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NKX6-2-Related Disorder

Synonyms: NKX6-2-Related Spastic Ataxia with Hypomyelination, SPAX8

, MD, , PhD, , MD, and , MD, PhD.

Author Information

Initial Posting: .

Summary

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 diagnosis are possible.

Diagnosis

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 global 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.

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).

Option 1

When the phenotypic and imaging findings suggest the diagnosis of NKX6-2-related disorder, use of a multigene panel is recommended.

An ataxia, spastic paraparesis, or hypomyelinating leukodystrophy multigene panel that includes NKX6-2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of NKX6-2-related spastic ataxia with hypomyelination, some panels for ataxia and/or spasticity may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity with hypomyelination on brain MRI, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in NKX6-2-Related Disorder

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
NKX6-2Sequence analysis 313/13 families 4
Gene-targeted deletion/duplication analysis 5Unknown (no data available)
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

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]
  • 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 global 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.

Differential Diagnosis

Hypomyelinating leukodystrophies and spastic ataxias (particularly when associated with hypomyelination) should be considered in the differential diagnosis of NKX6-2 related disorder. See Table 2.

Table 2.

Movement Disorders to Consider in the Differential Diagnosis of NKX6-2-Related Disorder

DisorderGene(s)MOIOverlapping Clinical FeaturesDistinguishing Clinical Features
OnsetMovement disorderBrain MRIOther
Pelizaeus-Merzbacher disease (PMD) (see PLP-Related Disorders)PLP1XLInfancy or early childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelination; cerebellar atrophyEarly-onset nystagmusNull PLP1 variants are associated w/mild demyelinating neuropathy & reduced levels of N-acetyl aspartate in cerebral white matter.
Pelizaeus-Merzbacher-like disease 1 (PMLD1)GJC2AREarly childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelination
  • Very similar to NKX6-2-related disorder
  • Developmental & speech delay
  • Preservation of cognition
In PMLD1:
  • Thinning of the corpus callosum in some
  • No cerebellar atrophy on MRI
POLR3-related leukodystrophyPOLR3A
POLR3B
POLR1C
AREarly childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelinationInPOLR3-related leukodystrophy:
  • Abnormal dentition
  • Hypogonadotropic hypogonadism
Hypomyelination w/atrophy of basal ganglia & cerebellum (H-ABC) (see TUBB4A-Related Leukodystrophy)TUBB4AADInfancy or childhoodPyramidal & cerebellarDiffuse cerebral hypomyelinationMotor developmental delayIn H-ABC:
  • Abnormalities of basal ganglia, particularly atrophy (a classic sign)
  • Aphonia or "whispering" dysphonia may be a feature. 1
Salla disease (see Free Sialic Acid Storage Disorders)SLC17A5ARBirthPyramidal & extrapyramidalHypomyelination
  • Psychomotor retardation
  • Seizures
In severe form of Salla disease:
  • Severe developmental delay
  • Coarse facial features
  • Hepatosplenomegaly
  • Cardiomegaly
  • Death usually in early childhood
1.

TUBB4A pathogenic variant c.4C>G causes the adult-onset disorder laryngeal dysphonia or whispering dysphonia (also known as DYT4 dystonia), with normal MRI.

See Hereditary Ataxia Overview, Hereditary Spastic Paraplegia Overview, and Leukodystrophy Overview.

See Spastic Ataxia: OMIM Phenotypic Series and Hypomyelinating Leukodystrophy: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

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.

Table 3.

Recommended Evaluations Following Initial Diagnosis of NKX6-2-Related Disorder

Organ SystemEvaluationComment
ConstitutionalHeight, weight, head circumferenceAssess for evidence of failure to thrive.
EyesOphthalmologic evaluationAssess for:
  • Reduced vision;
  • Abnormal ocular movement.
HearingAudiologic evaluationAssess for hearing loss.
CardiovascularConsideration of echocardiogramTo screen for congenital heart defects
RespiratoryAssessment of :
  • Airway
  • Pulmonary function
  • Secretion management
Sleep study to assess for apnea
GastrointestinalAssessment (particularly in later stages of disease) of:
  • Swallowing
  • Feeding
  • Nutritional status
Determine safety of oral vs gastrostomy feeding.
MusculoskeletalReferral to specialist in pediatric pain managementFor those who have pain due to deforming joint contractures
Referral to rehabilitation specialistTo evaluate mobility & ability to perform activities of daily living
GenitourinaryPhysical examination for cryptorchidism in malesRefer males w/cryptorchidism to urologist.
NeurologicReferral to pediatric neurologistAssess for evidence of spasticity &/or seizure activity.
Miscellaneous/
Other
Consultation w/clinical geneticist or genetic counselor
Developmental assessmentEvaluate the following:
  • Motor skills
  • Speech/language
  • General cognitive skills
  • Vocational skills
Referral to palliative care specialistWhen deemed appropriate by family & care providers
Family support/resources
  • Community or online resources (e.g., Parent to Parent)
  • Social work involvement for parental support
  • Home nursing referral if needed

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with NKX6-2-Related Spastic Ataxia with Hypomyelination

ManifestationTreatmentConsiderations/Other
EyesStandard treatment as per ophthalmology reviewCommunity vision services through early intervention or school district
HearingHearing aids may be helpful as per otolaryngologist.Community hearing services through early intervention or school district
Congenital heart defectStandard treatment per cardiologist
Respiratory insufficiencyStandard treatment as per respiratory review; consider assisted ventilation as appropriate.
  • Airway & pulmonary assessment for evidence of decreased pulmonary function or poor secretion management
  • Sleep study
Dysphagia/
Inadequate
nutrition
Nasogastric or gastrostomy tube may be required.Maintain a low threshold for clinical feeding evaluation &/or radiographic swallowing study when patient shows clinical signs &/or symptoms of dysphagia.
CryptorchidismStandard treatment per urologist
Spasticity
  • Physiotherapy (including stretching) to avoid contractures & falls
  • Trial of pharmaceutical agents (e.g., baclofen or tizanidine) as recommended by rehabilitation specialist
  • Assess for evidence of spasticity.
  • Consider need for positioning & mobility devices, disability parking placard.
SeizuresAntiepileptic drugsTypically difficult to control 1
Family/
Community
  • Appropriate social work involvement to connect families w/local resources, respite, & support
  • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
  • Ongoing assessment for need of palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics
1.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Global Developmental Disability / Intellectual Disability Educational Issues

Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the United States, early intervention is a federally funded program available in all states; it provides in-home services to target individual therapy needs.

Ages 3-5 years. In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; however, home-based services are provided for children too medically unstable to attend.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services are for those who require specially designed instruction / related services.
    • IEP services will be reviewed annually to determine if any changes are needed.
    • As required by special education law, children should be in the least restricted environment at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
  • 504 plan services can be considered for those who require accommodations or modifications including front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, enlarged text,and other accomodations.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency in the US that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and, in many cases, can improve it.

Feeding issues. Oral-motor dysfunction should be reassessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Feeds can be thickened or chilled to provide more safety but when severe feeding dysfunction is present, an NG-tube or G-tube may be necessary. Feeding therapy can be helpful to improve coordination or sensory-related feeding issues.

Prevention of Secondary Complications

The following additional recommendations are based on the leukodystrophies consensus [Van Haren et al 2015]:

  • Frequent repositioning and skin care to avoid skin sores in affected individuals who are not mobile
  • Yearly flu vaccination
  • Vitamin D supplementation (to prevent osteoporosis)

Surveillance

Table 5.

Recommended Surveillance for Individuals with NKX6-2-Related Disorder

Organ SystemEvaluationFrequency
EyesVisual acuity & eye movementAt each visit
HearingFormal audiology assessmentAs required
RespiratorySleep studies recommended if signs of apneaAs required
Gastrointestinal/
Feeding
Measurement of growth parametersAt each visit
Evaluation of nutritional status & safety of oral intakeAt each visit
NeurologicAssessment of developmental progressAt each visit
Assessment for progression of spasticity & contractures w/yearly hip & spine x-rayAt each visit
EEGIf concerns for new seizure activity or progression of seizures

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NKX6-2-related disorder is inherited in an autosomal recessive manner.

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one NKX6-2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with NKX6-2-related disorder are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a NKX6-2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the NKX6-2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the NKX6-2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)
    Email: information@sp-foundation.org
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

NKX6-2-Related Disorder: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
NKX6-210q26​.3Homeobox protein Nkx-6.2NKX6-2NKX6-2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for NKX6-2-Related Disorder (View All in OMIM)

605955NK6, DROSOPHILA, HOMOLOG OF, 2; NKX6-2
617560SPASTIC ATAXIA 8, AUTOSOMAL RECESSIVE, WITH HYPOMYELINATING LEUKODYSTROPHY; SPAX8

Gene structure. NKX6-2 (NM_177400.2) has three exons and encodes a protein of 277 amino acids (NP_796374.1).

Pathogenic variants. Known pathogenic variants are listed in Table 6.

Table 6.

NKX6-2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.121A>Tp.Lys41TerNM_177400​.2
NP_796374​.1
c.196delCp.Arg66GlyfsTer122
c.487C>Gp.Leu163Val
c.565G>Tp.Glu189Ter
c.589C>Tp.Gln197Ter
c.599G>Ap.Arg200Gln
c.606delinsTAp.Lys202Asnfs? 1
c.608G>Ap.Trp203Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

? = The predicted consequence of a frame-shifting variant changes Lys202 to Asn, but the new reading frame does not encounter a new translation termination (stop) codon.

Normal gene product. NKX6-2 is a recently identified member of the human homeobox gene family, which has more than 330 loci comprising 255 genes and 78 likely pseudogenes [Zhong & Holland 2011]. All homeobox family members share a sequence of 180 base pairs encoding a string of 60 self-folding amino acids [Gehring 1993] recognized as the homeodomain that acts as a transcription factor. NKX6-2 comprises 277 amino acids and has one functional domain – the homeobox (residues 151-204 of NP_796374.1).

Abnormal gene product. Truncating variants can be located throughout NKX6-2 and lead to disease through a loss-of-function mechanism. All reported pathogenic missense variants affect the major functional domain of NKX6-2, the homeobox. It is likely that disruption of the highly conserved homeobox sequence also disrupts DNA binding.

References

Literature Cited

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Chapter Notes

Author Notes

King Abdulaziz City for Science and Technology
Riyadh 12371, Saudi Arabia
Phone: +966 11 488 3555
Email: as.ude.tscak@aidem
Website

Saudi Human Genome Program
Website

King Salman Center for Disability Research
PO Box 94682
Riyadh 11614, Saudi Arabia
Phone:+966 11 4884401
Website

Acknowledgments

The authors would like to thank the patients and their families for their essential help with this work. We are grateful to the Spastic Paraplegia Foundation and the UK HSP Society, the Medical Research Council (MRC UK MR/J004758/1, G0802760, G1001253), the Wellcome Trust (WT093205MA and WT104033/Z/14/Z), the Brain Research Trust (BRT), the MSA Trust, the European Union Seventh Framework Programme FP7 (NeurOmics), Ataxia UK, the British Neurological Surveillance Unit (BNSU), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH), the Biomedical Research Centre (BRC), King Abdulaziz City for Science and Technology (KACST # 14-MED2007-20), and King Salman Center for Disability Research (KSCDR # 2180 004).

Revision History

  • 4 October 2018 (bp) Review posted live
  • 7 February 2018 (vc) Original submission
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