UNC80 Deficiency

Clinical characteristics: UNC80 deficiency is characterized by developmental delay, neonatal hypotonia, severe intellectual disability, dysmorphic facial features, strabismus, dyskinetic limb movements, and neurobehavioral manifestations. The majority of individuals do not learn to walk. All individuals lack expressive speech; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional common features include clubfeet, joint contractures, scoliosis, postnatal growth deficiency, increased risk of infections, sleeping difficulties, and constipation. Individuals have slow acquisition of developmental skills and do not have features suggestive of neurodegeneration.

Diagnosis/testing: The diagnosis of UNC80 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in UNC80 identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental services and educational support; melatonin and risperidone have been beneficial for treatment of sleep difficulties; standard treatments for irritability, seizures, spasticity, and dyskinesia; management of nystagmus and/or strabismus per ophthalmologist; feeding therapy or gastrostomy tube feeding as needed; standard management of constipation; braces and/or corrective surgeries as needed for orthopedic abnormalities.

Surveillance: Assess growth, nutritional status, safety of oral intake, and for constipation at each visit. Annual evaluations for developmental and educational needs, behavioral assessment, seizure management, ophthalmology examination, back exam for scoliosis, evaluation of contractures, and assessment of mobility and self-help skills.

Genetic counseling: UNC80 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UNC80 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the UNC80 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.