American Journal of Medical Genetics 46453-454 (1993)

Kohlschütter-Tonz Syndrome: Epilepsy, Dementia, and Amelogenesis Imperfecta

~~ ~~

Joel Zlotogora, Anna Fuks, Zvi Borochowitz, and Yoram Tal Department of Human Genetics (J.Z.) and Department of Pediatric Dentistry (AE.), Hadassah Medical Center, Hebrew Uniuersity Jerusalem; The Simon Winter Institute of Human Genetics (Z.B.) and the Department of Pediatrics (Y.T.), Bnai Zion Medical Center, Technion-Faculty of Medicine, Haifa, Israel

Kohlschütter-Tonz syndrome is a central ner- vous system (CNS) degenerative disease with convulsions and mental regression in which the affected children present with yellow teeth due to defective enamel. We present a family in which 2 affected children (a boy and a girl) were born to consanguineous parents. This report confirms the autosomal recessive inheritance of the disorder. The combination of a CNS and an enamel defect may represent pleiotropy o r a contiguous gene syndrome. O 1993 Wiley-Liss, Inc.

KEY WORDS: amelogenesis imperfecta, con- vulsions, degenerative disease of the brain, Kohlschütter- Tonz syndrome

INTRODUCTION Kohlschütter-Tonz syndrome (McK 226750) is a CNS

degenerative disease with convulsions and mental re- gression in which the affected children present with defective enamel and yellow teeth. Up to now, the syn- drome was reported in 2 families [Christodoulou et al., 1988; Kohlschütter et al., 19741 and was further diag- nosed in another two families [Witkop and Sauk, 19761. Here we report on 2 affected children, and offer further delineation of this syndrome, confirming its autosomal recessive inheritance.

CLINICAL REPORT The parents of the affected children are Druze first

cousins-once removed. They have 4 children; the first 2 are healthy. The two younger ones are described below.

L.E., a boy, was born after a normal pregnancy. Motor development was retarded: he sat at 12 months and walked at 2 years. He had a first convulsion during an

Received for publication September 22, 1992; revision received January 18, 1993.

Address reprint requests to Joel Zlotogora M.D., Department of Human Genetics, Hadassah Medical Center, P.O. Box 12000, Jeru- salem il 91120, Israel.

O 1993 Wiley-Liss, Inc.

episode of fever at 3 years. Thereafter he had another short convulsion at 6 years. At that time, physical find- ings and sweating were normal. The gait was spastic, the deep tendon reflexes were brisk and muscle tone was mildly increased. The teeth were yellow and dental ex- amination diagnosed amelogenesis imperfecta of the hy- pocalcified type. At 6 years the child was mentally re- tarded, functioning at the leve1 of 3 years.

SE., a girl, was also born after a normal pregnancy. After birth, congenital horizontal nystagmus was noted. Her first convulsion occurred at 12 months and there- after she had many tonic-clonic convulsions in spite of the anticonvulsive treatment. The convulsions always appeared during an episode of fever. At 16 months, she was only able to sit with help, she knew 2-3 words. Her head circumference was 44.5 cm (3rd centile); the physi- cal and neurological findings were normal; sweating was normal. The teeth were yellow and amelogenesis imperfecta was diagnosed.

Results of laboratory investigations performed in both children were normal and included blood and CSF routine biochemistry, amino acids in blood and urine, and organic acids in urine. Lysosomal enzymes includ- ing aryl sulfatase A, galactocerebrosidase, beta galac- tosidase, and beta hexosaminidase levels were al1 nor- mal. The EEG showed a diffusely slow pattern in both children.

The girl had a normal CT scan of the brain; her elec- troretinogram was almost extinct and the latency on the visual-evoked response was prolonged.

DISCUSSION Kohlschütter-Tonz syndrome (McKusick 226750) is

an inherited disorder dominated by involvement of the nervous system with convulsions, progressive spasticity and progressive mental deterioration (dementia). The characteristic finding is the yellowness of the teeth caused by a type of amelogenesis imperfecta. Both chil- dren reported here have the classical dental and neuro- logical manifestations. It is not clear whether the dis- case is progressive in these children. However, a t the age of 6 years, the older child had brisk reflexes and spas- ticity which were not found in the younger child and it may be that these signs appear only later in the course of the disease. Both children appear to function in a simi-

454 Zlotogora et al.

lar range of mental deficiency; it does not seem that there was any mental regression in the boy.

Amelogenesis imperfecta is a defect in enamel and occurs as an isolated trait or as various mendelian traits [Witkop and Sauk, 19761. The most common type is autosomal dominant, but X-linked and autosomal reces- sive forms are also well known. Defects of enamel as the only dental abnormality, are part of different inherited syndromes such as ectodermal dysplasia, tuberous scle- rosis, epidermolysis bullosa, the mucopolysaccha- ridoses, oculodento-osseous dysplasia [Witkop and Sauk, 19761. In al1 these syndromes, the enamel defect may be explained by a basic disturbance which affects many systems of the same origin, as in ectodermal dys- plasia, or because of an abnormal basic component of many tissues, such as in the mucopolysaccharidoses. In Kohlschütter-Tonz syndrome, the enamel defect present is the hypoplastic type and is a very characteristic find- ing in the syndrome. It may be that the CNS and enamel defects represent pleiotrophy. Another possibility is that the dental and CNS defects represent a contiguous gene syndrome. Contiguous gene syndromes have been demonstrated to exist in the last few years and some examples are Miller-Diecker syndrome or DiGeorge anomaly; adrenal hypoplasia with glycerokinase defi- ciency or Duchenne muscular dystrophy associated with chronic granulomatous disease and ornithine transcar- bamylase deficiency [Ledbetter and Cavenee, 19891.

Kohlschütter-Tonz syndrome was first reported in a family from Switzerland with 5 affected boys [Kohl- schütter et al., 19741. Later, the same group observed the syndrome in two other families, one with 1 affected boy and the other with 2 affected boys [Witkop and Sauk, 19761. Therefore, X-linked inheritance seemed probable. Another family was reported in which 7 chil-

dren were affected, 5 boys and 2 girls [Christodoulou et al., 19881. The possibility of autosomal recessive inheri- tance was then suggested, supported by the fact that both parents of the affected children (although non- consanguineous), originated from the same small town of approximately 5,000 inhabitants in Sicily. The pres- ent report confirms the existence of an autosomal reces- sive inheritance of the syndrome. The relative abun- dance of males affected with the syndrome seems to be due to the excess of males healthy or affected in the first family reported (10 males, 1 female). Another possi- bility is that an X-linked form of the disease exists, particularly since a gene for normal enamel formation is found on the X chromosome.

There does not seem to be a difference in the severity of the disease between the males and the females: in both families, the one reported by Christodoulou et al. [19881 and in the present report, the affected females have a disease very similar to the one in the affected males.

REFERENCES Christodoulou J, Hall RK, Menahem S, Hopkins IJ, Rogers JG (1988):

A syndrome of epilepsy, dementia and amelogenesis imperfecta: genetic and clinical features. J Med Genet 25827-830.

Kohlschütter A, Chappuis D, Meier C, Tonz O, Vassella F, Hersch- kowitz (1974): Familia1 epilepsy and yellow teeth-a disease of the CNS associated with enamel hypoplasia. Helv Paediat Acta 29:283-294.

Ledbetter DH, Cavenee WK (1989): Molecular cytogenetics: Interface of cytogenetics and monogenic disorders. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): “The Metabolic Basis of Inherited Dis- ease.” New York McGraw-Hill, pp 343-371.

Witkop CL, Sauk JJ (1976): Heritable defects ofenamel. In Stewart RE, Prescott GH (eds): “Oral Facial Genetics.” St. Louis: Mosby, pp 151-226.