Nkx6-2-Related Disorder

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.

Suggestive Findings

NKX6-2-related disorder should be suspected in individuals with the following clinical and brain MRI findings.

Clinical findings

• Onset between birth and age five years of either spasticity or hypotonia with rapid progression to spasticity (typically manifesting as spastic quadriplegia in those with early onset)
• Motor delay or developmental delay in those with a more severe phenotype
• Nystagmus
• Visual impairment manifest in severely affected children as loss of visual fixation and ocular pursuit and in older individuals as severe limitation of eye movements
• Hearing impairment
• Ataxia
• Dystonia particularly involving the upper limbs

Brain MRI findings

• Neonatal/childhood-onset disease. Diffuse and severe hypomyelination of subcortical and deep white matter including the external capsules; globi pallidi; thalami; and peridentate, mesencephalon, pons, and cerebellum as early as age nine months. T₂-weighted and FLAIR signal are diffusely increased in the white matter with corresponding iso- to hyperintense signal on T₁-weighted images (see Figure 1).
• Later-onset disease. The same findings as in neonatal/childhood-onset disease plus cerebellar atrophy and diffuse spinal cord volume loss with abnormal T₂-weighted hyperintensity of the ventral and dorsal horn cells

Figure 1.

T₁-weighted and T₂-weighted MRIs in NKX6-2-related disorder Column 1. Normal to hyperintense T₁-weighted white matter signal suggestive of hypomyelination observed in areas corresponding to the T₂-weighted hyperintense signal change (column 2) involving (more...)

Establishing the Diagnosis

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 (see Table 1).

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) or comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with ataxia and/or spasticity are more likely to be diagnosed using genomic testing (Option 2).

Clinical Description

NKX6-2-related disorder is characterized by a spectrum of progressive neurologic manifestations resulting from diffuse central nervous system hypomyelination. To date NKX6-2-related disorder has been reported in 25 individuals from 13 families [Anazi et al 2017, Chelban et al 2017, Dorboz et al 2017, Baldi et al 2018].

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 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), cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia), and loss of developmental milestones.

Affected individuals are born at term following uneventful pregnancy and delivery.

Nystagmus is usually the first manifestation and has been reported as early as age three months. Other ocular features include loss of visual fixation and ocular pursuit, reduced up-gaze, and limited voluntary eye movements [Chelban et al 2017, Dorboz et al 2017, Baldi et al 2018].

Pyramidal syndrome, characterized by increased muscle tone in the lower extremities, hyperreflexia, and positive Babinski sign, has been present in all affected individuals reported to date. Some children with neonatal onset presented with hypotonia that progressed to spasticity within a few months [Dorboz et al 2017, Baldi et al 2018].

Extrapyramidal syndrome can be associated with NKX6-2-related disorders and most frequently presents with cervical and/or limb dystonia that can lead to development of joint contractures.

Cerebellar syndrome develops during later infancy and is characterized by dysarthria, titubation, and truncal and limb ataxia. Complications such as dysphagia lead to recurrent aspirations and the need for gastrostomy feedings in more advanced stages [Dorboz et al 2017, Baldi et al 2018]. Not all children develop a cerebellar syndrome.

Walking and mobility vary. Children with neonatal onset and severe disease never achieve ambulation [Dorboz et al 2017, Baldi et al 2018]. At the milder end of the spectrum affected individuals achieve early motor milestones (sitting independently) but are not able to walk well or run. Mobility aids are used during childhood, and disease progression typically leads to wheelchair dependence in the second decade of life [Chelban et al 2017].

Cognitive function varies greatly. Severe developmental language and motor delay with arrested speech development was reported in children at the severe end of the spectrum [Anazi et al 2017, Dorboz et al 2017, Baldi et al 2018]. In contrast, some individuals have mild intellectual disability, and one individual has normal cognitive function and has completed a university degree [Chelban et al 2017]. However, in some instances cognitive function is difficult to assess fully due to severe motor impairment.

Seizures have been reported in some individuals. The motor phenotype can vary from severe [Anazi et al 2017] to mild. Clinically evident tonic seizures, secondary generalized seizures, and focal seizures have been confirmed on electroencephalography [Author, personal observation].

The following additional features have been reported:

• Failure to achieve head control
• Hearing impairment
• Recurrent apnea, with some children developing respiratory failure that leads to early death
• Congenital abnormalities including congenital heart disease and undescended testes

Neurophysiologic studies

• Normal electromyogram and nerve conduction studies [Chelban et al 2017]
  • Delayed visual evoked potentials [Dorboz et al 2017]
• Absent somatosensory evoked potentials
• On EEG, loss of age-based background activity and absent anterior-posterior gradient of background activity and multifocal epileptic discharges [Author, personal observation]

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been associated with biallelic NKX6-2 pathogenic variants.

Of note, biallelic pathogenic variants in the homeobox domain (c.487C>G, c.606delinsTA, c.565G>T, c.599G>A, c.589C>T, c.608G>A, c.196delC) are associated with a severe phenotype including early onset (i.e., soon after birth), severe psychomotor developmental delay, widespread hypomyelination on MRI, and rapid disease progression leading in some instances to death in the first years of life [Anazi et al 2017, Chelban et al 2017, Dorboz et al 2017, Baldi et al 2018].

Prevalence

Prevalence is not known. To date, 25 affected individuals from 13 families of different ethnic backgrounds (northern European, Arab, North African, Asian) have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NKX6-2-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations