ROGDI-Related Kohlschutter-Tonz Syndrome

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Homozygous or compound heterozygous ROGDI variants; a founder nonsense variant (p.Arg157*) accounts for a cluster of Druze families in northern Israel.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:8357021 SUPPORT Human clinical

"This report confirms the autosomal recessive inheritance of the disorder."

Affected siblings born to consanguineous parents support recessive inheritance.

PMID:22424600 SUPPORT Human clinical

"Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta."

The gene-discovery study describes the disease as autosomal recessive.

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Discussions and Knowledge Gaps

1

Does loss of ROGDI reduce V-ATPase assembly and the acidification of synaptic vesicles, ameloblast compartments and renal intercalated cells in mammalian cells?

KNOWLEDGE GAP OPEN rogdi_vatpase_acidification_untested_in_mammalian_cells

Attached to

pathophysiology#Impaired Rabconnectin-3-Dependent V-ATPase Assembly pathophysiology#Neuronal Presynaptic Dysfunction

ROGDI's role in V-ATPase assembly rests on yeast Rav2 complementation and interaction studies, and the acidification defect has been observed only in Rogdi-null mouse enamel. Neither V-ATPase assembly nor synaptic vesicle pH has been measured in ROGDI-deficient neurons, so the neurological branch of the pathograph and the explanation for the rare renal findings remain inferences.

Show evidence (1 reference)

PMID:40049412 SUPPORT In vitro / ex vivo

"The discovery of ROGDI as a novel Rabconnectin-3 interactor sheds new light on both Kohlschutter-Tonz syndrome and the mechanisms behind mammalian V-ATPase regulation."

Establishes the Rabconnectin-3 link without measuring acidification in patient-relevant mammalian cells.

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Pathophysiology

5

ROGDI Loss of Function

Biallelic nonsense, frameshift, splice-site and intragenic deletion variants abolish ROGDI protein. Most variants are expected to trigger nonsense-mediated decay or to disrupt the four-helix bundle that holds the protein's alpha domain together; the first missense variant was reported only in 2025, in trans to a frameshift.

ROGDI hgnc:29478

Rabconnectin-3 subunit bridging GO:0030674 ↓ DECREASED

Downstream

Impaired Rabconnectin-3-Dependent V-ATPase Assembly

Show evidence (4 references)

PMID:40049412 SUPPORT INDIRECT Computational

"Molecular modeling suggests that ROGDI may bridge the two Rabconnectin-3 subunits."

Structural modelling places ROGDI as an adaptor between Rabconnectin-3 alpha and beta.

PMID:22482807 SUPPORT Human clinical

"Wild-type ROGDI localizes to the nuclear envelope; ROGDI was not detectable in cells of affected individuals."

Patient cells homozygous for the founder nonsense variant lack ROGDI protein.

CGGV:assertion_dc4132b5-fd80-440b-b7ae-65f4d28f33f1-2022-06-21T160000.000Z SUPPORT Other

"The mechanism of pathogenicity is known to be homozygous or compound heterozygous loss of function."

ClinGen records biallelic loss of function as the disease mechanism.

+ 1 more reference

Impaired Rabconnectin-3-Dependent V-ATPase Assembly

ROGDI is the human homolog of yeast Rav2 and binds the N-terminal domains of both Rabconnectin-3 alpha (DMXL1/DMXL2) and beta (WDR7), probably bridging the two subunits. Rabconnectin-3 drives reassociation of the V1 and V0 sectors of the V-ATPase, which reactivates proton pumping and organelle acidification. Loss of ROGDI is therefore expected to reduce V-ATPase assembly; this has been shown by complementation in yeast and by interaction studies, not yet by direct measurement in patient cells.

V-ATPase assembly GO:0070070 ↓ DECREASED

Downstream

Defective Ameloblast Acidification During Enamel Maturation

Neuronal Presynaptic Dysfunction

Show evidence (2 references)

PMID:40049412 SUPPORT In vitro / ex vivo

"ROGDI shares extensive structural homology with yeast Rav2 and can functionally replace Rav2 in yeast."

ROGDI substitutes for the yeast V-ATPase assembly factor Rav2.

PMID:40049412 SUPPORT In vitro / ex vivo

"ROGDI binds to the N-terminal domains of both Rabconnectin-3 α and β, similar to Rav2 binding to Rav1."

ROGDI binds both Rabconnectin-3 subunits, as Rav2 binds Rav1 in the yeast RAVE complex.

Defective Ameloblast Acidification During Enamel Maturation

Enamel maturation requires cyclic acidification of the enamel organ so that matrix proteins are removed and hydroxyapatite crystals can grow. Rogdi-null mouse incisors show no cyclic acidification, reduced expression of the enamel matrix genes Enam, Amelx and Ambn, and altered expression of V-ATPase-interacting genes (Wdr72, Slc9a3r2, Atp6v0c).

ameloblast CL:0000059

cyclic acidification of maturation-stage enamel GO:0045851 ↓ DECREASED

Animal models

Rogdi exon 6-11 knockout mouse Mouse recapitulates Rogdi-null incisors lose cyclic enamel acidification.

Downstream

Hypomineralized Enamel

Show evidence (2 references)

PMID:38172607 SUPPORT Model organism

"Rogdi-/- teeth exhibit no signs of cyclic dental acidification."

Rogdi-null mice lack the cyclic acidification of maturation-stage enamel.

PMID:38172607 SUPPORT Model organism

"Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn."

Ameloblast enamel matrix gene expression is reduced in Rogdi-null incisors.

Hypomineralized Enamel

The enamel of both dentitions is soft, rough, porous and stained yellow to brown, the hypomature/hypocalcified form of amelogenesis imperfecta. This distinguishes ROGDI-related disease from the hypoplastic enamel defect of SLC13A5-related cases.

enamel mineralization GO:0070166 ↓ DECREASED

Downstream

Amelogenesis imperfecta

Yellow-brown discoloration of the teeth

Show evidence (2 references)

PMID:38172607 SUPPORT Model organism

"Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content."

Rogdi-null enamel is hypomineralized with immature crystals.

PMID:27600704 SUPPORT Human clinical

"In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI."

Histology of a patient's tooth shows hypocalcified enamel.

Neuronal Presynaptic Dysfunction

ROGDI is enriched at presynaptic sites, where it colocalizes with Bassoon and synaptic vesicle markers. Synaptic vesicles are loaded with neurotransmitter using the proton gradient generated by the V-ATPase, so loss of ROGDI is proposed to impair vesicle acidification and transmitter release. Rogdi-null mice have a lowered seizure threshold, hyperactivity and memory deficits. The precise synaptic defect has not been measured, and brain MRI is often normal early in the disease.

neuron CL:0000540

synaptic vesicle lumen acidification GO:0097401 ↓ DECREASED

Animal models

Rogdi exon 6-11 knockout mouse Mouse partially recapitulates Reproduces the behavioral and seizure-susceptibility consequences but shows only induced, not spontaneous, seizures.

Drosophila rogdi mutant Fruit fly partially recapitulates Shows a presynaptic GABAergic transmission defect in an invertebrate circuit.

Downstream

Epileptic encephalopathy

Developmental regression

Global developmental delay

Severe intellectual disability

Absent speech

Attention deficit hyperactivity disorder

Show evidence (2 references)

PMID:29150638 SUPPORT INDIRECT In vitro / ex vivo

"Thus, the neurological symptoms associated with Kohlschütter-Tönz syndrome may arise from presynaptic dysfunction."

ROGDI is a presynaptic protein in cultured neurons, suggesting a presynaptic disease mechanism.

PMID:38172607 SUPPORT INDIRECT Model organism

"Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility."

Rogdi-null mice have increased seizure susceptibility, consistent with but not a direct measure of presynaptic dysfunction.

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Pathograph

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Phenotypes

16

Digestive 1

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:24630287 SUPPORT Human clinical

"By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception."

Founder-variant patients become gastrostomy-fed by late adolescence.

Genitourinary 2

Nephrocalcinosis HP:0000121

Show evidence (2 references)

PMID:34939736 SUPPORT Human clinical

"we detected idiopathic bilateral nephrocalcinosis in this newly identified KTS patient."

Bilateral nephrocalcinosis in a ROGDI-confirmed patient.

PMID:39445602 SUPPORT Human clinical

"Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality."

Two ROGDI-confirmed siblings had nephrocalcinosis.

Distal renal tubular acidosis HP:0008341

Show evidence (1 reference)

PMID:39445602 SUPPORT Human clinical

"Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality."

Two ROGDI-confirmed siblings had distal renal tubular acidosis.

Head and Neck 2

Amelogenesis imperfecta VERY_FREQUENT HP:0000705

Show evidence (2 references)

PMID:37974187 SUPPORT Human clinical

"100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."

All reviewed ROGDI-related cases with available clinical data had amelogenesis imperfecta.

PMID:22482807 SUPPORT Human clinical

"All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta."

Every Druze founder-variant patient had amelogenesis imperfecta.

Yellow-brown discoloration of the teeth VERY_FREQUENT HP:0006286

Show evidence (2 references)

PMID:40960323 SUPPORT Human clinical

"Dental examinations revealed enamel defects consistent with amelogenesis imperfecta, including yellow-brown discoloration, soft enamel, and diastemas in both siblings."

Both ROGDI-confirmed siblings had yellow-brown, soft enamel.

ORPHA:1946 SUPPORT Other

"HP:0006286 | Yellow-brown discoloration of the teeth | Very frequent (99-80%)"

Orphanet lists yellow-brown teeth as very frequent in Kohlschutter-Tonz syndrome.

Integument 1

Hypohidrosis HP:0000966

Show evidence (1 reference)

ORPHA:1946 SUPPORT Other

"HP:0000966 | Hypohidrosis | Frequent (79-30%)"

Orphanet lists hypohidrosis as frequent in Kohlschutter-Tonz syndrome.

Musculoskeletal 1

Spasticity VERY_FREQUENT HP:0001257

Show evidence (2 references)

PMID:22482807 SUPPORT Human clinical

"Kohlschutter-Tonz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset, and it is characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta."

Spasticity is part of the core phenotype.

ORPHA:1946 SUPPORT Other

"HP:0001257 | Spasticity | Very frequent (99-80%)"

Orphanet lists spasticity as very frequent.

Nervous System 9

Epileptic encephalopathy VERY_FREQUENT HP:0200134

Show evidence (4 references)

PMID:40960323 SUPPORT Human clinical

"Kohlschütter-Tönz syndrome (KTS) (OMIM#226750) is a rare autosomal recessive disorder characterized by epileptic encephalopathy, developmental delay, and amelogenesis imperfecta."

Epileptic encephalopathy is a defining feature.

PMID:37974187 SUPPORT Human clinical

"100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."

All reviewed ROGDI-related cases had epilepsy.

PMID:37974187 SUPPORT Human clinical

"three (6.8%) patients had status epilepticus, 24 (61.5%) patients developed RE, and three (7.7%) patients became seizure-free."

Most reviewed patients (61.5%) developed refractory epilepsy; few became seizure-free.

+ 1 more reference

Status epilepticus OCCASIONAL HP:0002133

Show evidence (2 references)

PMID:37974187 SUPPORT Human clinical

"three (6.8%) patients had status epilepticus, 24 (61.5%) patients developed RE, and three (7.7%) patients became seizure-free."

Status epilepticus occurred in 3 of 44 reviewed ROGDI-related cases with available data.

PMID:34939736 SUPPORT Human clinical

"Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus."

A ROGDI-confirmed patient had prolonged super-refractory status epilepticus.

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:37974187 SUPPORT Human clinical

"100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."

All reviewed ROGDI-related cases had global developmental delay.

Developmental regression VERY_FREQUENT HP:0002376

Show evidence (2 references)

PMID:22522085 SUPPORT REVIEW SYNTHESIS Human clinical

"All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on."

Reviews the reported patients, all of whom regressed after seizure onset or were delayed from birth.

PMID:24630287 SUPPORT Human clinical

"By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception."

Describes the end state of progressive deterioration in founder-variant patients.

Severe intellectual disability FREQUENT HP:0010864

Show evidence (3 references)

PMID:29150638 SUPPORT BACKGROUND Human clinical

"Severe intellectual disability, impaired gross and fine motor skills, and spasticity are further characteristics of the syndrome, which may lead to death in childhood or early adulthood"

Summarizes the clinical picture of severe intellectual disability in KTS.

PMID:41153423 SUPPORT REVIEW SYNTHESIS Human clinical

"Speech delay was a prominent feature, with 67% being non-verbal, and most patients (76%) had profound/severe intellectual disability."

Across 54 reviewed ROGDI patients, 76% had profound or severe intellectual disability.

PMID:37974187 SUPPORT Human clinical

"Excluding one patient with incomplete documentation, 43 (100%) patients had IDDs"

Every reviewed patient with documentation had intellectual and developmental disability; the review does not grade severity, which is taken from the clinical descriptions.

Dystonia FREQUENT HP:0001332

Show evidence (1 reference)

PMID:37974187 SUPPORT Human clinical

"Descriptions of dystonia were reported in 34 patients, with 18 (52.9%) having dystonia and 16 (47.1%) not."

About half of reviewed ROGDI-related cases with documented motor findings had dystonia.

Absent speech FREQUENT HP:0001344

Show evidence (3 references)

PMID:22482807 SUPPORT Human clinical

"All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta."

None of the 12 founder-variant patients could speak.

PMID:37974187 SUPPORT Human clinical

"Language disorders were observed in all patients."

Language impairment was universal in the reviewed ROGDI-related cases.

PMID:41153423 SUPPORT REVIEW SYNTHESIS Human clinical

"Speech delay was a prominent feature, with 67% being non-verbal, and most patients (76%) had profound/severe intellectual disability."

Across 54 reviewed ROGDI patients, 67% were non-verbal.

Attention deficit hyperactivity disorder OCCASIONAL HP:0007018

Show evidence (1 reference)

PMID:37974187 SUPPORT Human clinical

"17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD)"

About one in six reviewed patients had an ADHD diagnosis.

Self-injurious behavior OCCASIONAL HP:0100716

Show evidence (1 reference)

PMID:37974187 SUPPORT Human clinical

"Emotional disorders, notably self-harm behaviors (9.1%), were also reported."

About one in eleven reviewed patients showed self-harm behavior.

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Genetic Associations

1

ROGDI (Causative)

Gene: ROGDI hgnc:29478 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:22424600 SUPPORT Human clinical

"Here, we report that KTS is caused by mutations in ROGDI."

Gene discovery in three families by autozygosity mapping and exome sequencing.

PMID:23086778 SUPPORT Human clinical

"By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype."

Replicates ROGDI as the cause of typical KTS in five further families.

PMID:37974187 SUPPORT Human clinical

"A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del)."

A homozygous intronic deletion was the causal variant in this patient. It lies 30-37 bp from the exon and was found by trio exome sequencing, so not every intronic ROGDI deletion escapes exome sequencing (contrast the deletions missed in PMID:23086778); whether one is captured depends on the capture design.

+ 1 more reference

Variants (1)

p.Arg157*

Founder nonsense variant (c.469C>T) homozygous in Druze families from a village in northern Israel, with about a 10% carrier rate locally.

Show evidence (1 reference)

PMID:22482807 SUPPORT Human clinical

"The nonsense mutation 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."

Establishes the founder variant and its local carrier frequency.

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Medical Actions

3

Antiseizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: perampanel CHEBI:71013

Platform: Small molecule

Seizures are often drug-resistant. Valproate, levetiracetam and other antiseizure medications are used; perampanel controlled seizures in a Chinese patient and terminated super-refractory status epilepticus in a Latvian patient. Vagus nerve stimulation and the ketogenic diet were ineffective in one reported patient. No disease-specific therapy exists.

Mechanism Target:

Epileptic encephalopathy

Show evidence (2 references)

PMID:37974187 SUPPORT Human clinical

"The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent."

Perampanel improved seizures in a ROGDI-confirmed patient followed for six years.

PMID:34939736 SUPPORT Human clinical

"Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus."

Perampanel terminated super-refractory status epilepticus in a single patient.

Restorative Dental Treatment

Action: restorative dental treatment under general anesthesia Ontology label: Dental Restoration NCIT:C60718

Restoration of hypomineralized, sensitive and caries-prone teeth, often under general anesthesia because of the neurological disability; anesthesia risk can limit care to conservative management.

Mechanism Target:

Amelogenesis imperfecta

Show evidence (1 reference)

PMID:40960323 SUPPORT Human clinical

"The younger sibling received successful restorative treatment under general anesthesia, while the older sibling's oral care was managed conservatively due to contraindications for general anesthesia."

Restorative dental care under general anesthesia was used in a ROGDI-confirmed sibling.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Recessive inheritance gives a 25% recurrence risk for carrier parents. Carrier testing is relevant in founder communities such as the Druze village where p.Arg157* reaches a carrier frequency of about 10%, and prenatal or preimplantation diagnosis is possible once the familial variants are known.

Show evidence (1 reference)

PMID:22482807 SUPPORT INDIRECT Human clinical

"The nonsense mutation 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."

A high local carrier frequency makes carrier testing and counseling relevant in this community.

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Diagnosis

3

Clinical recognition of the triad

There are no formal diagnostic criteria and no biochemical marker. Diagnosis is suspected from early-onset epilepsy with developmental delay or regression together with generalized amelogenesis imperfecta; a dental examination is a cheap clue in a child with epileptic encephalopathy. Hypocalcified rather than hypoplastic enamel points to ROGDI rather than SLC13A5.

Show evidence (2 references)

PMID:22522085 SUPPORT REVIEW SYNTHESIS Human clinical

"There are no known biochemical or other diagnostic markers of the condition."

No laboratory marker exists, so diagnosis rests on the clinical triad and genetics.

PMID:27600704 SUPPORT Human clinical

"Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene."

Dental phenotype helps distinguish the ROGDI and SLC13A5 forms.

Genome sequencing

Confirmation is by biallelic ROGDI variants. Exome sequencing can miss intronic deletions and exon-level deletions, so genome sequencing or copy-number analysis adds yield when exome sequencing is negative in a typical case.

whole genome sequencing NCIT:C101294

Show evidence (1 reference)

PMID:23086778 SUPPORT Human clinical

"is generally caused by loss of function mutations in ROGDI and identified intronic deletions in ROGDI that were missed using whole exome sequencing."

Intronic ROGDI deletions were missed by exome sequencing.

Electroencephalography and brain MRI

EEG findings range from normal to focal, multifocal or generalized discharges, with no specific pattern. Brain MRI is often normal early; atrophy, including of the hippocampus and cerebellar vermis, is reported in some patients.

electroencephalography NCIT:C38054

Show evidence (2 references)

PMID:37974187 SUPPORT Human clinical

"The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal."

EEG and MRI can be normal despite the clinical diagnosis.

PMID:38172607 SUPPORT BACKGROUND Human clinical

"Cerebral CT scans and MRI on selected KTS patients show brain atrophy, including a smaller hippocampus and hypoplasia of the cerebellar vermis"

Summarizes imaging findings reported in patients.

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Progression

3

Infantile onset

Age: Birth to 2 years

Seizures usually begin in the first or second year of life, in the Druze founder cohort between six and twelve months. Some children are delayed from birth; enamel defects appear as teeth erupt.

Show evidence (2 references)

PMID:22522085 SUPPORT REVIEW SYNTHESIS Human clinical

"Epilepsy usually starts within the first or second year of life."

Places seizure onset in infancy or early childhood.

PMID:24630287 SUPPORT Human clinical

"Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration."

Gives the onset window in the founder cohort.

Childhood regression

Age: Early childhood to adolescence

Psychomotor regression follows seizure onset, and the rate of decline tracks seizure severity. Course is variable, even between siblings with the same genotype.

Show evidence (1 reference)

PMID:22522085 SUPPORT REVIEW SYNTHESIS Human clinical

"Clinical course and disease severity are variable even within families."

Records intrafamilial variability in course.

Late adolescence and adulthood

Age: Late teens onward

In the founder cohort, patients were bedridden, gastrostomy-fed and spastic by their late teens or twenties. Death in childhood or early adulthood is reported; no survival figures exist.

Show evidence (2 references)

PMID:24630287 SUPPORT Human clinical

"In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties."

Describes the end state of the disease in the founder cohort.

PMID:29150638 SUPPORT BACKGROUND Human clinical

"Severe intellectual disability, impaired gross and fine motor skills, and spasticity are further characteristics of the syndrome, which may lead to death in childhood or early adulthood"

Summarizes reported early mortality.

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Prevalence

1

Worldwide

Point prevalence <1 in 1,000,000

Orphanet rarity class for ORPHA:1946, which includes SLC13A5-associated cases. About 54 genetically confirmed ROGDI cases had been reported by 2025 (PMID:41153423).

Show evidence (1 reference)

ORPHA:1946 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"

Orphanet assigns Kohlschutter-Tonz syndrome a worldwide point-prevalence class below one per million.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from ROGDI-Related Kohlschutter-Tonz Syndrome:

Developmental and epileptic encephalopathy 25 MONDO:0014392

Overlapping Features Biallelic SLC13A5 variants cause a ROGDI-negative presentation that was diagnosed clinically as Kohlschutter-Tonz syndrome. Seizures usually begin in the neonatal period and the enamel defect is hypoplastic rather than hypocalcified, with wide interdental spaces.

Distinguishing Features

Neonatal rather than infantile seizure onset.
Hypoplastic amelogenesis imperfecta with wide interdental spaces.
Biallelic SLC13A5 rather than ROGDI variants.

Show evidence (1 reference)

PMID:27600704 SUPPORT Human clinical

"We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI."

SLC13A5 explains ROGDI-negative KTS, with neonatal onset and hypoplastic enamel.

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Animal Models

2

Rogdi exon 6-11 knockout mouse

Deletes the exons removed in some patients. Recapitulates seizure susceptibility, hyperactivity, memory deficits and hypomineralized enamel.

Species

Mouse

Genotype

Rogdi-/- (deletion of exons 6-11)

Publication

PMID:38172607

Pathograph links

Defective Ameloblast Acidification During Enamel Maturation recapitulates fidelity: high observes: tissue Rogdi-null incisors lose cyclic enamel acidification.

Show evidence (1 reference)

PMID:38172607 SUPPORT Model organism

"Rogdi-/- teeth exhibit no signs of cyclic dental acidification."

Direct observation of the acidification defect in the model.

Neuronal Presynaptic Dysfunction partially recapitulates fidelity: moderate observes: organism Reproduces the behavioral and seizure-susceptibility consequences but shows only induced, not spontaneous, seizures.

Limitations: Seizures were provoked with pentylenetetrazol; the presynaptic or vesicle acidification defect itself was not measured.

Show evidence (1 reference)

PMID:38172607 SUPPORT Model organism

"Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility."

The model shows increased seizure susceptibility.

Drosophila rogdi mutant

Rogdi mutant flies sleep poorly because metabotropic GABA transmission onto wake-promoting dopaminergic neurons is reduced. The study proposes that a similar loss of GABAergic inhibition could underlie seizures in KTS; this has not been tested in a vertebrate model.

Species

Fruit fly

Genotype

rogdi loss-of-function mutant

Publication

PMID:28900300

Pathograph links

Neuronal Presynaptic Dysfunction partially recapitulates fidelity: low observes: organism Shows a presynaptic GABAergic transmission defect in an invertebrate circuit.

Limitations: The phenotype measured is sleep, not seizures; the circuit has no mammalian cortical counterpart, and V-ATPase function was not examined.

Show evidence (1 reference)

PMID:28900300 SUPPORT Model organism

"Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission."

Loss of fly Rogdi reduces a subset of GABAergic transmission.

{ }

Source YAML

click to show

name: ROGDI-Related Kohlschutter-Tonz Syndrome
category: Mendelian
creation_date: "2026-11-04T16:20:18Z"
synonyms:
- amelocerebrohypohidrotic syndrome
- Kohlschutter-Tonz syndrome
- Kohlschütter-Tönz syndrome
- KTZS
- epilepsy-dementia-amelogenesis imperfecta syndrome
- ROGDI-related disorder
description: >-
  An autosomal recessive neurodevelopmental and dental disorder caused by
  biallelic loss-of-function variants in ROGDI. It presents with the triad of
  early-onset, often drug-resistant epileptic encephalopathy, global
  developmental delay or psychomotor regression with severe intellectual
  disability and spasticity, and hypomineralized (hypomature) amelogenesis
  imperfecta with yellow-brown discoloration of both primary and permanent
  teeth. ROGDI is a subunit of the Rabconnectin-3 complex that assembles the
  vacuolar proton-pumping ATPase (V-ATPase), and defective V-ATPase-driven
  acidification is the leading model linking the enamel and neurological
  features.
notes: >-
  Named with the gene because Kohlschutter-Tonz syndrome is a clinical
  diagnosis with two genetic causes: biallelic SLC13A5 variants produce a
  ROGDI-negative presentation with neonatal epileptic encephalopathy and
  hypoplastic amelogenesis imperfecta (PMID:27600704), which MONDO files
  separately as developmental and epileptic encephalopathy 25 (MONDO:0014392).
  This entry is bound to MONDO:0009185, whose causal gene is ROGDI (OMIM
  226750), so the unqualified eponym would be broader than the entry.
  "ROGDI-related Kohlschütter-Tönz syndrome" is used in recent case reports
  (PMID:37974187, PMID:39445602). Orphanet's ORPHA:1946 covers both genes, so
  its phenotype frequencies describe the clinical syndrome rather than the
  ROGDI form alone. No GeneReviews chapter covers this disease.
disease_term:
  preferred_term: Kohlschutter-Tonz syndrome
  term:
    id: MONDO:0009185
    label: amelocerebrohypohidrotic syndrome
parents:
- developmental and epileptic encephalopathy
- amelogenesis imperfecta
- ectodermal dysplasia syndrome
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet rarity class for ORPHA:1946, which includes SLC13A5-associated
    cases. About 54 genetically confirmed ROGDI cases had been reported by 2025
    (PMID:41153423).
  evidence:
  - reference: ORPHA:1946
    reference_title: "Amelocerebrohypohidrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet assigns Kohlschutter-Tonz syndrome a worldwide point-prevalence class below one per million.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Homozygous or compound heterozygous ROGDI variants; a founder nonsense
    variant (p.Arg157*) accounts for a cluster of Druze families in northern
    Israel.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:8357021
    reference_title: "Kohlschütter-Tönz syndrome: epilepsy, dementia, and amelogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report confirms the autosomal recessive inheritance of the disorder."
    explanation: Affected siblings born to consanguineous parents support recessive inheritance.
  - reference: PMID:22424600
    reference_title: "Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta."
    explanation: The gene-discovery study describes the disease as autosomal recessive.
pathophysiology:
- name: ROGDI Loss of Function
  description: >-
    Biallelic nonsense, frameshift, splice-site and intragenic deletion
    variants abolish ROGDI protein. Most variants are expected to trigger
    nonsense-mediated decay or to disrupt the four-helix bundle that holds the
    protein's alpha domain together; the first missense variant was reported
    only in 2025, in trans to a frameshift.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ROGDI
    term:
      id: hgnc:29478
      label: ROGDI
  molecular_functions:
  - preferred_term: Rabconnectin-3 subunit bridging
    term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:40049412
    reference_title: "The ROGDI protein mutated in Kohlschutter-Tonz syndrome is a novel subunit of the Rabconnectin-3 complex implicated in V-ATPase assembly."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Molecular modeling suggests that ROGDI may bridge the two Rabconnectin-3 subunits."
    explanation: Structural modelling places ROGDI as an adaptor between Rabconnectin-3 alpha and beta.
  - reference: PMID:22482807
    reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wild-type ROGDI localizes to the nuclear envelope; ROGDI was not detectable in cells of affected individuals."
    explanation: Patient cells homozygous for the founder nonsense variant lack ROGDI protein.
  - reference: CGGV:assertion_dc4132b5-fd80-440b-b7ae-65f4d28f33f1-2022-06-21T160000.000Z
    reference_title: "ROGDI / amelocerebrohypohidrotic syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is known to be homozygous or compound heterozygous loss of function."
    explanation: ClinGen records biallelic loss of function as the disease mechanism.
  - reference: PMID:28638151
    reference_title: "The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tönz Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Disruption of the four-helix bundle by mutation results in significant destabilization of the structure."
    explanation: The crystal structure shows how patient-type truncations destabilize ROGDI.
  downstream:
  - target: Impaired Rabconnectin-3-Dependent V-ATPase Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40049412
      reference_title: "The ROGDI protein mutated in Kohlschutter-Tonz syndrome is a novel subunit of the Rabconnectin-3 complex implicated in V-ATPase assembly."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "We speculate that KTS is a disease resulting from impaired V-ATPase activity; ROGDI mutations impair the activity of the Rabconnectin-3 complex, which in turn results in decreased V-ATPase assembly and activity."
      explanation: >-
        The authors propose this step from ROGDI's role as a Rabconnectin-3
        subunit; reduced assembly has not been measured in ROGDI-deficient
        mammalian cells.
- name: Impaired Rabconnectin-3-Dependent V-ATPase Assembly
  description: >-
    ROGDI is the human homolog of yeast Rav2 and binds the N-terminal domains
    of both Rabconnectin-3 alpha (DMXL1/DMXL2) and beta (WDR7), probably
    bridging the two subunits. Rabconnectin-3 drives reassociation of the V1
    and V0 sectors of the V-ATPase, which reactivates proton pumping and
    organelle acidification. Loss of ROGDI is therefore expected to reduce
    V-ATPase assembly; this has been shown by complementation in yeast and by
    interaction studies, not yet by direct measurement in patient cells.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: V-ATPase assembly
    term:
      id: GO:0070070
      label: proton-transporting V-type ATPase complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:40049412
    reference_title: "The ROGDI protein mutated in Kohlschutter-Tonz syndrome is a novel subunit of the Rabconnectin-3 complex implicated in V-ATPase assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ROGDI shares extensive structural homology with yeast Rav2 and can functionally replace Rav2 in yeast."
    explanation: ROGDI substitutes for the yeast V-ATPase assembly factor Rav2.
  - reference: PMID:40049412
    reference_title: "The ROGDI protein mutated in Kohlschutter-Tonz syndrome is a novel subunit of the Rabconnectin-3 complex implicated in V-ATPase assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ROGDI binds to the N-terminal domains of both Rabconnectin-3 α and β, similar to Rav2 binding to Rav1."
    explanation: ROGDI binds both Rabconnectin-3 subunits, as Rav2 binds Rav1 in the yeast RAVE complex.
  downstream:
  - target: Defective Ameloblast Acidification During Enamel Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38172607
      reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Rogdi-/- mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms."
      explanation: The mouse study proposes impaired V-ATPase-driven acidification as the link to the enamel defect.
  - target: Neuronal Presynaptic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29150638
      reference_title: "The Kohlschütter-Tönz syndrome associated gene Rogdi encodes a novel presynaptic protein."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Thus, the neurological symptoms associated with Kohlschütter-Tönz syndrome may arise from presynaptic dysfunction."
      explanation: >-
        ROGDI's presynaptic localization motivates the neuronal branch; the
        link from V-ATPase assembly to synaptic dysfunction is a hypothesis
        not yet measured in ROGDI models.
- name: Defective Ameloblast Acidification During Enamel Maturation
  description: >-
    Enamel maturation requires cyclic acidification of the enamel organ so
    that matrix proteins are removed and hydroxyapatite crystals can grow.
    Rogdi-null mouse incisors show no cyclic acidification, reduced expression
    of the enamel matrix genes Enam, Amelx and Ambn, and altered expression of
    V-ATPase-interacting genes (Wdr72, Slc9a3r2, Atp6v0c).
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: ameloblast
    term:
      id: CL:0000059
      label: ameloblast
  biological_processes:
  - preferred_term: cyclic acidification of maturation-stage enamel
    term:
      id: GO:0045851
      label: pH reduction
    modifier: DECREASED
  evidence:
  - reference: PMID:38172607
    reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rogdi-/- teeth exhibit no signs of cyclic dental acidification."
    explanation: Rogdi-null mice lack the cyclic acidification of maturation-stage enamel.
  - reference: PMID:38172607
    reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn."
    explanation: Ameloblast enamel matrix gene expression is reduced in Rogdi-null incisors.
  downstream:
  - target: Hypomineralized Enamel
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38172607
      reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation."
      explanation: Enamel crystal growth depends on the pH cycling that is absent in Rogdi-null teeth.
- name: Hypomineralized Enamel
  description: >-
    The enamel of both dentitions is soft, rough, porous and stained yellow to
    brown, the hypomature/hypocalcified form of amelogenesis imperfecta. This
    distinguishes ROGDI-related disease from the hypoplastic enamel defect of
    SLC13A5-related cases.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: enamel mineralization
    term:
      id: GO:0070166
      label: enamel mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:38172607
    reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content."
    explanation: Rogdi-null enamel is hypomineralized with immature crystals.
  - reference: PMID:27600704
    reference_title: "SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI."
    explanation: Histology of a patient's tooth shows hypocalcified enamel.
  downstream:
  - target: Amelogenesis imperfecta
  - target: Yellow-brown discoloration of the teeth
- name: Neuronal Presynaptic Dysfunction
  description: >-
    ROGDI is enriched at presynaptic sites, where it colocalizes with Bassoon
    and synaptic vesicle markers. Synaptic vesicles are loaded with
    neurotransmitter using the proton gradient generated by the V-ATPase, so
    loss of ROGDI is proposed to impair vesicle acidification and transmitter
    release. Rogdi-null mice have a lowered seizure threshold, hyperactivity and
    memory deficits. The precise synaptic defect has not been measured, and
    brain MRI is often normal early in the disease.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic vesicle lumen acidification
    term:
      id: GO:0097401
      label: synaptic vesicle lumen acidification
    modifier: DECREASED
  evidence:
  - reference: PMID:29150638
    reference_title: "The Kohlschütter-Tönz syndrome associated gene Rogdi encodes a novel presynaptic protein."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Thus, the neurological symptoms associated with Kohlschütter-Tönz syndrome may arise from presynaptic dysfunction."
    explanation: ROGDI is a presynaptic protein in cultured neurons, suggesting a presynaptic disease mechanism.
  - reference: PMID:38172607
    reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility."
    explanation: >-
      Rogdi-null mice have increased seizure susceptibility, consistent with
      but not a direct measure of presynaptic dysfunction.
  downstream:
  - target: Epileptic encephalopathy
  - target: Developmental regression
  - target: Global developmental delay
  - target: Severe intellectual disability
  - target: Absent speech
  - target: Attention deficit hyperactivity disorder
phenotypes:
- category: Dental
  name: Amelogenesis imperfecta
  description: >-
    Present in every genetically confirmed patient; affects primary and
    permanent teeth, and is often what first prompts genetic referral.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."
    explanation: All reviewed ROGDI-related cases with available clinical data had amelogenesis imperfecta.
  - reference: PMID:22482807
    reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta."
    explanation: Every Druze founder-variant patient had amelogenesis imperfecta.
- category: Dental
  name: Yellow-brown discoloration of the teeth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Yellow-brown discoloration of the teeth
    term:
      id: HP:0006286
      label: Yellow-brown discoloration of the teeth
  evidence:
  - reference: PMID:40960323
    reference_title: "Kohlschütter-Tönz Syndrome: A Rare Clinical Entity with Amelogenesis Imperfecta in Two Siblings, Dental Management and Scoping Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental examinations revealed enamel defects consistent with amelogenesis imperfecta, including yellow-brown discoloration, soft enamel, and diastemas in both siblings."
    explanation: Both ROGDI-confirmed siblings had yellow-brown, soft enamel.
  - reference: ORPHA:1946
    reference_title: "Amelocerebrohypohidrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006286 | Yellow-brown discoloration of the teeth | Very frequent (99-80%)"
    explanation: Orphanet lists yellow-brown teeth as very frequent in Kohlschutter-Tonz syndrome.
- category: Neurological
  name: Epileptic encephalopathy
  description: >-
    Seizures begin in infancy or early childhood (in the Druze cohort between
    six and twelve months) and are often resistant to antiseizure medication;
    super-refractory status epilepticus has been reported. Seizure severity
    tracks the pace of cognitive and motor deterioration.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:40960323
    reference_title: "Kohlschütter-Tönz Syndrome: A Rare Clinical Entity with Amelogenesis Imperfecta in Two Siblings, Dental Management and Scoping Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kohlschütter-Tönz syndrome (KTS) (OMIM#226750) is a rare autosomal recessive disorder characterized by epileptic encephalopathy, developmental delay, and amelogenesis imperfecta."
    explanation: Epileptic encephalopathy is a defining feature.
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."
    explanation: All reviewed ROGDI-related cases had epilepsy.
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three (6.8%) patients had status epilepticus, 24 (61.5%) patients developed RE, and three (7.7%) patients became seizure-free."
    explanation: Most reviewed patients (61.5%) developed refractory epilepsy; few became seizure-free.
  - reference: PMID:24630287
    reference_title: "Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KTS, a genetic disease heralded by convulsions, \"yellow teeth,\" and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration."
    explanation: Seizure onset and severity predict the rate of deterioration in the Druze cohort.
- category: Neurological
  name: Status epilepticus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three (6.8%) patients had status epilepticus, 24 (61.5%) patients developed RE, and three (7.7%) patients became seizure-free."
    explanation: Status epilepticus occurred in 3 of 44 reviewed ROGDI-related cases with available data.
  - reference: PMID:34939736
    reference_title: "Kohlschütter-Tönz syndrome: Case report with novel feature and detailed review of features associated with ROGDI variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus."
    explanation: A ROGDI-confirmed patient had prolonged super-refractory status epilepticus.
- category: Neurodevelopmental
  name: Global developmental delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta."
    explanation: All reviewed ROGDI-related cases had global developmental delay.
- category: Neurodevelopmental
  name: Developmental regression
  description: >-
    Psychomotor regression usually follows seizure onset; by late adolescence
    patients in the Druze cohort were bedridden and gastrostomy-fed.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Psychomotor regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:22522085
    reference_title: "Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on."
    explanation: Reviews the reported patients, all of whom regressed after seizure onset or were delayed from birth.
  - reference: PMID:24630287
    reference_title: "Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception."
    explanation: Describes the end state of progressive deterioration in founder-variant patients.
- category: Neurodevelopmental
  name: Severe intellectual disability
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:29150638
    reference_title: "The Kohlschütter-Tönz syndrome associated gene Rogdi encodes a novel presynaptic protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Severe intellectual disability, impaired gross and fine motor skills, and spasticity are further characteristics of the syndrome, which may lead to death in childhood or early adulthood"
    explanation: Summarizes the clinical picture of severe intellectual disability in KTS.
  - reference: PMID:41153423
    reference_title: "ROGDI-Related Disorder Resulting from Disruption of Complex Interactive Neuro-Dental Developmental Networks: A Review and Description of the First Missense Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Speech delay was a prominent feature, with 67% being non-verbal, and most patients (76%) had profound/severe intellectual disability."
    explanation: Across 54 reviewed ROGDI patients, 76% had profound or severe intellectual disability.
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excluding one patient with incomplete documentation, 43 (100%) patients had IDDs"
    explanation: >-
      Every reviewed patient with documentation had intellectual and
      developmental disability; the review does not grade severity, which is
      taken from the clinical descriptions.
- category: Neurological
  name: Spasticity
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:22482807
    reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kohlschutter-Tonz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset, and it is characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta."
    explanation: Spasticity is part of the core phenotype.
  - reference: ORPHA:1946
    reference_title: "Amelocerebrohypohidrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001257 | Spasticity | Very frequent (99-80%)"
    explanation: Orphanet lists spasticity as very frequent.
- category: Neurological
  name: Dystonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Descriptions of dystonia were reported in 34 patients, with 18 (52.9%) having dystonia and 16 (47.1%) not."
    explanation: About half of reviewed ROGDI-related cases with documented motor findings had dystonia.
- category: Neurodevelopmental
  name: Absent speech
  description: >-
    Language is affected in all reported patients; about two thirds are
    non-verbal, and patients homozygous for the Druze founder variant did not
    acquire speech.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:22482807
    reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta."
    explanation: None of the 12 founder-variant patients could speak.
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Language disorders were observed in all patients."
    explanation: Language impairment was universal in the reviewed ROGDI-related cases.
  - reference: PMID:41153423
    reference_title: "ROGDI-Related Disorder Resulting from Disruption of Complex Interactive Neuro-Dental Developmental Networks: A Review and Description of the First Missense Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Speech delay was a prominent feature, with 67% being non-verbal, and most patients (76%) had profound/severe intellectual disability."
    explanation: Across 54 reviewed ROGDI patients, 67% were non-verbal.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD)"
    explanation: About one in six reviewed patients had an ADHD diagnosis.
- category: Behavioral
  name: Self-injurious behavior
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Self-harm behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emotional disorders, notably self-harm behaviors (9.1%), were also reported."
    explanation: About one in eleven reviewed patients showed self-harm behavior.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >-
    Late in the disease, patients lose the ability to feed orally and depend on
    gastrostomy feeding.
  phenotype_term:
    preferred_term: Gastrostomy-dependent feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:24630287
    reference_title: "Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception."
    explanation: Founder-variant patients become gastrostomy-fed by late adolescence.
- category: Integumentary
  name: Hypohidrosis
  description: >-
    The feature behind the name amelocerebrohypohidrotic syndrome. Orphanet's
    frequency covers both genetic causes of the syndrome, and recent
    ROGDI-confirmed series rarely mention sweating, so no frequency is given
    for the ROGDI form.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: ORPHA:1946
    reference_title: "Amelocerebrohypohidrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000966 | Hypohidrosis | Frequent (79-30%)"
    explanation: Orphanet lists hypohidrosis as frequent in Kohlschutter-Tonz syndrome.
- category: Renal
  name: Nephrocalcinosis
  description: >-
    Reported in a Latvian girl and in two Indian siblings; together with distal
    renal tubular acidosis it may reflect a renal V-ATPase defect, but the
    mechanism is unproven.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:34939736
    reference_title: "Kohlschütter-Tönz syndrome: Case report with novel feature and detailed review of features associated with ROGDI variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected idiopathic bilateral nephrocalcinosis in this newly identified KTS patient."
    explanation: Bilateral nephrocalcinosis in a ROGDI-confirmed patient.
  - reference: PMID:39445602
    reference_title: "Nephrocalcinosis, distal renal tubular acidosis and skeletal abnormality in two siblings with ROGDI -related Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality."
    explanation: Two ROGDI-confirmed siblings had nephrocalcinosis.
- category: Renal
  name: Distal renal tubular acidosis
  phenotype_term:
    preferred_term: Distal renal tubular acidosis
    term:
      id: HP:0008341
      label: Distal renal tubular acidosis
  evidence:
  - reference: PMID:39445602
    reference_title: "Nephrocalcinosis, distal renal tubular acidosis and skeletal abnormality in two siblings with ROGDI -related Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality."
    explanation: Two ROGDI-confirmed siblings had distal renal tubular acidosis.
progression:
- phase: Infantile onset
  age_range: Birth to 2 years
  notes: >-
    Seizures usually begin in the first or second year of life, in the Druze
    founder cohort between six and twelve months. Some children are delayed
    from birth; enamel defects appear as teeth erupt.
  evidence:
  - reference: PMID:22522085
    reference_title: "Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Epilepsy usually starts within the first or second year of life."
    explanation: Places seizure onset in infancy or early childhood.
  - reference: PMID:24630287
    reference_title: "Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration."
    explanation: Gives the onset window in the founder cohort.
- phase: Childhood regression
  age_range: Early childhood to adolescence
  notes: >-
    Psychomotor regression follows seizure onset, and the rate of decline
    tracks seizure severity. Course is variable, even between siblings with the
    same genotype.
  evidence:
  - reference: PMID:22522085
    reference_title: "Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Clinical course and disease severity are variable even within families."
    explanation: Records intrafamilial variability in course.
- phase: Late adolescence and adulthood
  age_range: Late teens onward
  notes: >-
    In the founder cohort, patients were bedridden, gastrostomy-fed and spastic
    by their late teens or twenties. Death in childhood or early adulthood is
    reported; no survival figures exist.
  evidence:
  - reference: PMID:24630287
    reference_title: "Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties."
    explanation: Describes the end state of the disease in the founder cohort.
  - reference: PMID:29150638
    reference_title: "The Kohlschütter-Tönz syndrome associated gene Rogdi encodes a novel presynaptic protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Severe intellectual disability, impaired gross and fine motor skills, and spasticity are further characteristics of the syndrome, which may lead to death in childhood or early adulthood"
    explanation: Summarizes reported early mortality.
diagnosis:
- name: Clinical recognition of the triad
  description: >-
    There are no formal diagnostic criteria and no biochemical marker.
    Diagnosis is suspected from early-onset epilepsy with developmental delay
    or regression together with generalized amelogenesis imperfecta; a dental
    examination is a cheap clue in a child with epileptic encephalopathy.
    Hypocalcified rather than hypoplastic enamel points to ROGDI rather than
    SLC13A5.
  evidence:
  - reference: PMID:22522085
    reference_title: "Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "There are no known biochemical or other diagnostic markers of the condition."
    explanation: No laboratory marker exists, so diagnosis rests on the clinical triad and genetics.
  - reference: PMID:27600704
    reference_title: "SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene."
    explanation: Dental phenotype helps distinguish the ROGDI and SLC13A5 forms.
- name: Genome sequencing
  description: >-
    Confirmation is by biallelic ROGDI variants. Exome sequencing can miss
    intronic deletions and exon-level deletions, so genome sequencing or
    copy-number analysis adds yield when exome sequencing is negative in a
    typical case.
  diagnosis_term:
    preferred_term: whole genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  evidence:
  - reference: PMID:23086778
    reference_title: "Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is generally caused by loss of function mutations in ROGDI and identified intronic deletions in ROGDI that were missed using whole exome sequencing."
    explanation: Intronic ROGDI deletions were missed by exome sequencing.
- name: Electroencephalography and brain MRI
  description: >-
    EEG findings range from normal to focal, multifocal or generalized
    discharges, with no specific pattern. Brain MRI is often normal early;
    atrophy, including of the hippocampus and cerebellar vermis, is reported in
    some patients.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal."
    explanation: EEG and MRI can be normal despite the clinical diagnosis.
  - reference: PMID:38172607
    reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cerebral CT scans and MRI on selected KTS patients show brain atrophy, including a smaller hippocampus and hypoplasia of the cerebellar vermis"
    explanation: Summarizes imaging findings reported in patients.
genetic:
- name: ROGDI
  gene_term:
    preferred_term: ROGDI
    term:
      id: hgnc:29478
      label: ROGDI
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Biallelic loss-of-function variants (nonsense, frameshift, splice-site,
    intragenic and exon-level deletions, and intronic deletions missed by
    exome sequencing). One missense variant has been reported, in trans to a
    frameshift.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_dc4132b5-fd80-440b-b7ae-65f4d28f33f1-2022-06-21T160000.000Z
    evidence:
    - reference: CGGV:assertion_dc4132b5-fd80-440b-b7ae-65f4d28f33f1-2022-06-21T160000.000Z
      reference_title: "ROGDI / amelocerebrohypohidrotic syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ROGDI | HGNC:29478 | amelocerebrohypohidrotic syndrome | MONDO:0009185 | AR | Definitive"
      explanation: ClinGen classifies ROGDI as Definitive for this disease, autosomal recessive.
  evidence:
  - reference: PMID:22424600
    reference_title: "Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report that KTS is caused by mutations in ROGDI."
    explanation: Gene discovery in three families by autozygosity mapping and exome sequencing.
  - reference: PMID:23086778
    reference_title: "Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype."
    explanation: Replicates ROGDI as the cause of typical KTS in five further families.
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del)."
    explanation: >-
      A homozygous intronic deletion was the causal variant in this patient.
      It lies 30-37 bp from the exon and was found by trio exome sequencing, so
      not every intronic ROGDI deletion escapes exome sequencing (contrast the
      deletions missed in PMID:23086778); whether one is captured depends on
      the capture design.
  - reference: ORPHA:1946
    reference_title: "Amelocerebrohypohidrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ROGDI | rogdi atypical leucine zipper | hgnc:29478 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet records ROGDI loss-of-function variants as disease-causing.
  variants:
  - name: p.Arg157*
    description: >-
      Founder nonsense variant (c.469C>T) homozygous in Druze families from a
      village in northern Israel, with about a 10% carrier rate locally.
    evidence:
    - reference: PMID:22482807
      reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The nonsense mutation 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."
      explanation: Establishes the founder variant and its local carrier frequency.
differential_diagnoses:
- name: Developmental and epileptic encephalopathy 25
  description: >-
    Biallelic SLC13A5 variants cause a ROGDI-negative presentation that was
    diagnosed clinically as Kohlschutter-Tonz syndrome. Seizures usually begin
    in the neonatal period and the enamel defect is hypoplastic rather than
    hypocalcified, with wide interdental spaces.
  disease_term:
    preferred_term: SLC13A5-related epileptic encephalopathy
    term:
      id: MONDO:0014392
      label: developmental and epileptic encephalopathy, 25
  distinguishing_features:
  - Neonatal rather than infantile seizure onset.
  - Hypoplastic amelogenesis imperfecta with wide interdental spaces.
  - Biallelic SLC13A5 rather than ROGDI variants.
  evidence:
  - reference: PMID:27600704
    reference_title: "SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI."
    explanation: SLC13A5 explains ROGDI-negative KTS, with neonatal onset and hypoplastic enamel.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Seizures are often drug-resistant. Valproate, levetiracetam and other
    antiseizure medications are used; perampanel controlled seizures in a
    Chinese patient and terminated super-refractory status epilepticus in a
    Latvian patient. Vagus nerve stimulation and the ketogenic diet were
    ineffective in one reported patient. No disease-specific therapy exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: perampanel
      term:
        id: CHEBI:71013
        label: perampanel
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Epileptic encephalopathy
  evidence:
  - reference: PMID:37974187
    reference_title: "Perampanel effectiveness in treating ROGDI-related Kohlschütter-Tönz syndrome: first reported case in China and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent."
    explanation: Perampanel improved seizures in a ROGDI-confirmed patient followed for six years.
  - reference: PMID:34939736
    reference_title: "Kohlschütter-Tönz syndrome: Case report with novel feature and detailed review of features associated with ROGDI variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus."
    explanation: Perampanel terminated super-refractory status epilepticus in a single patient.
- name: Restorative Dental Treatment
  description: >-
    Restoration of hypomineralized, sensitive and caries-prone teeth, often
    under general anesthesia because of the neurological disability; anesthesia
    risk can limit care to conservative management.
  treatment_term:
    preferred_term: restorative dental treatment under general anesthesia
    term:
      id: NCIT:C60718
      label: Dental Restoration
  target_mechanisms:
  - target: Amelogenesis imperfecta
  evidence:
  - reference: PMID:40960323
    reference_title: "Kohlschütter-Tönz Syndrome: A Rare Clinical Entity with Amelogenesis Imperfecta in Two Siblings, Dental Management and Scoping Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The younger sibling received successful restorative treatment under general anesthesia, while the older sibling's oral care was managed conservatively due to contraindications for general anesthesia."
    explanation: Restorative dental care under general anesthesia was used in a ROGDI-confirmed sibling.
- name: Genetic Counseling
  description: >-
    Recessive inheritance gives a 25% recurrence risk for carrier parents.
    Carrier testing is relevant in founder communities such as the Druze
    village where p.Arg157* reaches a carrier frequency of about 10%, and
    prenatal or preimplantation diagnosis is possible once the familial
    variants are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22482807
    reference_title: "A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nonsense mutation 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."
    explanation: A high local carrier frequency makes carrier testing and counseling relevant in this community.
animal_models:
- name: Rogdi exon 6-11 knockout mouse
  species: Mouse
  genotype: Rogdi-/- (deletion of exons 6-11)
  publication: PMID:38172607
  description: >-
    Deletes the exons removed in some patients. Recapitulates seizure
    susceptibility, hyperactivity, memory deficits and hypomineralized enamel.
  modeled_mechanisms:
  - target: Defective Ameloblast Acidification During Enamel Maturation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Rogdi-null incisors lose cyclic enamel acidification.
    evidence:
    - reference: PMID:38172607
      reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Rogdi-/- teeth exhibit no signs of cyclic dental acidification."
      explanation: Direct observation of the acidification defect in the model.
  - target: Neuronal Presynaptic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the behavioral and seizure-susceptibility consequences but
      shows only induced, not spontaneous, seizures.
    limitations: >-
      Seizures were provoked with pentylenetetrazol; the presynaptic or vesicle
      acidification defect itself was not measured.
    evidence:
    - reference: PMID:38172607
      reference_title: "The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility."
      explanation: The model shows increased seizure susceptibility.
- name: Drosophila rogdi mutant
  species: Fruit fly
  genotype: rogdi loss-of-function mutant
  publication: PMID:28900300
  description: >-
    Rogdi mutant flies sleep poorly because metabotropic GABA transmission onto
    wake-promoting dopaminergic neurons is reduced. The study proposes that a
    similar loss of GABAergic inhibition could underlie seizures in KTS; this
    has not been tested in a vertebrate model.
  modeled_mechanisms:
  - target: Neuronal Presynaptic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Shows a presynaptic GABAergic transmission defect in an invertebrate
      circuit.
    limitations: >-
      The phenotype measured is sleep, not seizures; the circuit has no
      mammalian cortical counterpart, and V-ATPase function was not examined.
    evidence:
    - reference: PMID:28900300
      reference_title: "Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission."
      explanation: Loss of fly Rogdi reduces a subset of GABAergic transmission.
discussions:
- discussion_id: rogdi_vatpase_acidification_untested_in_mammalian_cells
  prompt: >-
    Does loss of ROGDI reduce V-ATPase assembly and the acidification of
    synaptic vesicles, ameloblast compartments and renal intercalated cells in
    mammalian cells?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Rabconnectin-3-Dependent V-ATPase Assembly
  - pathophysiology#Neuronal Presynaptic Dysfunction
  rationale: >-
    ROGDI's role in V-ATPase assembly rests on yeast Rav2 complementation and
    interaction studies, and the acidification defect has been observed only in
    Rogdi-null mouse enamel. Neither V-ATPase assembly nor synaptic vesicle pH
    has been measured in ROGDI-deficient neurons, so the neurological branch of
    the pathograph and the explanation for the rare renal findings remain
    inferences.
  evidence:
  - reference: PMID:40049412
    reference_title: "The ROGDI protein mutated in Kohlschutter-Tonz syndrome is a novel subunit of the Rabconnectin-3 complex implicated in V-ATPase assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The discovery of ROGDI as a novel Rabconnectin-3 interactor sheds new light on both Kohlschutter-Tonz syndrome and the mechanisms behind mammalian V-ATPase regulation."
    explanation: Establishes the Rabconnectin-3 link without measuring acidification in patient-relevant mammalian cells.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: ROGDI-Related Kohlschutter-Tonz Syndrome · 2026-11-04T16:20:18Z · View source

New entry for MONDO:0009185 (amelocerebrohypohidrotic syndrome / Kohlschutter-Tonz syndrome, ROGDI). Named ROGDI-Related Kohlschutter-Tonz Syndrome because SLC13A5 is a second gene for the clinical diagnosis (PMID:27600704) and is curated by MONDO as DEE25, so the bare eponym is broader than this ROGDI-bound term; the ROGDI-related form is used in recent titles (PMID:37974187, PMID:39445602). Deep research: falcon was requested but not configured (no EDISON_API_KEY), so the run fell back to claude_code via --fallback; the report research/ROGDI-Related_Kohlschutter-Tonz_Syndrome-deep-research-claude_code.md resolved 19/19 references, had one ellipsis-paraphrased quote (PMID:27600704; the entry quotes the exact sentence), and passed just preflight-dr. Additional sources were found by PubMed search. Pathograph: ROGDI loss of function -> impaired Rabconnectin-3-dependent V-ATPase assembly -> (a) defective ameloblast acidification -> hypomineralized enamel, and (b) presynaptic dysfunction -> epilepsy and neurodevelopmental phenotypes; the neuronal branch is marked as inferred and a KNOWLEDGE_GAP discussion records that V-ATPase assembly has not been measured in mammalian ROGDI-null cells. Renal (nephrocalcinosis, dRTA) and hypohidrosis phenotypes are left unconnected because no mechanism is established. ClinGen Definitive (AR) recorded from the cached CGGV record. No GeneReviews chapter exists (just check-genereviews --online: NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (71/71), check-entity-refs, check-causal-targets, check-name-collisions and the snippet baseline gates. A pre-PR review by a fresh agent led to these changes: the ROGDI-to-V-ATPase and neuronal edges are marked INDIRECT and quote the sources' own speculation sentences; the ameloblast node is rebound to GO:0045851 pH reduction, because the defect is extracellular enamel acidification rather than vacuolar; ROGDI carries a protein-macromolecule adaptor activity molecular function (Rabconnectin-3 bridging, from structural modelling), so check-gene-activity-grounding passes; dystonia (52.9%), status epilepticus (6.8%) and refractory epilepsy (61.5%) figures are added from the PMID:37974187 full text; and the pooled Orphanet frequency on hypohidrosis is dropped. OLS searches for "drug-resistant epilepsy" and "refractory epilepsy" found no HP term, so the refractory figure sits in the epilepsy evidence. PR review round 1 (automated reviewer, changes requested): added reference_title to every evidence item with scripts/backfill_reference_titles.py (copied from references_cache frontmatter; this was also the failing CI check); added a diagnosis section (clinical triad and no biochemical marker; genome sequencing, because exome sequencing missed intronic ROGDI deletions per PMID:23086778; EEG and MRI) and a three-phase progression section; added Genetic Counseling; renamed the neuronal node to Neuronal Presynaptic Dysfunction, because PMID:29150638 used hippocampal neurons rather than cortical neurons; sourced the intellectual disability frequency from the 44-case review; cached PMID:41153423, which the prevalence notes cite. Skeletal abnormality (one family, PMID:39445602) was not added, because the source gives no more specific finding than a generic skeletal abnormality and a coarse HPO binding would add little.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-opus-5-5 5 citations 2026-11-04T16:07:35.122508

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

Phenotype	Suggested HPO (verify)	Onset / course	Frequency	Key evidence
Epilepsy / seizures (often drug-resistant; status epilepticus)	HP:0001250 Seizure; HP:0001250-descendants for focal/generalized	6–12 months (range: neonatal to 2 years); progressive	100% (43 ROGDI cases)	"100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta." — PMID:37974187
Global developmental delay / psychomotor regression	HP:0001263; HP:0002376 Developmental regression	Infancy; regression after seizure onset	100%	"All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on." — PMID:22522085
Amelogenesis imperfecta (hypocalcified/hypomature); yellow-brown teeth	HP:0000705; HP:0006286 Yellow-brown discoloration of the teeth	Present from tooth eruption; affects both dentitions	100%	Orphanet: "HP:0006286 \| Yellow-brown discoloration of the teeth \| Very frequent (99-80%)"
Absent or severely impaired speech	HP:0001344 Absent speech / HP:0002463 Language impairment	Childhood	~100%	"Language disorders were observed in all patients." — PMID:37974187
Severe intellectual disability	HP:0010864 Intellectual disability, severe	Progressive	Most	PMID:29150638
Spasticity	HP:0001257	Progressive; bedridden by the late teens or twenties	Very frequent (Orphanet)	"By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic…" — PMID:24630287
ADHD / hyperactivity	HP:0007018	Childhood	17.2%	PMID:37974187
Autism spectrum features	HP:0000729	Childhood	3.4% suspected	PMID:37974187
Self-injurious behavior	HP:0100716	Variable	9.1%	PMID:37974187
Hypohidrosis	HP:0000966	—	Frequent (79–30%, Orphanet)	Orphanet ORPHA:1946
Nephrocalcinosis	HP:0000121	Childhood	Rare (3 reported cases)	PMID:34939736; PMID:39445602
Distal renal tubular acidosis	HP:0008341	Childhood	Rare (2 families)	PMID:39445602; Tunisian family (c.646-2A>G, Clin Genet 2025, PMC12050240) [unverified]
Hyperammonemia	HP:0001987	—	Single report	Tunisian family [unverified]
Feeding difficulty / gastrostomy dependence	HP:0011968	Adolescence	Common in late disease	PMID:24630287
Rett-like phenotype	—	—	Case report (c.201-1G>T, Turkish girl) [unverified]	—

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

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).
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):
"We identified ROGDI as a Rav2 homolog and novel Rabconnectin-3 subunit."
"ROGDI binds to the N-terminal domains of both Rabconnectin-3 α and β, similar to Rav2 binding to Rav1."
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.
The effect then branches.
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

Model	Genotype	Recapitulation	Limitations	Evidence
Mouse (Mus musculus)	Rogdi⁻/⁻ (exon 6–11 deletion, a patient-like allele)	PTZ-induced seizures (susceptibility); hyperactivity; object-recognition memory deficit; hypomineralized and hypomature enamel; loss of cyclic enamel acidification; reduced Enam/Amelx/Ambn	No spontaneous seizures reported; hyperactivity is taken as a proxy for spasticity; renal and sweat phenotypes not reported	PMID:38172607
Drosophila	rogdi mutants	Memory defects (first identified in a memory screen, Dubnau et al. 2003 [unverified]); sleep loss through reduced GABA-B transmission onto wake-promoting dopaminergic neurons	Invertebrate; no teeth	Kim et al. 2017 Sci Rep (PMC5595912; PMID:28900300 [unverified])
Yeast (S. cerevisiae)	rav2Δ complemented by human ROGDI	Shows ROGDI function in V-ATPase assembly	Heterologous; no tissue phenotype	PMID:40049412
Rat hippocampal neurons (in vitro)	GFP-Rogdi	Presynaptic localization	Overexpression; localization only	PMID:29150638

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

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

Checked with linkml-reference-validator 0.5.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	10
Quoted claims found in source	9
Quoted claims not found in source	1
References weighed for topical relevance	19
On topic	19
Off topic	0

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

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	41
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	10
Terms named correctly	6
Terms named as a different term	0
Terms whose name is worth a second look	4

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.

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Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Checklist detail

7. Anatomical Structures

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Open Questions

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms whose name is worth a second look

Prefixes with no resolver