CLTC-Related Intellectual Disability

Disease Overview

Summary

CLTC-related intellectual disability (CRID) is a genetic condition characterized by developmental delays and mild-to-severe intellectual disability. There is a wide spectrum of severity. In addition to developmental delays and intellectual disability, affected individuals may also have behavioral problems, epilepsy, low muscle tone (hypotonia), walking problems (spastic or ataxic gait), or abnormal findings in their brain, eyes, or gastrointestinal tract. Some people with CRID may have an unusually small head size (microcephaly) and distinctive facial features.^{1, 2}

There is no cure for CRID. Treatment is based on what symptoms the affected person has. Physical, speech and occupational therapies are helpful for children with developmental delays. Affected people should be assessed by neurology, ophthalmology, gastroenterology (GI) and genetics specialists.

Introduction

CRID was first described in 2016.¹ It is a rare condition that has been described in approximately 30 people in the medical literature as of the end of 2024.^1,2 More information may become available in the future about CRID and how this condition may present.

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Synonyms

• intellectual developmental disorder, autosomal dominant 56
• autosomal dominant intellectual developmental disorder 56
• CLTC-related ID
• CLTC-related disorders

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Signs & Symptoms

CRID has a wide spectrum of severity, with some people having only mild intellectual disability with or without behavioral problems and others having severe intellectual disability and epilepsy that does not improve with medication. Most people present with global developmental delay and severe hypotonia.^{1,2 3}

• Intellectual disability: Most people with CRID have mild-to-severe intellectual disability.²
• Developmental delays: This means that the time a child reaches their developmental milestones is later than what would be expected for the average child their age. This can include delays in rolling over, walking and talking. Most children with CRID have developmental delays in speech and/or motor (movement) skills.²
• Behavioral symptoms: These can include autism and attention-deficit/hyperactivity disorder (ADHD).²
• Epilepsy: Some people with CRID have a seizure disorder (epilepsy). These seizures can begin between the newborn period and adulthood and respond well to anti-epilepsy drugs.²
• Hypotonia: Many affected babies have low muscle tone (hypotonia).²
• Ataxia: Some people have problems with coordination and balance (ataxia).²
• Walking difficulties in which a person appears to have one stiff leg.²
• Parkinsonism: This is a group of movement disorders characterized by bradykinesia, rigidity and rest tremor.^4,5
  • Onset can vary with some individuals presenting with early-onset parkinsonism and others presenting late in life.^4,5
• Abnormal brain findings on MRI: Magnetic resonance imaging (MRI) is noninvasive medical imaging that creates detailed images of the brain using a large magnet and radio waves. In many people with CRID, an MRI shows structural abnormalities in the brain such as:²
  • Corpus callosum hypoplasia: The corpus callosum is the band of nerve fibers that connects the left and right sides of the brain. Hypoplasia means it is underdeveloped or smaller than normal.
  • Asymmetric or dilated ventricles: The ventricles are fluid-filled spaces in the brain. They may appear enlarged or uneven in size.
  • Dilated Virchow–Robin spaces: These are small spaces around blood vessels in the brain. When they are dilated, it means they are larger than normal which can be a sign of abnormal brain development.
  • Frontal atrophy: The frontal lobe, the part of the brain involved in thinking, behavior and movement, may show atrophy, meaning it is smaller or has lost tissue.
  • Pontocerebellar atrophy: The pons and cerebellum are areas deep in the brain that help control movement and coordination. Atrophy here also means these areas are underdeveloped or have lost volume.
  • Abnormal myelination: Myelin is the protective coating around nerve fibers that helps brain signals travel quickly. Abnormal myelination means this coating didn’t develop properly which can affect brain function.
• Microcephaly: Some people with CRID have a small head size (microcephaly).²
• Vision problems: Some people with CRID have differences in how the eyes developed or how they function (ophthalmologic findings) which can lead to strabismus (one/both eyes are not aligned and deviate inward or outward, sometimes called a “lazy eye”); some people have other vision problems and need to wear glasses.²
• Gastrointestinal anomalies: These may include feeding difficulties and/or gastrointestinal reflux (spitting up or heartburn), difficulty shallowing (achalasia), and constipation and blockage of the small bowel (ileal atresia).²
• Distinctive facial features: These features may include a long face, high, narrow
• forehead, wide nasal bridge, eyes that are spaced farther apart, large and protruding ears, deep groove between the nose and upper lip, wide mouth, a thicker lower lip and large upper front teeth.²

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Causes

CRID is caused by changes (variants) in the gene CLTC. This gene is involved in the movement of molecules within cells and helps the cells in the brain (neurons) communicate. It is also involved in cell division. Disease causing (pathogenic) variants in CLTC keep it from doing these jobs in the brain and the rest of the body.⁶

The type and location of the gene variant may affect how severe the condition (genotype-phenotype correlation) is:³

• Missense variants (where just one part of the gene is changed) and in-frame deletions (where a small section is removed without changing the whole structure) usually cause more severe symptoms.
• Loss-of-function (LOF) variants such as nonsense, frameshift, or splice-site variants tend to cause milder symptoms because they reduce the gene’s activity rather than disrupting its structure.

CRID follows autosomal dominant inheritance.^{1, 2} Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Most people with CRID have a de novo variant that is not present in either parent.^{1, 2} In some people, this condition can be inherited from an affected parent. If parents of a person with CRID are tested and found not to carry a pathogenic variant in CLTC, the chance of having another child with CRID is estimated to be around 1%.

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Affected populations

CRID is extremely rare. It has been described in approximately 30 people in the medical literature as of the end of 2024.^{1, 2} Males and females have been diagnosed with CRID. Onset is at birth but may not be noted until developmental milestones are missed or seizures begin. The number of people affected by this disorder is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population.

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Disorders with Similar Symptoms

There are many neurodevelopmental disorders associated with different genes that can cause signs and symptoms similar to those seen in people with CRID. Variants in the TBR1 gene (intellectual developmental disorder with autism and speech delay), CNOT3 gene (intellectual developmental disorder with speech delay, autism, and dysmorphic facies) and the JARID2 gene (developmental delay with variable intellectual disability and dysmorphic facies) are just a few examples.

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Diagnosis

A diagnosis of CRID is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the CLTC gene. Because the signs and symptoms are not specific, a clinical diagnosis cannot be used for this disorder.

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Standard Therapies

Treatment is based on the medical problems that are present in an affected person. There is currently no cure for CRID, so patients are treated for their specific symptoms. A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), gastroenterologists, ophthalmologists, speech therapists, physical therapists, occupational therapists and other healthcare professionals may be involved in care.

Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

Due to the rarity of the disease, there are no treatment trials that have been tested in a large group of patients. There are no standardized treatment protocols or guidelines for affected people.

Management can include:

• Speech and language therapy
• Occupational therapy
• Physical therapy
• Neurodevelopmental assessments to assess academic ability
• Anti-seizure or anti-spasm medications.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Itai T, Miyatake S, Tsuchida N, et al. Novel CLTC variants cause new brain and kidney phenotypes. J Hum Genet. 2022;67(1):1-7. doi:10.1038/s10038-021-00957-3 https://doi.org/10.1038/s10038-021-00957-3
2. Nabais Sá MJ, Venselaar H, Wiel L, et al. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Genet Med. 2020;22(4):797-802. doi:10.1038/s41436-019-0703-y. https://doi.org/10.1038/s41436-019-0703-y
3. Pannone L, Muto V, Nardecchia F, et al. The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans. Front Mol Neurosci. 2023;16:1170061. Published 2023 May 31. doi:10.3389/fnmol.2023.1170061
4. Usnich T, Becker LF, Nagel I, Bäumer T, Münchau A. Partially Levodopa-Responsive Parkinsonism in a Carrier of a Novel Pathogenic CLTC Variant. Mov Disord Clin Pract. 2024;11(6):749-750. doi:10.1002/mdc3.14037
5. Nardecchia F, Bove R, Pollini L, et al. Improvement of Movement Disorder and Neurodevelopment under Selegiline in a CLTC-Deficient Patient. Mov Disord Clin Pract. 2023;10(9):1430-1432. Published 2023 Jul 19. doi:10.1002/mdc3.13834
6. Chahrour MH, Yu TW, Lim ET, et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 2012;8(4):e1002635. doi:10.1371/journal.pgen.1002635

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