O'Donnell-Luria–Rodan syndrome

Presentation

O'Donnell-Luria–Rodan syndrome nearly always involves neurodevelopmental challenges, including global developmental delay and mild-to-moderate intellectual disability. Children tend to hit motor milestones later than usual—on average, they start walking and saying their first words around 20 months, compared to roughly 12 months for typically developing kids. Physical growth, including height and weight, is usually normal. Speech delays are frequent, but most people eventually learn to communicate verbally; in rare instances, speech may regress or a person may remain nonverbal.

Velopharyngeal dysfunction can make speech harder. Muscle tone is often low, which improves with age but doesn't completely go away, sometimes causing feeding problems in infancy and constipation. Other digestive issues include vomiting and reflux. Some individuals have syndromic autism, which is more common in males.

Behavioral issues such as aggression, anxiety, repetitive movements, self-harm, and skin-picking can appear. Executive function problems, like trouble with flexible thinking and working memory, are common. About one-third of people have seizures, with females affected more often; seizure severity ranges widely, and severe cases can involve drug-resistant epilepsy or neonatal encephalopathy.

Roughly half experience trouble falling asleep and frequent waking. No consistent physical features are tied to the syndrome, but reported traits include a long head, large forehead, prominent cheeks, deep-set puffy eyes, downslanting palpebral fissures, hyperflexible joints, and usually a larger head size (though smaller head size is possible). Rarely, heart defects, kyphosis, tapering fingers, or undescended testis occur. Brain scans may be normal or show benign findings like a thin corpus callosum, white matter hyperintensities, or reduced cerebral and cerebellar volume.

Mechanism

The KMT2E gene, located on chromosome 7, provides the blueprint for the MLL5 enzyme. This enzyme is a histone modifier found in most human cells. MLL5 teams up with two other proteins, HCF-1 and OGT, to work with the transcription factor E2F1.

Together, they add a methyl group to a specific spot on histone 3, a modification known as H3K4me3. This change keeps chromatin open, which is essential for genes to be read. H3K4me3 helps drive the cell cycle forward from the G1 to S phase.

MLL5 also helps cells move from G2 into mitosis and supports the spindle apparatus during cell division. It further helps maintain the genome's stability. These processes are important in the developing nervous system and cerebral cortex, where they affect the environment around neurons and support cells. O'Donnell-Luria–Rodan syndrome arises from harmful changes in the KMT2E gene, such as missense, nonsense, frameshift, truncating, or splice-site variants.

Only one faulty copy of the gene is needed to cause the condition, likely due to haploinsufficiency. This means the syndrome follows an autosomal dominant inheritance pattern, with a 50% chance of passing it to a child. Most reported cases, however, occur spontaneously and are not inherited.

Management

Care for O'Donnell-Luria–Rodan syndrome is supportive, tailored to each person's symptoms and developmental needs to boost quality of life. Doctors periodically track head size and developmental milestones. Children with delays are referred for early intervention and special education, which can include physical, occupational, and speech therapy. If feeding problems persist, a feeding tube may be needed.

When seizures are suspected, an EEG and brain MRI may be done, and anti-seizure drugs are chosen based on the seizure type and severity. Care teams often include geneticists, developmental pediatricians, and neurologists. Genetic counselors help families understand recurrence risks and discuss family planning and prenatal testing. Palliative care and social workers can provide support for families and help with nursing home options.

Did You Know?

• Studies published between 2012 and 2016 identified KMT2E variants in individuals with non-syndromic autism.
• The syndrome was first described by physician geneticists Anne O'Donnell-Luria and Lance Rodan at Boston Children's Hospital/Harvard Medical School in 2019.
• As of 2025, around 120 individuals have been diagnosed with the condition.