Kohlschutter-Tonz Syndrome

A number sign (#) is used with this entry because Kohlschutter-Tonz syndrome (KTZS) is caused by homozygous or compound heterozygous mutation in the ROGDI gene (614574) on chromosome 16p13.

Description

Kohlschutter-Tonz syndrome is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Intellectual disability is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by Schossig et al., 2012 and Mory et al., 2012).

Clinical Features

Kohlschutter et al. (1974) described a family of farmers living in a valley of central Switzerland in which 5 brothers developed seizures between ages 11 months and 4 years. The children died after progressive mental deterioration at ages varying from 7 to 9 years. A sixth son may have been affected. Dental radiographs demonstrated absence of a normally mineralized enamel coating the teeth, The parents were not known to be related, but the geographic isolation suggested consanguinity. Schossig et al. (2012) reported a 9-year-old girl with the disorder who was found by genealogic studies to be distantly related to the family reported by Kohlschutter et al. (1974). She developed left-sided hemiconvulsive seizures at age 6 months that were difficult to treat initially, but medication could be discontinued at age 6 years. Her initial development was normal until the onset of seizures, and she spoke only in short simple sentences. She was related to the original family by the maternal line (6 generations ago) and the paternal line (9 generations ago); her parents were eighth cousins.

Kohlschutter et al. (cited by Witkop and Sauk, 1976) subsequently observed 2 other Swiss families, one with 2 affected boys and a second with 1 affected. The affected children seemed to develop normally until the onset of seizures at age 11 months to 4 years. This was followed by progressive mental deterioration and muscular spasticity. Some histologic changes were observed in the brain. Since no affected females were observed in 3 kindreds, the authors suggested X-linked inheritance.

Christodoulou et al. (1988) described a Sicilian family living in Australia in which 4 male and 2 female sibs were affected. Several mentally retarded females in the family were not available for examination. The parents, having come from the same small, close-knit town, may have been related, suggesting autosomal recessive inheritance.

Autosomal recessive inheritance was further suggested by the Druze family reported by Zlotogora et al. (1993) in which a boy and girl, born to consanguineous parents, had mental retardation, convulsions, and yellow teeth consistent with amelogenesis imperfecta of the hypocalcified type.

Petermoller et al. (1993) described the Kohlschutter syndrome in a brother and sister.

Musumeci et al. (1995) reported a brother and sister, born of consanguineous parents of Sicilian origin, with Kohlschutter syndrome. In addition to amelogenesis imperfecta with yellow teeth, seizures, severe developmental delay, and spasticity, both patients had broad thumbs and toes and enlargement of the lateral ventricles. The boy had occipital evoked spikes and hypoplasia of the cerebellar vermis.

Haberlandt et al. (2006) reported an 11-year-old boy with Kohlschutter-Tonz syndrome with less severe neurologic involvement compared to other reported cases. Seizures and developmental delay became apparent at age 8 months. He had a mildly asymmetric skull, coarse hair, upslanting palpebral fissures, and a smooth philtrum. Deciduous and permanent teeth were yellow and hypoplastic with crowding. He had generalized atonic or tonic-clonic seizures as well as focal seizures with secondary generalization; seizures were responsive to medication. MRI at age 6 years showed moderate ventricular enlargement and hypoplasia of the cerebellar vermis. Haberlandt et al. (2006) stated that 19 cases of the syndrome had been reported with clinical variability. Schossig et al. (2012) reported follow-up of the patient reported by Haberlandt et al. (2006) at age 18 years. His parents came from neighboring villages in East Tyrol (Austria). Epilepsy started when the boy was 5 months old, but later improved with cessation of seizures after age 7. Medication was discontinued at age 15 years. He could speak only 35 words and 2-word sentences, and had a social and friendly behavior.

Schossig et al. (2012) provided follow-up of 2 Moroccan sibs, aged 12 and 9 years, with Kohlschutter-Tonz syndrome, who were originally reported by Schossig et al. (2007). The unaffected parents were first cousins. Initial development of the affected boy appeared normal, but he developed refractory epilepsy at age 4 months, leading to loss of visual fixation and global developmental delay. His younger sister showed psychomotor delay from birth. She developed refractory seizures at age 12 months. The boy had no expressive language and the girl spoke only a few words. Both also had delayed motor development. The first teeth in the children erupted at ages 13 and 14 months, respectively, and the teeth were lusterless with a brownish discoloration.

Mory et al. (2012) reported 14 patients from 5 Druze families with KTZS. Three of the families were part of a large consanguineous kindred, and all the families originated from the same small village in northern Israel. Although the phenotype was consistent, it was variable. All patients had early-onset seizures, severe global developmental delay, spasticity and amelogenesis imperfecta. Age at onset of seizures ranged from birth to 3 years, although most had onset before 12 months of age. Treatment response varied, and about half had intractable seizures. Most patients were ambulant, but almost all had no speech development. The most severely affected individual had failure to thrive, microcephaly, and refractory convulsions. She was vegetative and died at age 2 years. In contrast, her 15-year-old sister was ambulant and could communicate with a few words, although she was severely intellectually disabled. In general, the severity of intellectual disability was related to the severity of the seizures, and the disorder could thus be considered an epileptic encephalopathy. Brain imaging of 7 patients showed evidence of cerebral atrophy in 4.

Inheritance

Reports of affected sibs and parental consanguinity indicate autosomal recessive inheritance of Kohlschutter-Tonz syndrome (Haberlandt et al., 2006).

Mapping

By linkage analysis of 5 families with Kohlschutter-Tonz syndrome, Lo (2009) found linkage to chromosome 16p13.3-p13.2 (maximum lod score of 3.05 at D16S423). The families had previously been reported by Christodoulou et al. (1988), Guazzi et al. (1994), Donnai et al. (2005), Musumeci et al. (1995), and Petermoller et al. (1993). Two of the pedigrees were consanguineous.

By linkage analysis and autozygosity mapping of several families with Kohlschutter-Tonz syndrome, Schossig et al. (2012) and Mory et al. (2012) independently and simultaneously mapped the disorder to chromosome 16p13.3.

Molecular Genetics

In affected members of 3 unrelated families with Kohlschutter-Tonz syndrome, Schossig et al. (2012) identified homozygous or compound heterozygous mutations in the ROGDI gene (614574.0001-614574.0004). The mutation in the first family (Schossig et al., 2007) was identified by linkage analysis and autozygosity mapping followed by whole-exome sequencing with confirmation by Sanger sequencing. The second patient had previously been reported by Haberlandt et al. (2006), and the third patient was found to be a distant relative of the original family reported by Kohlschutter et al. (1974). All the mutations were expected to be null, likely causing complete loss of protein function. Simultaneously and independently, Mory et al. (2012) identified a common truncating mutation in the ROGDI gene (R157X; 614574.0005) in 14 patients from 5 Druze families with KTZS. Both Schossig et al. (2012) and Mory et al. (2012) noted that yeast 2-hybrid screens had suggested an interaction between ROGDI and DISC1 (605210), a protein involved in cytoskeletal stability, neuronal migration, intracellular transport, and cell division (Camargo et al., 2007).

Using a combination of whole-exome sequencing, linkage analysis, and Sanger sequencing, Tucci et al. (2013) identified 4 different biallelic mutations in the ROGDI gene (see, e.g., 614574.0006-614574.0008) in affected members of 5 families with KTZS. Three of the families had previously been reported by Christodoulou et al. (1988), Musumeci et al. (1995), and Petermoller et al. (1993). In contrast, ROGDI mutations were not identified in 5 additional families with a similar phenotype, but who showed some atypical features (see HETEROGENEITY). Tucci et al. (2013) noted that the findings confirmed the reports of Schossig et al. (2012) and Mory et al. (2012) that loss-of-function variants cause KTZS. However, the report also suggested genetic heterogeneity of atypical forms of the disorder.

Heterogeneity

Guazzi et al. (1994) observed a family in which amelogenesis imperfecta was associated with ataxia, mental deterioration, and epilepsy. Donnai et al. (2005) reported a brother and sister with presumed Kohlschutter syndrome, born of unrelated parents. The sibs, 17 and 15 years of age, respectively, had delayed psychomotor development, seizures, and yellow teeth. Both had frequent facial flushing and intermittent sediment in the urine consisting of crystals that were 75% calcium phosphate and 25% magnesium ammonium phosphate. The sibs were fed by gastrostomy and communicated to some extent by eye-pointing. Donnai et al. (2005) stated that 25 patients from 8 families had been described. Tucci et al. (2013) excluded mutations in the ROGDI gene in the families previously reported by Guazzi et al. (1994) and Donnai et al. (2005). Tucci et al. (2013) reviewed the clinical features of the affected members of these families and considered them to have an atypical form of Kohlschutter-Tonz syndrome. Some individuals in the family of Guazzi et al. (1994) had only amelogenesis imperfecta, and the teeth were not truly yellow or missing enamel. The mode of inheritance was also complicated and not indicative of pure autosomal recessive inheritance. One of the affected sibs reported by Donnai et al. (2005) also had neurofibromatosis type I (162200), and both had severe feeding problems.

Tucci et al. (2013) ascertained 3 additional unrelated patients, 1 from the United States and 2 from the Netherlands, with an atypical form of the disorder and no mutations in the ROGDI gene. Although all had the core features of delayed development, seizures, and tooth abnormalities, variable atypical features included mild intellectual disability, severe spasticity of all 4 extremities, dysmorphic features, lack of overt seizures, and multiple warts. Tucci et al. (2013) suggested genetic heterogeneity for clinically atypical forms of KTZS.