Athabascan Brainstem Dysgenesis Syndrome (ABDS) is an extremely rare congenital syndrome characterized by brainstem dysgenesis. It presents with a variety of clinical features including congenital horizontal gaze palsy, sensorineural hearing loss, central hypoventilation, developmental delay, and facial nerve palsy.
This syndrome is caused by homozygous loss-of-function mutations in the HOXA1 gene 1). It is classified as a type of congenital cranial dysinnervation disorder (CCDD). CCDDs are a group of diseases resulting from developmental abnormalities of cranial motor neurons, broadly divided into two mechanisms: abnormal neural specification and abnormal axon guidance 1). ABDS falls into the former category.
Previously, it was sometimes misdiagnosed as Möbius syndrome, but it is now recognized as an independent syndrome with features not typically seen in Möbius syndrome, such as sensorineural hearing loss, horizontal gaze palsy, and central hypoventilation.
Moebius syndrome is a sporadic disorder characterized by non-progressive facial nerve palsy and impaired abduction of the eyes. ABDS involves sensorineural hearing loss, central hypoventilation, and moderate to severe developmental delay, which are not typically seen in Moebius syndrome. For details, see the section on “Diseases to be differentiated”.
ABDS presents with the following symptoms from birth.
Ocular Motor Findings
Horizontal gaze palsy: Bilateral impairment of horizontal conjugate gaze. Both abduction and adduction are limited.
Convergence preservation: Adduction during convergence is maintained. This is due to a defect in the abducens nucleus, while the convergence pathway of the oculomotor nerve is preserved.
Facial nerve palsy: The severity varies by case, but may present with a mask-like facial expression.
Systemic Findings
Sensorineural hearing loss: Confirmed by brainstem auditory evoked response (BAER). Bilateral.
Central hypoventilation: Respiratory failure without underlying lung disease or neuromuscular disease. Presents with hypoxia and respiratory acidosis.
Cardiovascular malformations: May be associated with vascular anomalies such as cardiac outflow tract abnormalities.
Vocal cord paralysis and epileptic seizures: Observed in some cases.
The causative gene for ABDS is HOXA1. Homozygous loss-of-function nonsense mutations in the HOXA1 gene produce a truncated protein 1). HOXA1 is an essential transcription factor for hindbrain patterning, and its deficiency causes bilateral Duane retraction syndrome-like eye movement disorder, sensorineural hearing loss, facial muscle weakness, central hypoventilation, vascular malformations, and intellectual disability 1).
The inheritance pattern is autosomal recessive. This is supported by the following findings:
All reports to date are limited to Athabaskan Native Americans.
| Tribe | Estimated prevalence | Notes |
|---|---|---|
| Navajo | 1 in 3,000 births | First reported |
| Apache | Unknown | Later case reports |
A genetic bottleneck (population size reduction) is thought to have concentrated rare alleles in the gene pool, leading to the high prevalence in this population.
To date, reported cases are limited to the Navajo and Apache tribes. However, Bosley–Salih–Alorainy syndrome caused by a different mutation in the HOXA1 gene has been reported in Saudi Arabian and Turkish populations, and HOXA1 deficiency itself can occur regardless of ethnicity.
The clinical diagnostic criteria for ABDS are as follows:
Genetic testing to identify loss-of-function nonsense mutations in the HOXA1 gene is available. It is useful for definitive diagnosis.
Möbius Syndrome
Common features: non-progressive facial nerve palsy, lateral gaze palsy
Differential points: Moebius syndrome usually does not involve sensorineural hearing loss, central hypoventilation, moderate to severe developmental delay, or vocal cord paralysis. Most cases are sporadic.
Ocular motility findings: Moebius syndrome presents with bilateral horizontal gaze palsy and mask-like facies, and may be accompanied by lagophthalmos and excessive tearing.
Bosley-Salih-Alorainy syndrome
Common features: HOXA1 deficiency, horizontal gaze palsy, hearing loss
Differential points: No central hypoventilation. More common in Saudi Arabian and Turkish populations. Caused by a frameshift (insertion) mutation in the HOXA1 gene, which differs from the nonsense mutation in ABDS.
Cerebrovascular malformation: Presents with bilateral Duane retraction syndrome type 3, and may be associated with autism and developmental delay.
HOXA1 genetic testing is available at the research level. If this syndrome is suspected based on clinical symptoms, referral to a specialized medical institution with a genetic medicine department is recommended.
There is currently no curative treatment for ABDS. Treatment is mainly symptomatic.
Oxygen supplementation and mechanical ventilation are necessary for central hypoventilation. Management similar to that for congenital central hypoventilation syndrome (CCHS) serves as a reference. In CCHS, options such as positive pressure ventilation via tracheostomy, non-invasive positive pressure ventilation (NIPPV), and diaphragmatic pacing are selected according to age and severity2)3).
In some patients, respiratory center activity has been reported to improve with age.
Hearing aids or cochlear implants should be considered for congenital sensorineural hearing loss. Early intervention with sign language is considered beneficial for preventing severe communication disorders.
Due to the high prevalence in Athabaskan populations, the following evaluations are recommended if any feature of ABDS is present.
Severity varies greatly among individuals. Some patients show improvement in respiratory center activity and swallowing function with age, but lifelong monitoring is required.
HOXA1 is a homeobox transcription factor that plays an essential role in hindbrain patterning, specifically the proper formation of rhombomeres. Studies in mouse models have shown that HOXA1 is involved in the normal development of the hindbrain, cranial nerves, inner ear, skull, and craniofacial structures. Additionally, its association with cardiovascular development has been reported.
In the abnormal neural specification of CCDDs, loss-of-function mutations in specific transcription factors required for brainstem patterning cause deficits in specific motor nuclei within the brainstem 1). In the case of HOXA1, abnormal development of rhombomeres occurs, particularly affecting the abducens motor neurons that originate from rhombomere 5.
Bilateral abducens nucleus deficiency leads to the following ocular motor disturbances.
Underdevelopment of the inner ear is thought to be related to abnormal signal transmission from the hindbrain neuroectoderm. HOXA1 is necessary for normal development of the inner ear, and its deficiency causes sensorineural hearing loss 1).
The exact mechanism of developmental delay has not yet been fully elucidated. The following multifactorial causes have been proposed.
This hypothesis is supported by the fact that developmental delay was not observed in two Navajo patients raised at low altitudes. Another hypothesis suggests that normal brainstem development itself is necessary for cognitive development.
Central hypoventilation in ABDS is caused by HOXA1 deficiency, while in congenital central hypoventilation syndrome (CCHS), which also features central hypoventilation, PHOX2B gene mutations are known to be the cause 2). PHOX2B is a transcription factor required for the development of CO₂-sensitive neurons in the retrotrapezoid nucleus (RTN) 4).
Mouse model studies have shown that the Phox2b27Ala/+ mutation causes not only central apnea but also obstructive apnea through hypoplasia of the hypoglossal nucleus 4). RTN-specific Phox2b deletion did not induce obstructive events, suggesting that impairment of hypoglossal motor neurons is the main cause of upper airway obstruction.
Both ABDS and CCHS present with central hypoventilation due to abnormalities in transcription factors involved in brainstem development, but the causative genes and pathophysiological mechanisms differ. Research findings from CCHS may be applicable to respiratory management strategies for ABDS.
HOXA1 deficiency can present with two phenotypes: ABDS (nonsense mutation) and Bosley-Salih-Alorainy syndrome (frameshift mutation). The relationship between mutation type and clinical features, as well as the identification of genetic modifiers, are future research topics. Advances in genetic research on CCDDs as a whole are expected to deepen the understanding of ABDS pathophysiology 1).
