ROGDI-Related Kohlschutter-Tonz Syndrome

1. Disease Information

Overview. Kohlschütter-Tönz syndrome (KTS) is an autosomal recessive disease of childhood onset. Its defining triad is early-onset epilepsy, global developmental delay or regression, and amelogenesis imperfecta (yellow-brown, soft enamel) of both primary and permanent teeth. - "Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta." — PMID:22424600 (Schossig et al., Am J Hum Genet 2012) - It was first described in a Swiss family in 1974 (Kohlschütter et al.), as noted in PMID:34939736 and PMID:23086778.

Identifiers | System | ID | |---|---| | MONDO | MONDO:0009185 (ClinGen label: "amelocerebrohypohidrotic syndrome") | | OMIM | #226750 (gene ROGDI 614574 [unverified]) | | Orphanet | ORPHA:1946 | | HGNC | hgnc:29478 | | ClinGen GDV | ROGDI–MONDO:0009185, AR, Definitive (CGGV:assertion_dc4132b5-…-2022-06-21) | | ICD-10 | No specific code. Usually coded under K00.5 (hereditary disturbances of tooth structure) plus G40.x [unverified]* | | MeSH | No specific descriptor. Indexed under Amelogenesis Imperfecta, Epilepsy and Dementia (MeSH keywords on PMID:22424600) |

Synonyms. Kohlschütter syndrome; amelocerebrohypohidrotic syndrome; epilepsy–dementia–amelogenesis imperfecta syndrome; ROGDI-related KTS.

Source type. All knowledge comes from aggregated case reports and small case series. There are about 43–66 reported cases in total: PMID:34939736 counts 43 genetically confirmed patients, and PMID:39445602 counts 66 reported cases, 44 of them genetically confirmed. There are no EHR-derived cohorts or registries.

2. Etiology

• Cause. Biallelic (homozygous or compound heterozygous) loss-of-function variants in ROGDI.
• "Here, we report that KTS is caused by mutations in ROGDI." — PMID:22424600
• ClinGen: "The mechanism of pathogenicity is known to be homozygous or compound heterozygous loss of function."
• Genetic risk factors. Consanguinity and founder alleles. A Druze founder allele (p.Arg157*) has a carrier rate of about 10% in one village (see §9).
• Environmental risk factors, protective factors and gene–environment interactions. None are known. No modifier genes have been identified. Variability in age of onset and severity within the same homozygous genotype suggests unidentified modifiers (PMID:22482807).

3. Phenotypes

Quality of life. The burden is severe: total dependence, drug-resistant seizures and loss of communication. No validated QoL instruments have been used. Brain MRI and EEG can be normal early on (PMID:37974187).

4. Genetic / Molecular Information

• Gene. ROGDI, 11 exons, NM_024589.3. It encodes a ~287-amino-acid protein that is conserved across metazoans. It is highly expressed in the brain and other organs (PMID:22424600).
• Variant classes (all predicted loss of function; no missense-only pathogenic alleles are well established):
• Frameshift: c.229_230del p.(Leu77Alafs*64) (PMID:22424600)
• Nonsense: c.286C>T p.(Gln96*) (PMID:22424600); c.469C>T p.(Arg157*), the Druze founder allele (PMID:22482807; reported as c.571C>T in PMID:24630287 because of a different transcript numbering)
• Splice: c.531+5G>C / c.532-2A>T (compound heterozygous, original Swiss family); c.117+1G>T; c.201-1G>T; c.646-2A>G (Tunisian); c.646-2_649del (Indian, PMID:39445602); c.46-37_46-30del (deep-intronic/branch-region deletion, Chinese patient, PMID:37974187)
• Multi-exon deletions: deleting exons 6–11 recapitulates a patient allele (modelled in mouse, PMID:38172607). A further family was found by Tucci et al. (PMID:23086778).
• Functional consequence. Protein loss: "ROGDI was not detectable in cells of affected individuals." — PMID:22482807. Structural destabilization: "Disruption of the four-helix bundle by mutation results in significant destabilization of the structure." — PMID:28638151.
• Classification. ClinVar lists multiple Pathogenic or Likely pathogenic LoF variants. ClinGen rates the gene–disease relationship Definitive (AR).
• Allele frequency. All alleles are rare in gnomAD, apart from the Druze founder allele, which is enriched in one village.
• Origin. Germline. No somatic, epigenetic or chromosomal mechanism is known.
• Genetic heterogeneity. ROGDI-negative "atypical KTS" families exist (PMID:23086778). SLC13A5 is the second gene: "SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS" — PMID:27600704.

5. Environmental Information

There are no known environmental, lifestyle or infectious contributors. This is not applicable for a Mendelian loss-of-function disorder.

6. Mechanism / Pathophysiology

Ordered causal chain

1. Biallelic ROGDI LoF variants (nonsense, frameshift, splice, deletion) lead to absent or unstable ROGDI protein. This is demonstrated in patient cells (PMID:22482807) and supported structurally (PMID:28638151).
2. Loss of ROGDI results in loss of a Rav2-homologous subunit of the Rabconnectin-3 (RC3) complex (DMXL1/2 = RC3α, WDR7 = RC3β). This is demonstrated in yeast complementation and mammalian co-IP (PMID:40049412):
3. "We identified ROGDI as a Rav2 homolog and novel Rabconnectin-3 subunit."
4. "ROGDI binds to the N-terminal domains of both Rabconnectin-3 α and β, similar to Rav2 binding to Rav1."
5. Loss of the RC3 bridge leads to impaired V1–V0 reassembly of the vacuolar H⁺-ATPase (V-ATPase) and therefore defective acidification of organelles and secretory compartments. This step is inferred from yeast Rav2 biology and from ROGDI co-localization in acidic lysosomes. Defective V-ATPase assembly has not yet been measured directly in ROGDI-null human cells.
6. The effect then branches.

7. 4a. Dental branch. Ameloblasts fail to generate the cyclic acidic/neutral pH modulation needed for enamel maturation. This results in hypomineralized, hypomature enamel, which is clinically amelogenesis imperfecta with yellow-brown teeth. In the mouse model (PMID:38172607):

   • "Rogdi-/- teeth exhibit no signs of cyclic dental acidification."
   • "Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn."
   • Expression of Wdr72, Slc9a3r2 and Atp6v0c is altered.

   WDR72 is itself a known amelogenesis imperfecta gene, so this convergence is suggestive. - 4b. Neuronal branch. ROGDI is a presynaptic protein: "Rogdi is enriched at synaptic sites" and colocalizes with Bassoon, Synaptophysin, Synapsin-1, VAMP2 and Mover (PMID:29150638). V-ATPase supplies the proton gradient that drives neurotransmitter loading into synaptic vesicles. Rabconnectin-3 is a synaptic-vesicle-associated V-ATPase regulator. Loss therefore plausibly leads to impaired vesicle acidification and loading, and to presynaptic dysfunction. This is inferred: "the neurological symptoms associated with Kohlschütter-Tönz syndrome may arise from presynaptic dysfunction" (PMID:29150638). - 4b′. GABAergic sub-branch (Drosophila). Rogdi supports metabotropic (GABA-B) GABAergic transmission. Loss results in disinhibition of a wake-promoting dopaminergic circuit, causing sleep loss (Kim et al. 2017, Sci Rep, PMID:28900300 [unverified PMID], PMC5595912). Reduced inhibitory tone is a candidate route to epilepsy, but this is inferred. 5. Presynaptic or inhibitory failure leads to network hyperexcitability, which shows clinically as early-onset, often drug-resistant epilepsy. The mouse shows pentylenetetrazol-induced seizures: "Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility." (PMID:38172607) 6. Recurrent seizures and the intrinsic synaptic defect result in epileptic encephalopathy, with psychomotor regression, absent speech, severe ID, spasticity and hyperactivity. The mouse shows hyperactivity and memory deficits (PMID:38172607). Seizure severity predicts the speed of deterioration (PMID:24630287). - 4c. Renal branch (rare). The V-ATPase on α-intercalated cells of the collecting duct drives distal acid secretion. Its dysfunction plausibly leads to distal RTA, which in turn leads to nephrocalcinosis (PMID:39445602; PMID:34939736). This is inferred from the parallel with ATP6V0A4/ATP6V1B1 dRTA. PMID:39445602 states that the mechanism is unknown. - 4d. Sweat glands (hypohidrosis). The mechanism is unknown. A V-ATPase role in eccrine secretion is speculative.

Checklist detail

• Pathways. V-ATPase assembly and regulation; lysosomal and vesicular acidification; synaptic vesicle cycle; GABA-B signalling (fly).
• Protein. Crystal structure (PMID:28638151): an elongated curved fold with an α domain (leucine-zipper-like four-helix bundle pairing H1 [res. 19–45] with H6 [res. 252–287]) and a β-sheet domain. Truncations disrupt the bundle. An early report placed ROGDI at the nuclear envelope (PMID:22482807); later work places it at presynaptic sites and lysosomes. A proposed DISC1 interaction has not been confirmed.
• Metabolic and biochemical. There are no diagnostic biochemical markers (PMID:22522085). Hyperammonemia was reported once.
• Immune system. Not involved.
• Omics. The only dataset is mouse incisor bulk RNA-seq (PMID:38172607). There are no human single-cell, spatial or proteomic data.

Suggested GO terms (verify): vacuolar acidification (GO:0007035); proton-transporting V-type ATPase complex assembly (GO:0070070) and its vacuolar child term; synaptic vesicle lumen acidification (GO:0097401); amelogenesis (GO:0097186); enamel mineralization (GO:0070166); presynapse (GO:0098793); lysosome (GO:0005764); Rabconnectin complex (GO:0043291). Suggested CL terms (verify): ameloblast (CL:0000059); neuron (CL:0000540); GABAergic neuron (CL:0011005); renal alpha-intercalated cell (CL:0005011).

7. Anatomical Structures

• Primary. Brain (cerebral cortex) [UBERON:0000955]; tooth enamel and enamel organ [UBERON:0001752 enamel] in both dentitions.
• Secondary. Kidney (collecting duct; nephrocalcinosis) [UBERON:0002113]; eccrine sweat glands [UBERON:0000423]; skeletal system (skeletal abnormality, PMID:39445602).
• Cell level. Ameloblasts, presynaptic neurons, and α-intercalated cells (by inference).
• Subcellular. Presynaptic terminal and synaptic vesicles (PMID:29150638); acidic perinuclear lysosomes (PMID:40049412); nuclear envelope in an early report (PMID:22482807).
• Lateralization. Bilateral and symmetric (generalized enamel defect; bilateral nephrocalcinosis).

8. Temporal Development

• Onset. Seizures start at 6–12 months in the Druze cohort (PMID:24630287), and usually in the first or second year of life (PMID:22522085). Some patients have delay from birth. Enamel defects appear at tooth eruption.
• Progression. Progressive neurodegeneration. Regression follows seizure onset. Patients are bedridden, tube-fed and spastic by the late teens or twenties: "In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties." (PMID:24630287)
• Variability. Variability is marked even within families and within the same genotype (PMID:22482807). Milder courses with preserved ambulation have been reported.
• Critical window. Early seizure control may slow deterioration, because seizure severity predicts the pace of decline (PMID:24630287). This is an inference; it has not been tested.

9. Inheritance and Population

• Inheritance. Autosomal recessive (HP:0000007): "This report confirms the autosomal recessive inheritance of the disorder." (PMID:8357021)
• Penetrance. Complete for biallelic LoF. Expressivity is variable. There is no anticipation.
• Prevalence. Below 1 per 1,000,000 (Orphanet: "<1 / 1 000 000 | Worldwide | Point prevalence"). About 43–66 published cases.
• Founder effect. The Druze p.Arg157* allele "was homozygous in all affected individuals, heterozygous in 10 of 100 unaffected individuals from the same Druze community, and absent from Druze controls from elsewhere." (PMID:22482807)
• Consanguinity. Common in reported families (Druze, Indian, Tunisian, Turkish and Malian).
• Geography. Worldwide, in sporadic families: Switzerland, Austria, Israel, the UK, Italy, Brazil, Latvia, China, India, Tunisia, Turkey and Mali.
• Sex ratio. About 1:1 (8F/8M in PMID:24630287).

10. Diagnostics

• Clinical criteria. There are no formal criteria. Diagnosis rests on the triad of early epilepsy, developmental delay or regression, and generalized amelogenesis imperfecta. A dental examination is a cheap, high-yield clue in any child with epileptic encephalopathy.
• Laboratory. No biomarkers (PMID:22522085). Renal evaluation is worth considering: venous blood gas, urine pH, urinary calcium and renal ultrasound for dRTA and nephrocalcinosis (PMID:39445602).
• EEG and MRI. EEG shows multifocal or generalized epileptiform activity. MRI is often normal early (PMID:37974187); cerebral and cerebellar atrophy can appear later [unverified].
• Dental histology and imaging. Histology shows hypocalcified amelogenesis imperfecta: "the histological evaluation of a molar … from an individual with ROGDI-associated KTZS revealed hypocalcified AI" (PMID:27600704). Hypoplastic amelogenesis imperfecta instead suggests SLC13A5.
• Genetic testing.
• Exome or genome sequencing (trio preferred), or epilepsy and amelogenesis imperfecta panels that include ROGDI and SLC13A5.
• Deep-intronic and branch-point variants (c.46-37_46-30del) and multi-exon deletions mean that genome sequencing or CNV analysis can add yield.
• RNA studies or long-read cDNA sequencing resolve splice variants (Tunisian report, PMC12050240).
• CMA, karyotype, FISH, mtDNA testing and repeat-expansion testing are not indicated except for CNV detection.
• Differential diagnosis.
• SLC13A5 KTS-like (neonatal onset, hypoplastic amelogenesis imperfecta, citrate transporter)
• Other developmental and epileptic encephalopathies (SCN1A, CDKL5, Rett/MECP2)
• Enamel-renal syndrome (FAM20A)
• Amelogenesis imperfecta with nephrocalcinosis; dRTA (ATP6V0A4, ATP6V1B1)
• Neuronal ceroid lipofuscinoses
• Screening. No newborn screening. Carrier screening or cascade testing in founder populations (Druze). Prenatal or preimplantation diagnosis is possible once the familial variants are known.

11. Outcome / Prognosis

• Progressive. Most patients become completely dependent, with absent speech, spasticity and gastrostomy feeding, by the late teens or twenties (PMID:24630287).
• Death in childhood or early adulthood is reported: "which may lead to death in childhood or early adulthood" (PMID:29150638). No survival statistics exist.
• Complications. Refractory and super-refractory status epilepticus (PMID:34939736); aspiration and feeding problems; dental caries and attrition from soft enamel; nephrocalcinosis.
• Prognostic factors. Age of seizure onset and seizure severity predict the speed of decline (PMID:24630287).

12. Treatment

There is no disease-modifying therapy. Management is symptomatic and multidisciplinary.

• Antiseizure medication (NCIT:C15986 Pharmacotherapy; verify).
• Seizures are often resistant to multiple antiseizure medications (PMID:29150638).
• Perampanel (an AMPA-receptor antagonist) has reported benefit in two cases:
  • "Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus." (PMID:34939736)
  • "The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent." (PMID:37974187)
• This is case-level evidence only. The CHEBI or NCIT ID for perampanel needs a lookup.
• Dental care (NCIT dental restoration or Therapeutic Procedure terms; look these up). Options include restorative treatment, crowns, preventive fluoride, and treatment under general anesthesia where feasible: "The younger sibling received successful restorative treatment under general anesthesia, while the older sibling's oral care was managed conservatively…" (PMID:40960323)
• Renal. Alkali therapy (citrate or bicarbonate) for dRTA, by analogy with standard dRTA care. No KTS-specific trial exists.
• Supportive and rehabilitative. Physical therapy (NCIT:C15302), occupational and speech therapy, antispasticity management, gastrostomy (nutritional support), ADHD and behavioral management (NCIT:C15747 Supportive Care).
• Experimental. There are no clinical trials (no NCT or ICTRP entries found). Gene-replacement or V-ATPase-modulating approaches are conceptual only. The structure paper mentions drug-development implications (PMID:28638151).
• Pharmacogenomics. None known.

13. Prevention

• Primary. Genetic counseling (NCIT:C15240), carrier testing in consanguineous or founder communities, and prenatal or preimplantation genetic diagnosis.
• Secondary. Early recognition through dental findings, and early genetic diagnosis.
• Tertiary. Aggressive seizure control, dental protection, renal surveillance, nutrition and prevention of aspiration.
• No vaccines, public-health or environmental measures apply.

14. Other Species / Natural Disease

• Orthologs. ROGDI is conserved in C. elegans, D. melanogaster (rogdi), D. rerio, X. laevis and M. musculus (PMID:38172607). The functional yeast homolog is RAV2 (complementation shown, PMID:40049412).
• Naturally occurring animal disease. None found in OMIA.

15. Model Organisms

Gaps. There are no zebrafish or patient-iPSC neuron or organoid models. No study has directly measured V-ATPase assembly or synaptic-vesicle pH in ROGDI-null mammalian neurons. That experiment would test step 3 of the causal chain, which is currently inferred. The mouse lacks spontaneous seizures, which is a candidate HUMAN_MODEL_MISMATCH discussion for the entry.

Key Open Questions

1. Does ROGDI loss reduce V-ATPase assembly and acidification of synaptic vesicles, ameloblast compartments and collecting-duct cells in mammals?
2. Why do only a few patients show dRTA and nephrocalcinosis? It may be an under-ascertained feature, or it may depend on the allele.
3. Are the GABA-B and dopaminergic findings in the fly relevant to human epileptogenesis?
4. Does perampanel's benefit extend beyond the two reported cases?

Sources

• Cached in the repo (references_cache/): PMID:8357021, 22424600, 22482807, 22522085, 23086778, 24630287, 27600704, 28638151, 29150638, 34939736, 37974187, 38172607, 39445602, 40049412, 40960323; ORPHA:1946; the ClinGen CGGV assertion.
• Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila (PMC5595912)
• The Rogdi knockout mouse is a model for Kohlschütter–Tönz syndrome (PMC10764811)
• Transcript Long-Read Sequencing Unveils the Molecular Complexity of a Novel ROGDI Splicing Variant in a Tunisian Family With KTS (PMC12050240)
• InteractiveFly: rogdi GeneBrief
• KTS case report with novel feature (RSU)

Reference Validation

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Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:27600704 (abstract only): "the histological evaluation of a molar … from an individual with ROGDI-associated KTZS revealed hypocalcified AI"
• closest text in source: "In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI"

Term Validation

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Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• MONDO:0009185 (3 mentions) - the report calls it "ClinGen label: "amelocerebrohypohidrotic syndrome"; MONDO calls it amelocerebrohypohidrotic syndrome
• HP:0007018 (1 mention) - the report calls it "ADHD / hyperactivity"; HP calls it Attention deficit hyperactivity disorder
• HP:0000729 (1 mention) - the report calls it "Autism spectrum features"; HP calls it Autistic behavior, and lists "Autism spectrum disorders" among its other names
• HP:0011968 (1 mention) - the report calls it "Feeding difficulty / gastrostomy dependence"; HP calls it Feeding difficulties

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

39 of 41 terms resolved to a current term; the rest could not be looked up either way.