Last updated:
4/2/2024
Years published: 2024
NORD gratefully acknowledges Kate Richardson, MS, CGC and Hope Northrup, MD, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital, Afif Ben-Mahmoud, PhD, Neurological Disorder Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar and Hyung-Goo Kim, PhD, Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, for the preparation of this report.
Summary
TLK2-related neurodevelopmental disorder is a genetic disorder that primarily causes differences in development. There are also other medical problems in people with this disorder including growth, behavior, eye and gastrointestinal problems. This disorder is caused by genetic changes (disease-causing variants) in the TLK2 gene. TLK2-related neurodevelopmental disorder has been reported to have variable expressivity, meaning there is a range of symptoms that can occur in people affected with this condition.
The average age of onset for many symptoms begins in childhood. Symptoms include developmental delay, intellectual disability, autism, speech and language delay, behavioral problems, facial differences, small head size (microcephaly), gastrointestinal problems (constipation and diarrhea) low weight and short height. Additional medical problems can include feeding difficulties, lazy eye (strabismus), vision loss, seizures (epilepsy), curvature of the spine (scoliosis) and joint hypermobility.
Introduction
TLK2-related neurodevelopmental disorder was first defined in 2018. As of 2024, 42 patients have been described in the medical literature.
People with TLK2-related neurodevelopmental disorder have a range of neurodevelopmental features and other symptoms. Neurodevelopmental features include developmental delay, intellectual disability, learning difficulties, autism, hyperactivity, inattention, anxiety, social difficulties and obsessive-compulsive disorder. Rarely, patients have normal intelligence. Other features can include small head size (microcephaly), seizures (epilepsy), weak muscles (hypotonia) and differences in brain structure or shape (brain malformations). Other symptoms include issues with the gastrointestinal system, including diarrhea, feeding difficulties in infancy and constipation. In terms of growth and bones, individuals with TLK2-related neurodevelopmental disorder can have low body weight, obesity, short stature, curvature in the spine (scoliosis), flat feet (pes planus), extremely flexible joints (hypermobility) and tightening of muscles or joints (contractures). Other medical problems can include recurrent ear infections (otitis media), lazy eye (strabismus), vision abnormalities and extra hair (hypertrichosis).
The most common facial features are a limited ability to open eyes widely (blepharophimosis), a broad tip to the nose, eyes that are set farther apart (hypertelorism), thin upper lip, eyes that slant upwards, extra skin fold near the inner eye (epicanthal folds), pointed chin, small or malformed ears and a long and/or asymmetric face.
TLK2-related neurodevelopmental disorder is caused by genetic changes (disease-causing variants) in the TLK2 (tousled-like kinase 2) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a disease-causing variant in a gene occurs, not enough protein is made, or the protein does not work properly. Depending on the function of the protein, this can affect different parts of the body.
The TLK2 gene creates a protein called an enzyme named tousled-like kinase 2 (TLK2). This enzyme is important for fixing mistakes in genetic information (DNA) and making sure cells divide correctly. When not enough TLK2 is produced or it doesn’t work properly, this can affect how genes are turned on and off and can lead to health problems, especially related to the brain. TLK2 also helps with putting together and taking apart the structures that hold our DNA, which affects how our genes work. The TLK2 enzyme is most active when cells are copying DNA before dividing. Variants in the TLK2 gene can cause problems in how cells divide and repair themselves, resulting in the signs and symptoms of TLK2-related neurodevelopmental disorder.
TLK2-related neurodevelopmental disorder follows an autosomal dominant pattern of inheritance. 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. Most of the TLK2 gene variants associated with this condition have been de novo. Rarely, a TLK2 gene variant has been noted to be inherited from a parent. 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.
As of 2024, 42 people with TLK2-related neurodevelopmental disorder have been reported in the medical literature. The number of people affected by this disorder is unknown because rare disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population. With available information currently, males and females as well as all ethnicities are affected equally.
A diagnosis of TLK2-related neurodevelopmental disorder is based on molecular genetic testing that shows a disease-causing (pathogenic) variant in the TLK2 gene. This condition cannot be diagnosed based on signs and symptoms.
Treatment is based on the medical problems that are present in an affected person. A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), speech pathologists, physical therapists, gastroenterologists (stomach doctors) and other healthcare professionals can 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 individuals.
Management can include:
Information on current clinical trials is posted on the Internet at www.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:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Simon B, Lou HJ, Huet-Calderwood C, et al. Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry. Nat Commun. 2022;13(1):749. Published 2022 Feb 8. doi:10.1038/s41467-022-28427-0
Woods E, Spiller M, Balasubramanian M. Report of two children with global developmental delay in association with de novo TLK2 variant and literature review. Am J Med Genet A. 2022;188(3):931-940. doi:10.1002/ajmg.a.62580https://doi.org/10.1002/ajmg.a.62580
Töpf A, Oktay Y, Balaraju S, et al. Severe neurodevelopmental disease caused by a homozygous TLK2 variant. Eur J Hum Genet. 2020;28(3):383-387. doi:10.1038/s41431-019-0519-x https://doi.org/10.1038/s41431-019-0519-x
Segura-Bayona S, Stracker TH. The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease. Cell Mol Life Sci. 2019;76(19):3827-3841. doi:10.1007/s00018-019-03208-z
Reijnders MRF, Miller KA, Alvi M, et al. De novo and inherited loss-of-function variants in TLK2: clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder. Am J Hum Genet. 2018;102(6):1195-1203. doi:10.1016/j.ajhg.2018.04.014 https://doi.org/10.1016/j.ajhg.2018.04.014
Lelieveld SH, Reijnders MR, Pfundt R, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19(9):1194-1196. doi:10.1038/nn.4352https://doi.org/10.1038/nn.4352
Klimovskaia IM, Young C, Strømme CB, et al. Tousled-like kinases phosphorylate Asf1 to promote histone supply during DNA replication. Nat Commun. 2014;5:3394. Published 2014 Mar 6. doi:10.1038/ncomms4394
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