Athabascan Brainstem Dysgenesis Syndrome

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Article initiated by:

Andrew Go Lee, MD, Arjun Merchant, Nita Bhat, MBBS, MS, Shruthi Harish Bindiganavile, MBBS, MS

All contributors:

Arjun Merchant, Nagham Al-Zubidi, MD, Bayan Al Othman, MD, Nita Bhat, MBBS, MS

Assigned editor:

Bayan Al Othman, MD, Caroline DeBenedictis, MD

Review:

Assigned status Up to Date

 by Bayan Al Othman, MD on May 17, 2024.

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Contributing Editors:	add

Athabascan Brainstem Dysgenesis Syndrome

DiseasesDB

33191

OMIM

601536

Disease Entity

Athabascan Brainstem Dysgenesis Syndrome (ABDS) is a very rare genetic syndrome affecting the brainstem of the central nervous system that consists of congenital horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, and other variable features that can include facial paresis.

Disease

Athabascan Brainstem Dysgenesis Syndrome (ABDS) is a very rare genetic syndrome affecting the brainstem of the central nervous system that consists of congenital horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, and other variable features that can include facial paresis. Previously, these patients were mistakenly diagnosed with Möbius syndrome due to similar features such as facial weakness; however, this was ultimately found to be a distinct syndrome with characteristic features such as sensorineural deafness, horizontal gaze palsy and central hypoventilation not seen in typical Möbius syndrome.

Etiology

The genetic cause of ABDS has been determined to be HOXA1 deficiency, in which disruption of normal motor neuron development leads to loss of normal brainstem function. Genetically, patients with ABDS have been found to be homozygous for 2 loss-of-function non-sense mutations in the HOXA1 gene that lead to a truncated protein product. Mouse model studies have demonstrated that this gene is responsible for the proper development of hindbrain, cranial nerves, inner ear, skull, and craniofacial features. It also appears to be linked with cardiovascular development. Within the hindbrain, the HOXA1 gene plays a major role in rhombomere development, and this is primarily affected in the disease. Since one of these rhombomeres, specifically rhombomere 5, gives rise to abducens motor neurons, this explains the characteristic ocular motility dysfunction seen with this disease. The relationship between HOXA1 and developmental delay is yet to be fully elucidated, but proposed theories consider global cerebral hypoxia to play a role or the possibility of cognitive development requiring normal development of the brainstem.

Risk Factors

To date, cases have been identified only in the indigenous peoples of Athabascan Native American heritage, specifically, those of the Navajo and Apache tribes. Previously, the disease was only found in people from the Navajo tribe with an estimated incidence of 1 in 3000 live births, but additional cases have been reported in the Apache tribe. Possible genetic bottleneck shared by both the Navajo and Apache tribes may have attributed to onset of disease in this population when the total population decreased to allow for rare alleles to become more prevalent in the gene pool.

The inheritance of ABDS is autosomal recessive, and this is supported by its presence in a very specific population, equal distribution between males and females, and its prevalence in families of consanguineous parents. Additionally, multiple siblings with consanguineous parents were found to harbor the disease.

Pathophysiology

The pathophysiology of ABDS is thought to be related to involvement of various control centers and nuclei in the brainstem. Absence of bilateral abducens nuclei is thought to result in complete loss of lateral rectus function and loss of medial rectus function only with conjugate lateral gaze. Abduction during convergence is still intact in these patients. The cause of inner ear involvement with resulting deafness may be related to dysfunctional signaling from hindbrain neuroectoderm during development. Developmental delay appears to be secondary to global cerebral hypoxia that is multifactorial in nature. The combination of central hypoventilation, the higher altitude at which populations of Athabascan Native Americans reside, and vascular malformations all may contribute to this hypoxia. This theory is corroborated by the fact that 2 of the Navajo patients raised at a significantly lower altitude did not have developmental delay.

Diagnosis

Diagnostic criteria have been proposed by Holve et. al.

1. Sensorineural deafness confirmed with brainstem auditory evoked responses (BAER)
2. Horizontal gaze palsy present upon conjugate lateral gaze but intact medial gaze with convergence
3. Central hypoventilation demonstrated by hypoxia and/or respiratory acidosis without underlying lung or neuromuscular disease
4. Developmental delay
5. Any one of the following: facial paresis, vocal cord paresis, seizures, or cardiac outflow tract abnormalities

Genetic Testing is also available to search for the presence of the loss-of-function non-sense mutation in the HOXA1 gene.

Differential diagnosis

Möbius syndrome

Möbius syndrome is a well-established congenital brainstem disorder that is usually sporadic with a presentation that shares similar characteristics to that of ABDS. Minimal criteria include the presence of non-progressive facial weakness and ocular abduction impairment. However, Möbius syndrome does not commonly present with sensorineural hearing loss, central hypoventilation, moderate to severe developmental delay, or vocal cord paresis.

Bosley-Salih-Alorainy syndrome

Bosley-Salih-Alorainy syndrome consists of bilateral Duane retraction syndrome type 3 (horizontal gaze palsy), cerebral vascular malformations, and deafness but without central hypoventilation. It also variably includes autism and/or developmental delay. The disease is mostly found in those of Saudi Arabian or Turkish descent. The genetic basis is very similar to ABDS (HOXA1 deficiency), but the Saudi Arabian population has been found to have a frameshift (insertion) mutation that leads to a prematurely truncated protein rather than the non-sense mutation seen in the Athabascan population.

Management

ABDS is managed with supportive treatment. This includes supplemental oxygen and mechanical ventilation.

Due to high prevalence in Athabascan population, further investigation for concurrent abnormalities should be undertaken when one feature is present to rule out ABDS. Additional suspicion should be present for patients from other ethnic groups that may have sporadic disease. This should also include those presenting with recurrent aspiration pneumonia as this has also been linked with the disease.

Prognosis

Limited number of cases show that the prognosis depends on the severity of the associated clinical features. Select patients were found to achieve improved respiratory drive and swallowing function with age. Developmental milestones are delayed in these patients, and IQ scores measuring non-verbal intelligence show moderate to severe intellectual disability. Early interventions with sign language communication may be beneficial to prevent severe communication deficits and/or developmental delay.

Exact causes of death are not fully understood as autopsies were not performed due to Navajo cultural practices.