| O'Donnell-Luria–Rodan syndrome | |
|---|---|
 | |
| Features can includelarge head size and forehead, prominent cheeks andnasolabial folds, deep-set eyes, and downslantingpalpebral fissures. | |
| Specialty | Medical genetics and genomics |
O'Donnell-Luria–Rodan syndrome is anultra-raregenetic disorder caused bypathogenic variants of theKMT2E gene. The clinical features generally includedevelopmental delay,intellectual disability,decreased muscle tone, sleep disturbances,syndromic autism andseizures. The syndrome occurs due toinsufficient levels of anenzyme involved ingene expression andcell cycle regulation, effectingdevelopment of the nervous system. The condition can occur spontaneously (de novo) or beinherited in anautosomal dominant manner.
Several genetic diseases share symptoms with O'Donnell-Luria–Rodan syndrome. The disease is diagnosed usinggenetic andgenomic testing in suspected individuals with characteristic presentation. Approach to management issupportive — aimed at improvingquality of life — and consists ofearly interventions,special education andanti-seizure medications. It was first delineated in 2019 and around 120 individuals have been diagnosed with the condition as of 2025.
Almost all individuals with O'Donnell-Luria–Rodan syndrome haveneurodevelopmental symptoms ofglobal developmental delay and mild-to-moderateintellectual disability.[1] Children can have delays in achievingdevelopmental milestones andmotor skills; for example, the average age of walking and speaking first words is around 20 months (compared to around 12 months for unaffected children).Physical growth is typically not affected, with normal height and weight.Delays in speech are common, although most eventually developverbal communication. In rare cases,speech regression can occur or individuals may remainnonverbal.[2] Speech can be further complicated byvelopharyngeal dysfunction.[3] Children may havedecreased muscle tone, which improves with age but does not fully resolve; this may cause feeding difficulties in infancy and constipation. Additional gastrointestinal issues include vomiting and reflux.[4]
Some affected individuals may havesyndromic autism; this is more common in males than females.Behavioral abnormalities such asaggression,anxiety,repetitive movements,self-harm andskin-picking are sometimes present.[2] Problems withexecutive functioning are common, including difficulties withflexible thinking andworking memory.[5] Less commonly, individuals may haveattention deficit hyperactivity disorder. About one-third of people with O'Donnell-Luria–Rodan syndrome experienceseizures; this affects females more than males.[4] Seizure severity varies; in severe cases,drug-resistant epilepsy and seizures causingneonatal encephalopathy have been reported.[6] Approximately half of affected individuals havedifficulty falling asleep and experience frequent awakenings.[7]
No distinctphysical features are consistently associated with O'Donnell-Luria–Rodan syndrome. However, reported features includelong head and large forehead, prominent cheeks andnasolabial fold, deep-set andpuffy eyes, downslantingpalpebral fissures, andhyperflexible joints.[8] Most have alarger head size, but some can have asmaller head size. Rarely, individuals can haveheart defects,kyphosis, tapering fingers andundescended testis.[1]Neuroimaging can be normal or showbenign brain abnormalities such as thincorpus callosum,white matter hyperintensities, reducedcerebral andcerebellar volume.[9]
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The KMT2E gene onchromosome 7 (7q22.3) providesinstructions for makinghistone-lysineN-methyltransferase 2E (also known as MLL5), ahistone-modifying enzyme widely produced by most human cells.[10] Histone-lysineN-methyltransferase 2E forms a protein complex withhost cell factor C1 (HCF-1) andproteinO-GlcNAc transferase (OGT), which then interacts withtranscription factor E2F1 (E2F1). This interaction contributes toH3K4me3,[11] anepigeneticmodification in whichhistone 3 (H3) is tri-methylated (me3) at the fourthlysine position (K4).[12]
Methylation atH3K4 is necessary to have anopen chromatin, which is consequently essential forgene transcription.[13] H3K4me3 leads togene expression, promotingcell cycle progression from theG1 toS phase.[11] Histone-lysineN-methyltransferase 2E also mediates cell transition fromG2 phase tomitosis,[14] and sustains thespindle apparatus during the latter. Furthermore, the enzyme helps maintain the structure and accuracy of thegenome through the cell cycle.[15] Processes involving histone-lysineN-methyltransferase 2E are active duringdevelopment of the nervous system and in thecerebral cortex where they influence the local environment aroundneurons and supportingneuroglia.[16]
O'Donnell-Luria–Rodan syndrome is caused bypathogenic or likely pathogenic variants of the KMT2E gene, disrupting the function of histone-lysineN-methyltransferase 2E. These can occur due tomissense,nonsense,frameshift,protein-truncating orsplice-site changes in the gene. Only a single abnormal KMT2E gene copy is needed to cause the disease, hence the condition is hypothesized to occur due tohaploinsufficiency — in which the remaining normal copy does not produce enough protein for proper function.[4] As a result, the syndrome follows anautosomal dominant inheritance pattern, and an affected individual has a 50% chance ofpassing it on to each offspring. However, most reported cases in the medical literature have beende novo, meaning the variants arose spontaneously and were not inherited from either parent.[1]
Individuals with a missense pathogenic variant in the KMT2E gene tend to have amore significant disease presentation compared to other variant types. This presents as more severe seizures,[17] and a higher prevalence of drug-resistant epilepsy. They also more often have a smaller than average head size — contrary to the larger than average head size more commonly seen with O'Donnell-Luria–Rodan syndrome — and more severe intellectual disability.[4]
O'Donnell-Luria–Rodan syndrome shares clinical findings with several genetic disorders. These includeKabuki syndrome,Wiedemann–Steiner syndrome[5] and other genetic syndromes with intellectual disability.Genetic testing typically begins withchromosomal microarray analysis usingSNP array oroligonucleotide. If that is nondiagnostic, further testing may include an intellectual disability multigene panel that includes the KMT2E gene or comprehensivegenomic testing such asexome orgenome sequencing. While exome sequencing is the most commonly used method, genome sequencing can also be used to assessnoncoding regions affectinggene regulation orsplicing and identifyingstructural variants that can be missed by exome sequencing.[4]
There is no consensus on diagnostic criteria for O'Donnell-Luria–Rodan syndrome. Diagnosis involves confirming the presence of a pathogenic or likely pathogenic KMT2E gene variant in an individual with typical clinical characteristics. When avariant of uncertain significance (VUS) is found, testing of the parents may help decide whether the variant isde novo or inherited. A new VUS in presence of clinical features or one inherited from an affected parent supports the diagnosis; conversely, a VUS inherited from an unaffected parent may suggest it is abenign variant — not causing the disease.[4]
Management of O'Donnell-Luria–Rodan syndrome issupportive, and focuses on addressing the individual's specific symptoms and developmental needs to improve theirquality of life.Head circumference and developmental milestones are monitored periodically. Children with developmental delays are referred forearly interventions andspecial education, which may involvephysical therapy to work on motor skills,occupational therapy to improve on daily functioning andspeech therapy to support language development.[4]
In cases of persistent feeding difficulties, afeeding tube placement may become necessary. If seizures are suspected, further evaluation withelectroencephalography (EEG) andbrain MRI may be performed.[4] Because seizure types vary from person to person, selection ofanti-seizure medications is personalized based on the type and severity of seizures.[18]
Specialists routinely involved in care includephysician geneticists,developmental pediatricians andneurologists.Genetic counselors help families in assessing risk of other family members having the disorder and explore options forfamily planning andprenatal testing.Palliative care andsocial work can further assist in exploring options for family support andnursing home placements.[4]
Studies published between 2012 and 2016 identified variants in the KMT2E gene in individuals withnon-syndromic autism.[19][20][21] O'Donnell-Luria–Rodan syndrome was first described by physician geneticists Anne O'Donnell-Luria and Lance Rodan atBoston Children's Hospital/Harvard Medical School in 2019.[2] As of 2025, around 120 individuals have been diagnosed with the condition.[22]
