NKX6-2-Related Disorder

Excerpt

Clinical characteristics: NKX6-2-related disorder is characterized by a spectrum of progressive neurologic manifestations resulting from diffuse central nervous system hypomyelination. At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of early motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination) and cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia) with loss of developmental milestones. To date NKX6-2-related disorder has been reported in 25 individuals from 13 families.

Diagnosis/testing: The diagnosis of NKX6-2-related disorder is established in a proband with typical clinical and neuroimaging findings and biallelic pathogenic variants in NKX6-2 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic and typically involves a multidisciplinary team of specialists in the areas of developmental pediatrics, neurology, pediatric rehabilitation, orthopedics, PT/OT, social work, nutrition, pulmonary/sleep medicine, ophthalmology, audiology, and palliative care.

Surveillance: Sleep studies for evidence of apnea. Routine assessment of: nutritional status and safety of oral intake; development; progression of spasticity and contractures.

Genetic counseling: NKX6-2-related disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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 NKX6-2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.