O’Donnell–Luria–Rodan Syndrome (ODLURO): KMT2E-related neurodevelopmental disorder

Literature and regulatory information updated: 4 October 2026

0. Initial Reference Table

1. Introduction

O’Donnell–Luria–Rodan syndrome is a genetic neurodevelopmental condition whose recognition depends more on the combination of clinical assessment and molecular diagnosis than on an immediately recognisable facial appearance. One child may have speech delay, hypotonia and school difficulties, normal stature and no epileptic seizures; another may have profound delay and early epilepsy. Both may have a causal KMT2E alteration. The term KMT2E-NDD makes the gene involved explicit and avoids confusion between partially similar eponyms. HIST1H1E should refer to Rahman syndrome, an entity with a different molecular mechanism and surveillance requirements. [1, 4]

The initial description published in 2019 brought together 38 individuals from 36 families, including sequence variants and deletions involving KMT2E. A second multinational cohort published in 2022 added 18 individuals, with 17 distinct variants, and strengthened evidence for familial transmission with milder expression in the parent. These studies established a consistent association with developmental delay and a broad spectrum of severity. They are not incidence studies: participants were identified through genetics services, sequencing projects and international collaboration, with selection based on clinical manifestations. [6, 7]

GeneReviews, published in April 2024, synthesised information on 61 individuals described in the literature at that time. This number should be read with its date, because subsequent publications exist. More recent expansion includes an Italian series of seven children, North American studies of cognition and learning, and a behavioural investigation published in a 2026 volume. Increasing descriptions help identify previously underestimated needs, but do not eliminate selection problems, small samples or possible overlap of participants between articles. Automatically adding all published samples would produce an unreliable worldwide count. [1, 8–11]

The clinical value of identifying the aetiology is concrete: it enables explanation of the developmental course, organisation of interventions, recognition of treatable complications, guidance for the school and calculation of transmission risks. The diagnosis alone does not predict future communication ability, response to medication or degree of independence. Family guidance should combine knowledge from published series with longitudinal observation of the individual. The absence of a specific molecular treatment does not diminish the value of symptomatic treatment and early intervention. [1]

2. Molecular Genetics and Pathophysiology

2.1. Gene, protein and chromatin regulation

KMT2E belongs to the KMT2 family of chromatin regulators. Despite its historical designation as a methyltransferase, the protein differs from other members in having no established intrinsic histone methyltransferase activity. It acts as a reader of chromatin marks and participates in the organisation of gene expression. The PHD domain, standing for plant homeodomain, recognises marks such as histone H3 lysine 4 trimethylation, abbreviated H3K4me3. The SET domain does not, on its own, justify concluding that the protein catalyses that methylation. This distinction matters because the pathophysiology cannot be reduced to a simple failure to produce an epigenetic mark. [1, 2]

KMT2E function relates to transcriptional regulation, cell-cycle progression and genomic stability. Experimental studies also link it to haematopoiesis and spermatogenesis, but these biological functions do not automatically equate to obligatory clinical manifestations in the germline syndrome. In the nervous system, reduced function may disrupt expression programmes during development. The relationship between these changes and different human cognitive profiles remains incompletely understood; the cellular mechanism does not yet provide a clinical biomarker for grading intellectual disability or selecting an antiepileptic drug. [1]

ClinGen classifies the relationship between KMT2E and complex neurodevelopmental disorder as definitive and assigns sufficient evidence of haploinsufficiency sensitivity, with a score of 3. The score of 0 for triplosensitivity means that sufficient evidence for that relationship is absent from the curation, rather than guaranteeing that any duplication containing the gene is benign. The outcome of a copy-number alteration also depends on its extent, adjacent genes and genomic configuration. [12]

2.2. Variant classes and interpretation of the mechanism

RNA degradation due to premature termination, usually termed nonsense-mediated decay or NMD, depends on the termination codon position and transcript architecture. Some terminal alterations may escape this mechanism and produce altered proteins. Therefore, the PVS1 loss-of-function criterion in the ACMG/AMP guidelines should not be applied at maximum strength to all truncating variants solely on the basis of their class name. The biologically relevant transcript, exon involved and predicted or experimental consequence modify the strength of the evidence. [13]

Most known causal variants arose de novo. However, families with maternal or paternal transmission and milder manifestations in the parent exist, including learning difficulties or social functioning problems. An adult without a previous diagnosis should not automatically be considered clinically unaffected; school history, development, any epilepsy and adaptive assessment are needed. Conversely, identifying an inherited variant does not prove that it explains the child's phenotype: interpretation should consider classification, segregation and expressivity. No robust population estimate of penetrance is available that would permit converting a causal variant into a precise individual prognosis. [1, 7]

Genetic evidence favours haploinsufficiency for many alterations, but the mechanism of all missense variants has not been demonstrated. Gain-of-function or dominant-negative hypotheses have been proposed to explain some severe phenotypes; these remain hypotheses requiring confirmation. Clinical classification should assess each variant without presuming that different mechanisms correspond to treatments already available. [1]

2.3. HGVS nomenclature and informative examples

Human Genome Variation Society nomenclature, abbreviated HGVS, requires an identified reference sequence. A variant description should include the transcript and its version, distinguish the DNA alteration from the protein consequence and, when using genomic coordinates, specify the assembly. KMT2E has several transcripts: numbering in one publication should not be transferred to another transcript without comparison. A classification recorded in a database should likewise be considered alongside the quality of review; a single submission is not equivalent to expert-panel consensus. [15, 16]

ACMG/AMP recommendations classify variants as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign. A variant of uncertain significance, abbreviated VUS, should not be used alone to establish ODLURO, decide on irreversible procedures or assign reproductive risks as if causality had been demonstrated. An adverse computational prediction does not replace the combination of clinical, population, familial and functional evidence. Confirmation of de novo occurrence may strengthen interpretation, but does not automatically make any rare variant the cause of disease. [1, 16]

2.4. Genotype–phenotype correlation and related diseases

In the 2024 synthesis, five individuals with pathogenic missense variants formed a more severely affected subgroup: all had epilepsy, four had refractory epilepsy and three had microcephaly. These numbers describe five selected cases, rather than the risk applicable to all people with a KMT2E missense substitution. Some truncating variants are also associated with significant epilepsy. A 2025 review focused on individuals with epilepsy did not establish a clear correlation capable of predicting the course from the variant. The genotype guides the hypothesis but does not replace individual neurological assessment. [1, 19]

Deletions of 7q22.2–q22.3 may include KMT2E and other genes. In these cases, more evident dysmorphic features, malformations or greater severity should not be attributed exclusively to ODLURO. Analysis of the interval, genes encompassed and other genomic alterations is part of the diagnosis. A urinary abnormality in a case with a contiguous deletion should not be generalised into a universal indication for urological surveillance in people with intragenic KMT2E variants. [1, 18]

The reference clinical sources do not establish another distinct germline Mendelian disease caused by KMT2E that imposes a second routine protocol on all patients. Investigation of the gene in neoplasia and its historical name MLL5 do not, by themselves, demonstrate hereditary predisposition to leukaemia or another cancer in ODLURO syndrome. These sources provide no basis for importing tumour screening from PTEN, DNMT3A or other epigenetic-regulator syndromes merely because they belong to related biological groups. New symptoms should be investigated according to the usual clinical indications. [1, 5]

2.5. Mechanistic update from September 2026

A preprint by O’Chan and colleagues, deposited on bioRxiv on 22 September 2026, describes a preference of KMT2E for the combined H3K4me3Q5ser mark, which includes histone H3 serotonylation. In experimental models, the protein recruited the NCoR/HDAC3 complex and limited the spread of H3K9ac acetylation; intervention targeting this spread corrected transcriptional abnormalities in neurons with haploinsufficiency. This is preclinical research, not yet peer reviewed, rather than a demonstration of therapeutic benefit in people with ODLURO. It does not support prescribing serotonin, supplements or epigenetic modulators. [20]

3. Clinical Spectrum and Manifestations by System

3.1. Available frequencies and limitations of comparison

Table values come from the case compilation available when GeneReviews was published. Denominators differ because not all manifestations were assessed or described in every individual. Missing information should not be counted as absence of the sign. Increased targeted sleep and behavioural assessment in recent series may modify the observed frequency without demonstrating a biological change in the disease. Counselling should present these proportions as descriptions of the clinical literature, with their limitations, rather than exact personal probabilities. [1]

3.2. Development, cognition and communication

Delay may affect several areas, with a particular impact on expressive language and articulation. Most described individuals developed verbal language, but some have very limited verbal communication. In the experience assembled in 2024, all individuals beyond infancy had acquired independent walking; this does not guarantee the same trajectory in a young child with severe manifestations. The age of skill acquisition varies, so follow-up should record abilities actually attained and new acquisitions rather than imposing a single expected age for the entire syndrome. [1]

Intellectual disability and language delay are not equivalent. A child may understand more than they can express, and attention or speech difficulties may limit test performance. Assessment should include intellectual functioning, receptive and expressive language, motor coordination and adaptive behaviour. A low global score does not adequately describe all abilities. The functional profile determines how to teach, adapt communication and support daily activities. Reassessment during development identifies needs that become apparent only as educational demands increase. [1]

Abreu and colleagues described speech apraxia and velopharyngeal dysfunction without cleft palate in an individual with a truncating variant and cerebellar hypoplasia. The report adds motor and resonance components to communication assessment. It does not establish the frequency of these abnormalities or demonstrate that every speech difficulty in ODLURO has the same cause; articulation or resonance abnormalities should be assessed according to the specific signs. [21]

A North American series of ten patients, published in 2025, found relative strengths in verbal reasoning and vocabulary, with more pronounced difficulties in non-verbal reasoning, working memory, word reading and arithmetic. The verbal versus non-verbal comparison was significant in this sample, but the retrospective study does not define a mandatory profile. Another study assessed learning difficulties through carer reports in 11 participants with ODLURO, within a sample of 50 people with three syndromes, identifying difficulties in several domains. Results support individual assessment rather than automatic prediction of school performance. [9, 10]

True regression, with loss of previously acquired skills, should be distinguished from stagnation, fluctuating performance or increased environmental demands. Although described in some cases, it is not a reason to assume that all deterioration results from the natural course of KMT2E. It should prompt investigation of seizures, sleep changes, pain, medication effects and concomitant diagnoses. Unexplained progressive deterioration warrants reconsideration of the aetiological hypothesis, even after an apparently explanatory molecular result. [1]

3.3. Behaviour and mental health

The spectrum includes autism, attention difficulties, anxiety, rigidity, altered emotional regulation, aggression and self-injury in some individuals. Apparent sociability does not exclude autism; repetitive, sensory and flexibility difficulties may coexist with social interest. Interpretation requires clinical assessment and developmental context. Suddenly emerging behaviours should first prompt investigation of triggers, particularly constipation, reflux, dental pain, sleep deprivation or medication effects, without automatic attribution to a primary psychiatric problem. [1]

The behavioural study published in a 2026 volume highlighted anxiety, attention, executive function and associations between sleep and behavioural regulation. It used instruments such as the Social Responsiveness Scale, second edition, SRS-2. Elevated scores on this scale describe difficulties in social responsiveness and associated behaviours; they do not replace an autism diagnosis or establish its population prevalence. The practical relevance is to assess these domains explicitly, including in people whose verbal language may conceal adaptive difficulties. [11]

3.4. Neurology and epilepsy

Seizures are heterogeneous, including focal, generalised manifestations and spasms in certain cases. They may emerge at different ages; absence of seizures in early childhood does not permit declaring absence of future risk. In investigating episodes, witness descriptions and safely obtained home videos may help distinguish epileptic events from stereotypies, sleep changes or other phenomena. No electroencephalographic pattern confirms ODLURO. Classification of seizure type and epilepsy syndrome, where possible, guides treatment more directly than the gene name. [1]

Zhu and colleagues assembled 30 individuals with ODLURO and epilepsy in 2025 from the literature and DECIPHER. Among ten with medication information, approximately 70% required two or more antiepileptic drugs. Selection based on epilepsy prevents applying this value to everyone with ODLURO. Moreover, polytherapy alone does not demonstrate drug resistance: data on regimen appropriateness and seizure control are needed. The review reinforces heterogeneity and the inadequacy of correlations between variant and course. [19]

3.5. Growth, skull, dysmorphology and neuroimaging

Height and weight are generally within normal ranges. Macrocephaly may be absolute, above two standard deviations, or relative to height; GeneReviews considers a difference of at least one standard deviation between head circumference and height scores to be relative macrocephaly. Serial measurements, appropriate charts and body proportions are more informative than an isolated observation. Macrocephaly is not mandatory, and microcephaly, particularly described in some severe cases, does not exclude the condition. [1]

Facial traits may include dolichocephaly, a high forehead, deep-set eyes, downslanting palpebral fissures and periorbital or cheek fullness. They are subtle, variable and insufficiently specific for visual diagnosis. Marked overgrowth, body asymmetry, macroglossia or important ectodermal signs should broaden the differential. The Oxford approach to overgrowth emphasises family history, longitudinal anthropometry and seeking signs that distinguish syndromes; these principles are useful, but the historical tables do not directly describe the natural history of KMT2E. [1, 5]

Magnetic resonance imaging, abbreviated MRI, may be normal or reveal abnormalities such as corpus callosum hypoplasia, ventriculomegaly, cysts and delayed myelination. Other malformations have been reported, but there is no specific pattern or sufficiently stable population estimate to communicate a single probability of abnormality. The Italian series of seven children confirmed diverse findings, including ventricular, callosal and myelination abnormalities. A normal MRI does not exclude ODLURO; a non-specific finding does not confirm it and should be interpreted in the neurological context. [1, 8]

3.6. Gastrointestinal features, feeding and sleep

Constipation is the most frequent gastrointestinal complaint in reference descriptions. Gastro-oesophageal reflux, vomiting and reduced intestinal motility may also occur. The impact includes pain, food refusal, behavioural changes and sleep disturbance. Growth, intake, hydration, stool frequency and consistency, swallowing difficulty and signs of aspiration should be assessed. The need for tube feeding or gastrostomy is individual, not an obligatory intervention because of the diagnosis. Persistent vomiting or weight loss requires its own investigation. [1]

Sleep difficulties include sleep initiation and frequent awakenings. Investigation should establish routine, environment, schedules, relationship to medication, nocturnal motor episodes and symptoms of respiratory obstruction. An ODLURO diagnosis does not demonstrate melatonin deficiency in each person or justify immediate pharmacological treatment. Carers' health is also affected by repeatedly interrupted nights, making an approach assessing both the individual's sleep and the family's ability to maintain an intervention plan useful. [1]

3.7. Mobility and other systems

Hypotonia may improve with growth but persist as difficulties in endurance, balance or coordination. Joint hypermobility and motor difficulties warrant functional assessment and therapies, looking for pain, limitations and injury risk. It is inappropriate to turn all motor delay into a diagnosis of primary muscle disease. Examination showing progressive weakness, loss of ambulation or focal neuromuscular signs requires additional investigation. [1]

Hearing, vision, oral health and general examination should be included in developmental care, because treatable abnormalities may worsen communication and learning. In contrast to H1-4/Rahman, reference information on ODLURO does not support a universal package of echocardiography, thyroid tests, densitometry or screening for genital malformations without a clinical indication. This does not prevent investigation of a murmur, growth changes, fractures or cryptorchidism when present; it merely prevents automatic transfer of recommendations from another syndrome to KMT2E. [1, 4]

4. Clinical Recognition and Warning Signs

4.1. When to include KMT2E in investigation

ODLURO should be considered in a person with global developmental delay or intellectual disability associated with hypotonia, language delay, relative macrocephaly, epilepsy, autism, constipation or sleep changes. None of these signs is obligatory in isolation. A history of learning difficulties in a parent may support a dominant hypothesis, but most families have no recognised history. Absence of dysmorphic features or major malformations should not delay genetic assessment of a persistent neurodevelopmental problem. [1]

Examination should reconstruct the trajectory from pregnancy, birth and early acquisitions, including motor coordination, language, interaction, independence and any skill loss. A three-generation pedigree helps identify transmission, other inheritance patterns or possible distinct diagnoses. Head circumference, height and weight should be measured together, tone and reflexes assessed, and signs guiding differential diagnosis sought. The hypothesis should remain broad when the combination of manifestations lacks sufficient specificity to select a single gene. [1, 5]

4.2. Situations requiring urgent assessment or a change of hypothesis

Once a causal variant is found, acquired problems and a second diagnosis remain possible. Indiscriminate attribution of new symptoms to the syndrome may delay treatment of infection, pain or epilepsy. The molecular result organises follow-up but does not replace usual clinical reasoning. [1]

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria and molecular confirmation

There are no published consensus clinical criteria permitting ODLURO diagnosis through a score of signs. Diagnosis is established by combining compatible manifestations with a heterozygous pathogenic or likely pathogenic KMT2E variant. In deletions, the affected interval should be characterised. Gene-targeted investigation is appropriate for an already known familial variant; in an undiagnosed child, the non-specific phenotype favours a broader genomic approach. [1]

The report should identify the variant, zygosity, transcript and version, method used, coverage and deletion/duplication analysis, classification, rationale and parental testing when performed. VUS classification is not resolved by the number of signs that “match” the syndrome. Molecular evidence must be assessed for sufficiency and other causes sought where appropriate. Interpretations may change with additional information, warranting a reassessment and contact policy discussed with the family. [1, 16]

5.2. Current choice of tests

The 2021 ACMG guideline recommends exome/genome as a first- or second-line investigation for children with developmental delay, intellectual disability or congenital abnormalities. The 2025 AAP report places genome or exome with chromosomal microarray analysis in the first stage of investigation without a specific hypothesis. Microarray may be performed in parallel or sequentially with exome; it may be unnecessary after genome with adequate copy number variant analysis. Choice also depends on technical coverage and resources. [23, 24]

The same report moves fragile X testing and metabolic screening to the second stage in non-specific presentations, retaining early targeted investigation when suggestive signs exist. It is inappropriate to delay investigation of a treatable cause in the presence of regression, decompensation or specific metabolic signs. [24]

GeneReviews estimates that sequencing identifies approximately 95% of described pathogenic variants and that microarray and deletion/duplication methods recover an additional proportion. These values describe the classes of abnormalities observed in published cases. They are not 95% clinical sensitivity for diagnosing any suspected individual, and should not be added as independent fractions because methods may detect the same deletions. Actual sensitivity depends on platform, coverage, analysis and variant class. [1]

5.3. Practical algorithm

1. Document the developmental problem: longitudinal history, examination, anthropometry, adaptive functioning and pedigree; identify seizures, regression or other signs requiring immediate assessment. [1]
2. Explain tests and obtain consent: discuss possible results, VUS, additional findings and family implications; choose a broad investigation when the phenotype is non-specific. [1]
3. Investigate sequence and copy number variants: define exome/genome or an appropriate panel and supplement deletion analysis when needed. [1]
4. Interpret the KMT2E result: confirm nomenclature, mechanism, classification and clinical compatibility; test parents and delineate contiguous abnormalities. [1]
5. If there is only a VUS: expand clinical information, segregation and, when useful and available, functional studies; do not automatically close the differential diagnosis. [1]
6. If the result does not clarify aetiology: review coverage and classes of abnormalities not investigated, consider other diagnoses and plan reanalysis according to clinical context and laboratory capacity. [1]
7. After confirmation: initiate baseline assessment, the functional therapeutic plan and family counselling, without waiting for all possible complications to manifest. [1]

In a person with epilepsy and intellectual disability, ILAE guidance on genetic testing favours broad sequencing with copy number variant analysis and pre- and post-test counselling. Negative or uncertain results should be reconsidered in the light of evolution and newly available analyses. Identification of a genetic cause is not, by itself, an absolute contraindication to epilepsy surgery assessment; the decision depends on clinical data and a specialist team. [25]

5.4. Baseline assessment after diagnosis

The table adapts the assessments proposed in GeneReviews, including its indication criteria for EEG and MRI. Hearing and vision should be considered in developmental and language assessment, because problems in these systems may be treatable and alter interpretation of abilities. No specific biochemical test for ODLURO exists, nor an MRI signature that obviates the molecular result. [1]

6. Differential Diagnosis

6.1. ODLURO, Rahman and Tatton-Brown–Rahman

The summarised differences come from GeneReviews and the Oxford approach to overgrowth. The word “Rahman” in two eponyms does not imply the same gene. In the H1-4 syndrome, ectodermal, dental, skeletal, cardiac and thyroid abnormalities may guide recognition and assessment. They should not be incorporated as frequencies or mandatory recommendations for ODLURO. The molecular distinction should appear in the clinical report and documents given to the family, preventing a search using the wrong name from leading to inappropriate counselling. [1, 4, 5]

6.2. Other diagnoses to consider

Differential diagnosis should be guided by additional signs and mechanisms that the chosen method can detect. Segmental growth or skin changes may require investigation of mosaicism in appropriate tissue, whereas a hypothesis of an imprinting abnormality may require a specific methylation test. The table is clinical guidance; it does not replace interpretation of each person's features or establish that protocols for the listed conditions apply to KMT2E. [1, 5]

A presentation appearing compatible with ODLURO may remain molecularly unexplained. In this situation, treatment of identified needs should continue while investigation is reviewed. Developmental intervention does not depend on confirming an eponym, and an uncertain variant should not prevent investigation of another, more explanatory cause. [1]

7. Treatments and Risk Management Strategies

7.1. Objectives and organisation of care

Treatment seeks to improve communication, participation, mobility, learning, independence and comfort, as well as control complications. There is no single pharmacological protocol for KMT2E or antiepileptic drug demonstrated to be specifically effective for the syndrome. GeneReviews recommends multidisciplinary supportive care. The required team varies: clinical genetics and developmental paediatrics may coordinate assessment, with neurology, speech and language therapy, physiotherapy, occupational therapy, psychology, gastroenterology, nutrition and sleep medicine according to manifestations. Priorities should be defined by functional problems and goals agreed with the person and family. [1]

Goals should be observable: communicating a need, tolerating a school routine, acquiring a self-care activity, reducing pain episodes or sleeping with fewer interruptions. This enables benefit assessment even when the overall developmental measure does not change rapidly. Increasing consultations and therapies should be balanced against family capacity and opportunities for daily participation. A professional responsible for coordination helps integrate recommendations, recognise adverse effects and avoid incompatible plans across services. [1]

Table interventions derive from GeneReviews management recommendations; they do not represent comparative efficacy trials specific to KMT2E. Attribution of improvement to a single component should be avoided when several supports were initiated simultaneously or the child continues acquiring skills naturally. [1]

7.2. Communication, education and behaviour

Augmentative and alternative communication, abbreviated AAC, includes gestures, symbols, communication boards and speech-generating devices. Selection depends on comprehension, vision, hearing, motor function and opportunities for use. GeneReviews emphasises that AAC does not prevent speech development; it may facilitate communication and support language. It is unnecessary to wait until all verbal attempts fail before assessing this resource. Its usefulness should be tested in the environments where the person lives, and carers and teachers need guidance to use it consistently. [1]

Apparently fluent language may coexist with difficulties in working memory, flexibility and educational skills. Assessment should seek discrepancies between domains and translate the profile into practical supports: adjusted instructions, divided tasks, adequate time, visual resources and monitoring of adaptive skills. The profiles described in section 3.2 reinforce this individual attention but do not validate a single ODLURO educational programme. The effect of adaptations on participation and skill acquisition should be assessed without reducing the person to a test score. [1]

In the United States, GeneReviews describes early intervention programmes from 0 to 3 years, developmental preschool education from 3 to 5 years and individualised education programmes, known as IEPs, with annual review. It also mentions accommodations under Section 504, state developmental disability services and financial support subject to eligibility. These are examples from the US system: they should not be presented as universal rights or age limits in European countries or Brazil. In other systems, equivalent local services and the criteria actually applicable should be sought. [1]

When autism is present, behavioural interventions appropriate to the profile and needs may be used, including applied behaviour analysis in selected contexts. Intervention should support communication, participation and skills while respecting the person's tolerance. Severe aggression, self-injury or destructive behaviour requires specialist assessment and a safety plan. Before adding psychotropic drugs, pain, sleep, feeding, environment and existing medications should be investigated. Pharmacological choice follows the specific psychiatric indication and age, rather than an alleged corrective action on KMT2E. [1]

7.3. Epilepsy: treatment by seizure type and emergency plan

Treatment should be led by neurology, classifying seizures and integrating EEG, imaging and development. Some patients respond to usual medications, while others require combinations or assessment in a specialist centre. Decisions should consider efficacy, effects on attention and behaviour, interactions, renal/hepatic function, feeding and possible pregnancy. There is no evidence for starting preventive antiepileptic medication in everyone with a KMT2E variant without seizures. [1]

The written plan should explain how to recognise seizures, measure duration, protect the person and use rescue medication when prescribed, identifying when to activate emergency response. NICE considers a seizure lasting five minutes or more to be convulsive status epilepticus and recommends urgent treatment according to the individual plan or emergency protocol. The rescue drug and dose should be prescribed for the specific age, weight, route and product; the following table is not a rescue regimen. [22]

7.4. Examples of symptomatic therapy: doses, formulations and labels

Doses are per dose where specified; 30 mg/kg twice daily corresponds to 60 mg/kg/day. The US and European examples should not be interchanged indiscriminately across different age groups. Oral solution should be measured with a calibrated device. The situation of a person with ODLURO depends on seizure type, age and regimen: approval for epilepsy is not equivalent to approval to modify the syndrome. [26, 27]

A centralised European authorisation does not guarantee access, reimbursement or availability of each formulation in every country. Prescribing should use the available product's label and local pathways. No data permitting quantification of specific access in Portugal or Brazil were identified in the syndrome sources consulted. The distinction between authorised indication, clinical extrapolation and off-label use should appear in the therapeutic decision where applicable.

7.5. Ketogenic diet and advanced interventions

GeneReviews describes developmental regression during a ketogenic diet in a published case and mentions an additional personal observation. The relationship with seizure control is not uniform across the source passages. These reports warrant caution and monitoring of development, feeding and clinical status when the diet is considered. They do not demonstrate an absolute contraindication, but neither do they demonstrate KMT2E-specific benefit. The indication should be discussed by an epilepsy and nutrition team, weighing alternatives and an explicit follow-up plan. [1]

In cases of insufficient control, event classification, dose adequacy, adherence and adverse effects should be confirmed before presuming strategy failure. Referral to an epilepsy centre enables discussion of case-appropriate options, including specialist investigation. A genetic cause does not exclude all assessment of non-pharmacological options, but there is no universal indication for surgery or another advanced intervention solely because of an ODLURO diagnosis. [1, 25]

7.6. Sleep, feeding and gastrointestinal symptoms

The sleep approach begins with routine and environment, identification of pain, reflux, constipation, medication and nocturnal events. A diary may help distinguish sleep initiation difficulty, awakenings and daytime somnolence and assess response. Formulation and objective should be explicit if pharmacological treatment is used: improving sleep differs from modifying development, and experience with one formulation is not equivalent to another. Pharmacological choice should observe the age, formulation and indication requirements described in the table in section 7.4. [1]

Nutritional assessment should prioritise sufficient, safe feeding. Feeding and swallowing therapy, consistency adjustments and nutritional support are selected according to the identified problem. When intake or swallowing does not permit adequate, safe nutrition, enteral support should be discussed with the team and family. The procedure requires its own clinical decision; it should not follow solely from the syndrome name. [1]

Constipation and reflux are treated according to age-specific protocols and gastrointestinal assessment. Intake measures, a bowel routine, pharmacological treatment when necessary and review of contributing factors may reduce distress. Suspected dysmotility or persistent vomiting may warrant specialist investigation. No diet, supplement or gastrointestinal medication has been demonstrated to be specific to ODLURO, and symptoms do not authorise attribution of all abdominal pain to the genetic disease. [1]

7.7. Research, registries and therapeutic horizon

Searches in public study and literature indexes cannot prove that no unretrieved study ever exists or is beginning. Participation should be assessed according to the actual protocol, objectives, consent, burdens and eligibility. Data collection projects, biomarker studies and therapeutic trials are different categories. Results from chromatin models do not justify clinical use of an epigenetic drug as syndrome treatment without appropriate human evidence. [1, 20]

7.8. Special populations and situations

In infants, hypotonia, feeding and development should be assessed without extrapolating doses for older children. During school-age childhood, demands emerge that may make language, attention and adaptation difficulties more evident. In adolescence and adulthood, the plan should include social participation, mental health, possible independence, sexual health and continuity of care. Chronological age alone does not determine decision-making capacity; information should be adapted and offered directly to the person whenever possible. [1]

If a woman with ODLURO is planning pregnancy, genetic transmission should be discussed and medications reviewed individually, particularly those used for epilepsy or psychiatric problems. No validated KMT2E-specific obstetric protocol exists or evidence for presuming that the diagnosis implies a particular gestational complication. Medication should not be stopped abruptly without specialist assessment; guidance should follow the specific drug and clinical risk. [1]

8. Reproductive Options and Family Counselling

8.1. Clarifying the molecular event in the family

The first step is to confirm that the result explains the diagnosis and test parents for the identified variant. If the alteration is present in one parent, their developmental and learning history should be investigated, as the phenotype may be mild. Reference information documents maternal and paternal transmission and families with more than one affected child. “Usually de novo” therefore does not mean “always de novo”. [1]

When the variant is undetected in parental blood, de novo occurrence is considered, but the possibility of germline or gonosomal mosaicism remains. Blood testing does not directly assess all gametes and may not detect low-level mosaicism. Subtle clinical expression also does not exclude mosaicism. The meaning of the result should be explained without assigning blame to habits, pregnancy events or parental decisions. [1]

The table's values and limitations derive from GeneReviews counselling. Repeated pregnancy does not alter the principle of Mendelian transmission of a constitutional dominant variant. Greater male representation in some series does not change the probability of a son or daughter inheriting the variant. In cases with a deletion or rearrangement, parental investigation should be adapted to genomic structure, because a chromosomal mechanism may require additional analysis. [1]

8.2. Reproductive options

After identifying the causal variant, conception without testing, prenatal diagnosis through an appropriate procedure, preimplantation genetic testing for monogenic disease, abbreviated PGT-M, use of donated gametes and other options according to the family's values and circumstances may be discussed. Discussion should preferably precede pregnancy, be non-directive and supported by understandable information. Technical and regulatory availability varies by country and centre. [1]

Prenatal diagnosis and PGT-M investigate the familial alteration but do not reliably predict intellectual disability, epilepsy or independence. Normal ultrasonography does not exclude ODLURO, whose core clinical features often become evident after birth. Available information on variants and molecular classes is insufficient to turn a fetal result into an exact severity prediction. This uncertainty should form part of consent, avoiding prognostic promises unsupported by cohorts. [1]

Usual non-invasive prenatal aneuploidy screening is not equivalent to a diagnostic test targeting the familial KMT2E variant. The method should be chosen with the genetics and fetal medicine team. If a parent has a causal variant, offering targeted testing to at-risk relatives may be appropriate, accompanied by counselling and clinical needs assessment. The decision to test should consider the objective and implications for the person rather than technical possibility alone. [1]

8.3. Information for the person and family

The result should be delivered with clear nomenclature and a clinical summary distinguishing ODLURO/KMT2E from Rahman/H1-4. Explaining what the test demonstrated, what remains unpredictable and what care is recommended facilitates future decisions and reduces erroneous information obtained through searches using similar eponyms. Conversations may need repeating as new stages of development, reproduction or care transition arise. [1, 4]

9. Special Considerations: Population Diversity and Epidemiology

9.1. Distribution and sample selection

The population frequency of ODLURO is not established. Principal sources describe international collaboration rather than sampling permitting prevalence estimation for the United States, Europe or any country. Access to sequencing and specialist services influences identification. Adults with mild difficulties may never have undergone genomic investigation, and children with complex needs may be more readily referred. Absence of a national rate does not mean the condition exists only in countries publishing cases. [1]

The Simons Searchlight portal reports more than 120 people identified by 2025. This is information from a research and family resource, with a different framework from the 61 cases in the 2024 bibliographic compilation. It should not be interpreted as a homogeneous cohort with complete assessment or used as the numerator of a population rate. Appropriate comparison requires knowledge of criteria, possible overlap and the definition of “identified”. [1, 31]

9.2. Sex, ancestry and founder populations

The first cohort had more than 70% male participants. GeneReviews also notes exploratory sex differences: in an analysis of people with truncating variants, seizures were described in 3/7 females and 1/21 males. Small denominators, selection and assessment differences prevent treating these proportions as consolidated risks for each sex. They imply neither X-linked inheritance nor preferential transmission to children of one sex. [1, 6]

No well-established founder effect determining a different screening approach was identified in the principal articles and background sources consulted. A recurrent variant in unrelated families does not, by itself, demonstrate common ancestry: it may result from mutational recurrence or better recognition. Predominance of de novo variants likewise does not exclude transmitting families, but reduces the utility of assuming a founder variant without specific data. [1]

The consulted sources do not provide robust population estimates specific to Portugal or Brazil. It is inappropriate to extrapolate a European series' size to these countries or convert participation of centres or authors in an article into national prevalence. Care should consider language, test access, education, family resources and population-adapted instruments. Cultural or linguistic differences may influence assessment and questionnaires and should be considered before attributing all difficulty to the syndrome. [1]

9.3. European network and family resources

ERN-ITHACA, the European network for rare malformations, intellectual disability and neurodevelopmental disorders, is the relevant network for this context. Its neurodevelopment group brings together clinical expertise, intellectual disability/autism, psychiatry and genetics. Referral depends on national services and pathways; the network's existence does not imply automatic direct consultation in any country. [32]

Simons Searchlight provides KMT2E information and opportunities for research participation. Unique, listed in support sources, also provides accessible information on rare genetic abnormalities. Family resources may reduce isolation and support communication with services, but personal reports do not replace clinical assessment or permit extrapolation of medication response. Materials using the correct molecular entity should be sought. [1, 31, 33]

10. Illustrative Clinical Case

10.1. Published case: splicing alteration and epilepsy

Cao and colleagues described a Chinese boy assessed at 3 years and 9 months for nocturnal seizures, with developmental delay. Exome and familial confirmation identified the de novo c.1248+1G>T variant in KMT2E. A minigene demonstrated exon 12 skipping. Initially normal MRI subsequently showed delayed myelination. Valproate with topiramate was used; after seizure recurrence and treatment adjustment, the last reported follow-up recorded one year without seizures, with an altered EEG background. These are data from one case, not a syndrome-specific therapeutic regimen. [17]

The functional assay and exon skipping are presented in Figure 2 of the original article. The article uses NM_182931 without specifying a version; historical nomenclature is retained here without inventing normalisation. [17]

The case illustrates the distinction between recognising a neurological problem, finding a variant and demonstrating its molecular consequence. An initially normal MRI does not close aetiological investigation. An individual's subsequent response does not prove superiority of that medication combination, and recurrence requires clinical assessment regardless of the genetic result. In guiding the family, test results, seizure follow-up and persistent developmental needs should be separated. [1]

10.2. Complementary published case: synonymous variant

Benvenuto and colleagues described an Italian boy aged six years, with first words at three years, normal EEG and non-specific MRI abnormalities. A panel of 338 genes identified the de novo NM_182931.3:c.186G>A, p.(Ala62=) variant after negative microarray and FMR1 testing. RNA analysis showed products of 315 and 215 base pairs, with exon 4 skipping confirmed by sequencing. The case illustrates how a synonymous variant can alter RNA processing. [14]

The practical value is to retain relevant splicing variants in interpretation and use appropriate functional assays when they can clarify causality. This does not mean every synonymous variant needs an assay or that a computational prediction alone is sufficient. A negative investigation using one method does not exclude classes of abnormalities it does not investigate, and the overall clinical picture should guide subsequent steps. [1]

11. Prognosis and Long-Term Follow-Up

11.1. Development, independence and survival

The course varies and frequently permits progressive skill acquisition. Most people in reference series developed verbal language and walking, but some have substantial support needs. Current severity should be assessed through actual functioning and opportunities for participation, without assuming a uniform trajectory. Control of sleep, pain, feeding and seizures may improve daily functioning even while the genetic cause remains. [1]

Life expectancy is insufficiently characterised. GeneReviews mentions a person alive at 54 years, demonstrating survival into adulthood, but a single case does not permit estimating mortality or declaring normal life expectancy. Series are dominated by paediatric assessment, and many adults may remain undiagnosed. There is no basis for presenting survival curves, lifetime epilepsy risk or fixed independence probabilities. [1]

11.2. Individualised surveillance

The table adapts GeneReviews surveillance, based on assessment at each visit and the clinical problem. It should not be transformed into an indiscriminate investigation calendar. No specific recommendation mandates serial EEG or MRI in all asymptomatic patients. Additional investigations and intervals depend on manifestations, treatment and individual risks. Review of each intervention's effect is necessary so an ineffective or poorly tolerated prescription does not remain merely because it was previously initiated. [1]

11.3. Transition to adult care

The ERN-ITHACA guideline published in a 2026 volume, with electronic publication in October 2025, recommends starting adulthood planning at 13–14 years, with review at least annually. It proposes a named professional, coordination in adult care, a complete clinical summary and an individual plan. Transfer should occur with relative stability, rather than depending solely on a rigid age. Accessible communication, participation of the person, functional and mental health assessment, medications, social needs and continuity of contacts must be prepared. [34]

For ODLURO, the transition summary should include the molecular diagnosis with correct nomenclature, seizure status and emergency plan where one exists, means of communication, adaptive profile, therapies and adverse effects. The objective is for the new service to maintain care without relying on the family to reconstruct the entire history at every consultation. Independence may include different support levels, and decision-making capacity should be assessed by task and with appropriate adaptations. [1]

Education, occupational activity, relationships, sexual health and reproduction should be discussed in a manner adapted to the person. Genetic counselling may need revisiting when patients themselves begin making reproductive decisions. Parents having understood the diagnosis during childhood does not guarantee that the person has received it accessibly in adolescence or adulthood. [1]

11.4. Reassessment of genetic information and research participation

Follow-up should ensure the molecular report remains available and that a pathway for reanalysis exists when the result was uncertain, the technique limited or the phenotype changed. A well-established causal test need not be systematically repeated merely because a particular interval has elapsed. Updating knowledge about the variant, phenotypes and new resources may be useful, particularly at transition or reproductive planning. Registry participation should be voluntary and distinguish data collection from therapeutic intervention. [1, 25, 31]

12. Summary and Final Considerations

ODLURO syndrome is associated with KMT2E. HIST1H1E/H1-4 corresponds to Rahman syndrome and DNMT3A to Tatton-Brown–Rahman syndrome; this distinction prevents diagnostic and surveillance errors. The core of ODLURO is developmental delay with variable expression, frequently involving language, hypotonia, behaviour and head circumference. Epilepsy, sleep and gastrointestinal problems require targeted assessment but do not necessarily occur in everyone. [1, 4, 5]

Confirmation depends on rigorously interpreted molecular evidence. A VUS does not confirm the syndrome, a synonymous variant may affect splicing and a contiguous deletion may have additional effects. Available frequencies describe clinical series rather than population risks. Care combines developmental intervention and symptomatic treatment, with attention to doses, ages and regulatory differences. Counselling should explain transmission, residual mosaicism and limitations of severity prediction, accompanying the person from childhood into adulthood. [1]

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