Kohlschütter-Tönz syndrome

Kohlschütter-Tönz syndrome
Classification and external resources
Specialty neurology
ICD-10 G40.8
OMIM 226750
DiseasesDB 32947

Kohlschütter-Tönz syndrome (KTS), also called Amelo-cerebro-hypohidrotic syndrome[1] is a rare inherited syndrome characterized by epilepsy, dementia, intellectual disability, and yellow teeth caused by amelogenesis imperfecta (abnormal formation of tooth enamel).[2] It is a type A ectodermal dysplasia.[3]

It is autosomal recessive and symptoms appear in early childhood. The syndrome was first described in 1974 by Alfried Kohlschütter and colleagues.[4] Only 24 affected individuals are known as of 2012. The disease has not been connected to any other known epileptic syndromes.[5] Some but not all cases are associated with mutations in a gene called ROGDI.[6][7] Another gene that has been associated with this condition is the SCL13A5 gene [8]Diagnoses of this syndrome have occurred in Switzerland, Sicily, the Northern Israel Druze community as well as some other parts of Western Europe.[7]

Discovery

In 1974, Dr. Tönz brought an infant suffering from a fatal brain disease to the attention of Alfried Kohlschütter. The infant's symptoms included loss of motor skills, mental disability, epilepsy, and missing enamel. The infant also showed signs of myelin breakdown and did not produce the same amount of sweat as a normal person which resulted in the development of the term amelo-cerebro-hypohydrotic syndrome. A connection between the neurological and enamel symptoms is unknown.[9]

Diagnosis

Diagnosis occurs based on the two most common features of this syndrome: epilepsy and symmetrical enamel hypoplasia also known as Amelogenesis Imperfecta. Because the tooth discoloration caused by amelogensis imperfecta is often thought to be caused by environmental factors or other diseases, diagnosis of this syndrome is sometimes overlooked. The onset of symptoms can occur when the patient is between one month and four years old, contributing to the misconception that tooth discoloration is due to the environment.[2][7][10]

Symptoms

The only symptoms seen consistently in all 24 diagnosed cases are epilepsy, amelogenesis imperfecta in both primary and secondary teeth, and developmental delay. All symptoms experienced are experienced in varying degrees across each case.

There are some physical symptoms that have been associated with KTS. The most prominent symptom is amelogenesis imperfecta which gives the teeth a stained brown-yellow color. The enamel is thin, rough, and prone to crumbling. Two types of amelogenesis imperfecta (AI) have been seen in KTS patients. The first is Hypoplastic which is caused by the enamel being underdeveloped, and the second is hypo-calcified which causes the enamel to be soft and chalky. AI originated as a heterogeneous syndrome but has been observed as homogeneous in the case of KTS.[5][6][11] Other physical symptoms that some cases have presented with include broad thumbs and toes, microcephaly, coarse hair, mildly asymmetric skull, up slanting palpebral fissures which is where the outside corners of the eyes are higher than normal, and smooth philtrum which is where the upper lip does not have a dip in the center.[5][11]

KTS also presents itself with symptoms that affect the patient's ability to function. To varying degrees, patients either do not develop or have under developed language skills as well as under developed ambulance which is the ability to move around. Patients also present with global developmental delay. The severity of these symptoms is correlated with the intensity, frequency, and age of onset of the patient's epilepsy as well as their responsiveness to treatment for the epileptic attacks. In some severe cases, patients develop spastic tetraplegia which is the loss of function in all four limbs.[2][6][7]

The extreme variability of symptoms was well represented in one family with 5 affected children. The first child was in a vegetative state and died at age 2. The second child showed psychomotor developmental delay at 1 month old, and epilepsy unresponsive to treatment at 9 months old. This child was also nonverbal and non ambulant. The third child's epilepsy was responsive to treatment and was ambulant, but she had an intellectual disability and only slight verbal abilities. The fourth child demonstrated developmental delay at age 6 months and had epileptic attacks that were only partially responsive to treatment. This child was non verbal and awkwardly ambulant. The fifth child was ambulant, but nonverbal and had epilepsy that was partially responsive to treatment. This variation has been seen across other cases of KTS as well.[7]

Gene Mutations

The pedigrees of KTS patients suggest autosomal recessive inheritance. Although several mutations in the RODGI gene have been linked to the cause of KTS, the connection between the enamel defect and the altered brain function of patients has not yet been found.[2]

RODGI

The RODGI gene is located on chromosome 16 and contains 11 exons. The RODGI protein contains 287 amino acids and has a leucine zipper form. The function of this protein is not currently known. Expression studies have shown that the gene has high expression in the hippocampus. It is also highly expressed in other parts of the adult brain, spinal cord, peripheral blood, heart, and bone marrow. These studies showed low level of expression in the fetal brain which is consistent with the onset of symptoms occurring no earlier than one month after birth. Protein staining has provided evidence supporting that the RODGI protein may be a part of the nuclear envelope. Studies also suggest that RODGI may interact with DISC1 which is involved in neuronal proliferation and migration and differentiation of cortical interneurons.[7]

All RODGI mutations which include frameshift, nonsense, and splice site mutations cause premature mRNA degradation or protein structure alteration that results in the lack of function of the protein.[6]

Frameshift Mutations

One family had a frameshift mutation called c.366dupA. This duplication that caused the frameshift resulted in a premature stop codon in the RODGI gene after the 19th amino acid.[5]

Nonsense Mutation

A mutation called c.507delC which is the deletion of a cytosine at position 507 resulted in a nonsense mutation.[5] A nonsense mutation is a point mutation that results in a premature stop codon. Five affected families contained the nonsense mutation called c.268C>T where a thymine is in the place of a cytosine at position 268 on exon 5.[6]

Splice-Site Muation

There are three different splice-site mutations that have been identified in KTS patients. One is known as c.45+9_45+20del and prevents the recognition of the splice site at intron 1. This results in a frameshift in the gene causing a premature stop codon in exon 3.[5] Another is known as c.531+5G>C. This mutation destroys the splice acceptor and donor sites resulting in an in-frame deletion. The protein resulting from this gene has a highly altered structure and is not functional. The last is known as c.532=2A>T and occurs in intron 7. This also destroys the splice donor and acceptor sites due to the inclusion of 83 extra nucleotides before exon 8 in the mRNA. This mutation causes non-sense mediated decay of the mRNA.[6]

Related Gene Mutations

Due to the fact that not all 10 affected families were found to have a mutation in RODGI, and the noted variability between affected individuals, it is possible this syndrome is a contiguous gene syndrome. A contiguous gene syndrome occurs when multiple genes are affected by an alteration in a short chromosomal region.[9]

Amelogenesis Imperfecta is known to be caused by other genetic mutations. Two examples are in chromosome 4 open reading frame 26 (C4orf26) and in the SLC24A4 which both segregate in an autosomal recessive manner.[12][13]

Brain Imaging

Consistent abnormalities in brain imaging across all cases have not yet been discovered, but individual cases do show altered brain activity.

Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) in one family showed mild atrophy of the cranial vermis as well as a small pons.[5] Different types of atrophy including cerebellar in four individuals and basal ganglia has been evident through MRIs.[2][7]

Electroencephalography

Electroencephalography (EEG) in one patient showed epileptiformic activities in the frontal and frontotemporal areas as well as increased spike waves while the patient was sleeping.[5] Another patient's EEG showed occipital rhythms in background activity that was abnormal, focal discharges over the temporal lobe, and multifocial epileptiform activity.[11] Several patients showed a loss of normal background activity.[2]

Treatments

Most patients suffering from KTS have epilepsy that is resistant to anti-epileptic agents. Some patients showed a partial response to treatment, but very few were able to stop their epilepsy through treatment.[5] One case was responsive to treatment using Phenobartbital and vigabatrin which are both anti-epileptic agents.[11] Spasticity can be treated with baclofen, but not all patients are responsive to the treatment.[5]

References

  1. ↑ "Amelo-cerebro-hypohidrotic syndrome". Orphanet. September 2006. Retrieved 20 November 2012.
  2. 1 2 3 4 5 6 Schossig, Anna; Nicole I. Wolf; Ines Kapferer; Alfried Kohlschütter; Johannes Zschocke (May 2012). "Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter–Tönz syndrome". European Journal of Medical Genetics. Elsevier. 55 (5): 319–322. doi:10.1016/j.ejmg.2012.02.008. ISSN 1769-7212. PMID 22522085.
  3. ↑ Visinoni, Átila F.; Toni Lisboa-Costa; Nina A.B. Pagnan; Eleidi A. Chautard-Freire-Maia (13 August 2009). "Ectodermal dysplasias: Clinical and molecular review". American Journal of Medical Genetics. Wiley. 149A (9): 1980–2002. doi:10.1002/ajmg.a.32864. ISSN 1552-4833. PMID 19681154.
  4. ↑ Kohlschütter, A; Chappuis D; Meier C; Tönz O; Vassella F; Herschkowitz N (October 1974). "Familial epilepsy and yellow teeth--a disease of the CNS associated with enamel hypoplasia". Helv Paediatr Acta. 29 (4): 283–94. PMID 4372200.
  5. 1 2 3 4 5 6 7 8 9 10 Tucci, Arianna; Kara E, Schossig A, Wolf NI, Plagnol V, Fawcett K, Paisán-Ruiz C, Moore M, Hernandez D, Musumeci S, Tennison M, Hennekam R, Palmeri S, Malandrini A, Raskin S, Donnai D, Hennig C, Tzschach A, Hordijk R, Bast T, Wimmer K, Lo CN, Shorvon S, Mefford H, Eichler EE, Hall R, Hayes I, Hardy J, Singleton A, Zschocke J, Houlden H (19 October 2012). "Kohlschütter-Tönz Syndrome: Mutations in ROGDI and Evidence of Genetic Heterogeneity". Human Mutation. 34 (2): 296–300. doi:10.1002/humu.22241. ISSN 1098-1004. PMID 23086778. Cite uses deprecated parameter |coauthors= (help)
  6. 1 2 3 4 5 6 Schossig, Anna; Nicole I. Wolf, Christine Fischer, Maria Fischer, Gernot Stocker, Stephan Pabinger, Andreas Dander, Bernhard Steiner, Otmar Tönz, Dieter Kotzot, Edda Haberlandt, Albert Amberger, Barbara Burwinkel, Katharina Wimmer, Christine Fauth, Caspar Grond-Ginsbach, Martin J. Koch, Annette Deichmann, Christof von Kalle, Claus R. Bartram, Alfried Kohlschütter, Zlatko Trajanoski, and Johannes Zschocke (6 April 2012). "Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome". American Journal of Human Genetics. The American Society of Human Genetics/Elsevier. 90 (4): 701–707. doi:10.1016/j.ajhg.2012.02.012. ISSN 0002-9297. PMC 3322220Freely accessible. PMID 22424600. Cite uses deprecated parameter |coauthors= (help)
  7. 1 2 3 4 5 6 7 Mory, A; Dagan E; Illi B; Duquesnoy P; Mordechai S; Shahor I; Romani S; Hawash-Moustafa N; Mandel H; Valente EM; Amselem S; Gershoni-Baruch R (6 April 2012). "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome". American Journal of Human Genetics. The American Society of Human Genetics/Elsevier. 90 (4): 708–14. doi:10.1016/j.ajhg.2012.03.005. ISSN 0002-9297. PMC 3322231Freely accessible. PMID 22482807.
  8. ↑ doi: 10.1093/brain/awv263
  9. 1 2 Kohlschütter, A., Chappuis, D., Meier, C., Tönz, O., Vassella, F., & Herschkowitz, N. (1974). Familial epilepsy and yellow teeth--a disease of the CNS associated with enamel hypoplasia. Helv Paediatr Acta, 29(4), 283-294.
  10. ↑ Bailleul-Forestier, I., Berdal, A., Vinckier, F., de Ravel, T., Fryns, J., & Verloes, A. (2008). The genetic basis of inherited anomalies of the teeth. Part 2: Syndromes with significant dental involvement. European Journal of Medical Genetics, 51(5), 383-408. doi:10.1016/j.ejmg.2008.05.003
  11. 1 2 3 4 Haberlandt, E., Svejda, C., Felber, S., Baumgartner, S., Gunther, B., Utermann, G., & Kotzot, D. (2006). Yellow teeth, seizures, and mental retardation: A less severe case of Kohlschutter-Tonz syndrome. American Journal of Medical Genetics Part A, 140A(3), 281-283. doi:10.1002/ajmg.a.31071
  12. ↑ Parry D.; Brookes S.; Logan C.; Poulter J.; El-Sayed W.; Al-Bahlani S.; Mighell A. (2012). "Mutations in C4orf26, Encoding a Peptide with In Vitro Hydroxyapatite Crystal Nucleation and Growth Activity, Cause Amelogenesis Imperfecta". American Journal of Human Genetics. 91 (3): 565–571. doi:10.1016/j.ajhg.2012.07.020. PMID 22901946.
  13. ↑ Parry D.; Poulter J.; Logan C.; Brookes S.; Jafri H.; Ferguson C.; Mighell A. (2013). "Identification of Mutations in SLC24A4, Encoding a Potassium-Dependent Sodium/Calcium Exchanger, as a Cause of Amelogenesis Imperfecta". American Journal of Human Genetics. 92 (2): 307–312. doi:10.1016/j.ajhg.2013.01.003. PMID 23375655.

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