concentration within the cell. In addition, TRPM3 pathogenic variants result in an enhanced response to heat and the neurosteroid pregnenolone sulfate [Van Hoeymissen et al 2020, Zhao et al 2020].

Mechanism of disease causation. Gain of function

TRPM3-specific laboratory technical considerations. There are more than 25 isoforms of TRPM3 due to alternative splicing [Oberwinkler & Philipp 2014].

Author Notes

Dr David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.

Dr Matthew Lines's research focus is on the clinical description and gene identification of rare metabolic diseases.

Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.

Drs Dyment and Innes are investigators with Care for Rare – SOLVE, a pan Canadian collaboration to investigate the causes of rare genetic diseases and improve the clinical care for patients and families affected by them.

Acknowledgments

Dr David Dyment would like to acknowledge the helpful discussion, expertise, and advice from Drs Joris Vriens and Thomas Voets of the University of Leuven, Leuven, Belgium.

There is an active Facebook family support group for families of children with TRPM3-related neurodevelopmental disorder.

Revision History

• 23 February 2023 (sw) Review posted live
• 2 November 2022 (dd) Original submission

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