DENND5A is a protein expressed in many cell types and tissues, and thus the effects of DENND5A mutations can be observed in multiple body systems. However, DENND5A is highly expressed in the nervous system. Most phenotypes are neurological. The most prevalent phenotypes observed in individuals with biallelic DENND5A mutations include:
• Global developmental delay
• Seizures, which onset within the first year of life and rarely in utero
• Ventriculomegaly, particularly of the lateral ventricles
• Reduced corpus callosum volume
• Reduced cerebral cortex volume
• Hypotonia and/or hypertonia
• Microcephaly
Approximately half of all known individuals with DENND5A variants also have problems related to breathing and digestion. These symptoms include:
• Oropharyngeal dysphasia
• Chronic constipation
• GERD
• Recurrent aspiration
• Episodes of oxygen desaturation
Expressive and receptive language are often affected, and only a minority of individuals can speak in complete sentences at a developmentally appropriate age. Gross and fine motor skills are also affected.
Importantly, not all individuals with DENND5A mutations display every feature. Some present with autism spectrum disorder but show a normal brain MRI, do not have seizures, and have little to no language or motor deficits.
DENND5A