ATN1- Related Neurodevelopmental Disorder

Clinical characteristics: ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include infantile hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial features and hand and foot differences are common. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT). To date, 18 individuals with ATN1-NDD have been identified.

Diagnosis/testing: The diagnosis of ATN1-NDD is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in a 16-amino-acid sequence of exon 7 in ATN1 in which histidine is in every other position (His-X; HX motif), identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for ATN1-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in clinical genetics, neurology, ophthalmology, gastroenterology, cardiology, and general pediatrics.

Surveillance: Regular clinic visits are recommended due to the complexity of the medical and developmental issues. The frequency of visits should be decided on a person-by-person basis, but may need to be greater (e.g., every 3-6 months) in the first two years of life, then stretching to visits every six months to one year when the child is stable.

Agents/circumstances to avoid: In individuals with MRI-confirmed stenosis of the craniocervical junction, caution is required when manipulating the head and neck for airway management.

Genetic counseling: ATN1-NDD is an autosomal dominant condition typically caused by a de novo pathogenic variant. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo ATN1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.