Athabaskan Brainstem Dysgenesis Syndrome

Athabascan brainstem dysgenesis syndrome (ABDS) is a very rare genetic disorder that affects the development of the brainstem and related structures in early fetal life. It is characterized by abnormalities in eye movement (horizontal gaze palsy), hearing loss (sensorineural deafness), impaired automatic breathing (central hypoventilation), and developmental delays in motor and cognitive function. In individuals with ABDS, the hindbrain (which gives rise to the brainstem) does not form correctly, leading to malformations of cranial nerves, blood vessels, and heart outflow tracts. Most patients present in infancy with feeding difficulties, breathing irregularities, and failure to thrive. MalaCardsNCBI

ABDS arises from loss-of-function mutations in the HOXA1 gene, a master regulator of early brainstem motor-neuron development. When HOXA1 is nonfunctional, key neuronal pathways that control eye movements, breathing, and hearing fail to form normally. This results in the characteristic clinical picture of gaze palsy, deafness, and hypoventilation Wikipedia.

ABDS is inherited in an autosomal recessive pattern, meaning that an affected individual carries two altered copies of the HOXA1 gene—one from each parent. To date, only about 34 individuals worldwide have been reported with biallelic HOXA1 variants. A founder mutation (c.76C>T, p.Arg26Ter) is highly prevalent among Navajo and Apache populations, leading to an estimated incidence of 0.5–1 per 1,000 live births on the White River Apache Reservation and 1 per 3,000 live births in the Navajo Nation. Genetic testing of HOXA1 confirms the diagnosis. NCBI

Types

Patients with HOXA1 mutations exhibit two closely related phenotypes:

• Athabascan Brainstem Dysgenesis Syndrome (ABDS) – Primarily reported in individuals of Navajo and Apache descent, ABDS features horizontal gaze palsy, bilateral sensorineural deafness, central hypoventilation requiring ventilatory support, developmental delay, and congenital heart defects involving the outflow tracts. NCBI

• Bosley–Salih–Alorainy Syndrome (BSAS) – Described in families from the Middle East (Turkey, Saudi Arabia), BSAS shares many features with ABDS (horizontal gaze palsy, deafness, vascular anomalies) but typically lacks central hypoventilation and shows milder intellectual impairment. BSAS is associated with a different founder HOXA1 variant (c.175dupG, p.Val59GlyfsTer119). NCBI

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15 Causes

1. Homozygous HOXA1 Nonsense Mutation (c.76C>T, p.Arg26Ter)
   A single-base change in the HOXA1 gene introduces a premature stop codon, truncating the HOXA1 protein essential for hindbrain segmentation. WikipediaNCBI

2. Alternate HOXA1 Founder Variant (c.175dupG, p.Val59GlyfsTer119)
   This frameshift mutation, common in Middle Eastern families, leads to loss of HOXA1 function and underlies BSAS. NCBI

3. Autosomal Recessive Inheritance
   Both parents carry one mutated HOXA1 allele; a 25% chance exists that each child will inherit two defective copies and develop ABDS. NCBI

4. Founder Effect in Isolated Populations
   Geographic and cultural isolation among Athabascan peoples amplified the frequency of the HOXA1 c.76C>T variant over generations. NCBI

5. Consanguineous Marriages
   Marriages between relatives increase the risk that both partners carry the same HOXA1 founder mutation. NCBI

6. Loss of Hindbrain Segmentation Signals
   HOXA1 normally directs the formation of rhombomeres in the embryonic hindbrain; its absence disrupts this segmentation, leading to brainstem dysgenesis. NCBI

7. Impaired Abducens Nerve Development
   Without HOXA1, the abducens (VI) nerve nucleus fails to form correctly, causing horizontal gaze palsy. NCBI

8. Defective Inner Ear Morphogenesis
   HOXA1 mutations interfere with the development of cochlear and vestibular structures, resulting in sensorineural deafness and balance deficits. NCBI

9. Abnormal Carotid Artery Formation
   Embryonic blood vessels supplying the brain develop abnormally, leading to internal carotid artery hypoplasia or other vascular anomalies. NCBI

10. Central Hypoventilation Mechanism Loss
    Neuronal circuits in the medulla that regulate involuntary breathing fail to develop, causing dangerous pauses in respiration. NCBI

11. Congenital Heart Outflow Malformations
    HOXA1 plays a role in cardiac neural crest cell migration; its absence leads to defects such as tetralogy of Fallot or double-outlet right ventricle. NCBI

12. Neural Crest Cell Migration Failure
    Mutant HOXA1 disrupts the migration of multipotent neural crest cells, affecting craniofacial, cardiac, and vascular development. NCBI

13. Altitude-Exacerbated Hypoxia
    High-altitude living in some Athabascan communities may worsen brain oxygenation deficits, compounding developmental delays. NCBI

14. Secondary Cerebral Atrophy
    Chronic hypoventilation and vascular anomalies can lead to reduced brain volume over time, further impairing function. NCBI

15. Genetic Drift and Population Bottlenecks
    Historical events reducing population size among Native American tribes increased the relative frequency of deleterious HOXA1 alleles. NCBI

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10 Symptoms

1. Horizontal Gaze Palsy – Inability to move both eyes fully to the side, due to underdevelopment of the abducens nerve nucleus. MalaCardsNCBI

2. Bilateral Sensorineural Deafness – Hearing loss from inner ear and nerve defects, often profound from birth. MalaCardsNCBI

3. Central Hypoventilation – Pauses in breathing during sleep or wakefulness, requiring mechanical ventilation. MalaCardsNCBI

4. Developmental Delay – Delayed milestones in motor skills (sitting, walking) and speech, varying in severity. MalaCardsNCBI

5. Intellectual Disability – Cognitive impairment ranging from mild learning difficulties to global developmental delay. NCBI

6. Facial Paresis – Weakness or twitching of facial muscles due to underdevelopment of the facial nerve. MalaCardsNCBI

7. Vocal Cord Paresis – Reduced vocal cord movement leading to weak cry and risk of aspiration. NCBI

8. Swallowing Dysfunction – Difficulty coordinating swallowing, often requiring gastrostomy feeding tubes. NCBI

9. Seizures – Occasional tonic–clonic seizures reported in some individuals, emerging in early childhood. MalaCardsNCBI

10. Autistic Features – In some cases, behaviors on the autism spectrum, including repetitive movements and social interaction challenges. MalaCardsNCBI

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20 Diagnostic Tests

Physical Examination

1. Neurological Exam – Assessment of cranial nerve function, motor tone, reflexes, and gait to identify brainstem deficits. NCBI

2. Ocular Motility Assessment – Observation of voluntary and reflex eye movements to confirm horizontal gaze palsy. NCBI

3. Respiratory Observation – Monitoring breathing patterns during sleep and wakefulness for evidence of hypoventilation. NCBI

4. Cardiac Auscultation – Listening for murmurs or abnormal heart sounds indicating outflow tract malformations. NCBI

Manual Tests

5. Oculocephalic (“Doll’s Eye”) Reflex – Turning the head side to side while observing involuntary eye movements; absence indicates brainstem dysfunction. NCBI

6. Head Impulse Test – Rapid head rotations to test vestibulo–ocular reflex and inner ear function. NCBI

7. Gag Reflex Test – Stimulation of the posterior pharynx to assess cranial nerves IX and X integrity. NCBI

Lab and Pathological Tests

8. HOXA1 Genetic Sequencing – DNA analysis to detect pathogenic variants confirming diagnosis. NCBI

9. Complete Blood Count (CBC) – Baseline evaluation for any hematologic anomalies. NCBI

10. Arterial Blood Gas (ABG) – Measurement of blood oxygen and carbon dioxide levels to quantify hypoventilation. NCBI

11. Metabolic Panel – Assessment of electrolyte and metabolic status that may affect respiratory drive. NCBI

12. Infection Screen – Ruling out congenital infections (TORCH panel) that can mimic neurological syndromes. NCBI

Electrodiagnostic Tests

13. Brainstem Auditory Evoked Potentials (BAEPs) – Objective measurement of neural pathway conduction in auditory nerves. NCBI

14. Nerve Conduction Studies (NCS) – Evaluation of peripheral nerve function to exclude neuromuscular causes of hypoventilation. NCBI

15. Electromyography (EMG) – Assessment of muscle electrical activity, particularly in facial and respiratory muscles. NCBI

16. Polysomnography – Overnight sleep study to monitor breathing, oxygen saturation, and arousal patterns. NCBI

Imaging Tests

17. Brain MRI – Detailed visualization of brainstem structure, rhombomere segmentation, and cerebral atrophy. NCBI

18. CT Angiography of Carotids – Imaging of carotid arteries to detect hypoplasia or other anomalies. NCBI

19. High-Resolution Inner Ear CT – Evaluation of cochlear and vestibular bone structure for common cavity deformities. NCBI

20. Echocardiography – Ultrasound assessment of cardiac anatomy to identify outflow tract malformations. NCBI

Non-Pharmacological Treatments

Management relies on a multidisciplinary approach, integrating respiratory support, rehabilitation therapies, and educational interventions. These strategies are adapted from guidelines for congenital central hypoventilation and pediatric developmental disorders Frontiers. Below are 20 evidence-based, non-drug therapies:

1. Mechanical Ventilation Training

   • Description: Caregiver instruction in using noninvasive ventilation (BiPAP) or tracheostomy ventilators.

   • Purpose: Ensure adequate breathing during sleep and respiratory crises.

   • Mechanism: Supports alveolar ventilation, prevents hypoxia and hypercapnia.

2. Respiratory Physiotherapy

   • Description: Chest-percussion, postural drainage, and assisted coughing techniques.

   • Purpose: Clear secretions and maintain airway patency.

   • Mechanism: Mobilizes mucus, reduces infection risk.

3. Positioning Therapy

   • Description: Use of specialized chairs and cushions to optimize posture.

   • Purpose: Prevent contractures and aspiration.

   • Mechanism: Aligns head and trunk to facilitate swallowing and breathing.

4. Speech and Swallowing Therapy

   • Description: Exercises to strengthen tongue and pharyngeal muscles.

   • Purpose: Improve swallowing safety and vocal clarity.

   • Mechanism: Enhances neuromuscular control of oropharyngeal structures.

5. Occupational Therapy

   • Description: Fine-motor skill training and adaptive equipment recommendations.

   • Purpose: Promote independence in daily activities.

   • Mechanism: Targets sensorimotor integration through task practice.

6. Physical Therapy

   • Description: Range-of-motion exercises and supported standing.

   • Purpose: Prevent muscle atrophy and joint stiffness.

   • Mechanism: Stimulates neuromuscular pathways and promotes circulation.

7. Aquatic Therapy

   • Description: Supervised exercises in warm water pools.

   • Purpose: Reduce spasticity and improve motor control.

   • Mechanism: Buoyancy decreases joint load, water resistance strengthens muscles.

8. Constraint-Induced Movement Therapy

   • Description: Restricting the stronger limb to force use of the weaker side.

   • Purpose: Enhance motor function in affected limbs.

   • Mechanism: Neural plasticity through repetitive use.

9. Sensory Integration Therapy

   • Description: Activities that provide tactile, vestibular, and proprioceptive input.

   • Purpose: Improve sensory processing and behavior.

   • Mechanism: Re-trains brain circuits to integrate sensory information.

10. Music Therapy

    • Description: Rhythm-based activities and vocal exercises.

    • Purpose: Enhance speech, emotional expression, and coordination.

    • Mechanism: Engages auditory-motor neural networks.

11. Animal-Assisted Therapy

    • Description: Interaction with therapy animals under supervision.

    • Purpose: Reduce anxiety, improve social skills.

    • Mechanism: Oxytocin release and motivational engagement.

12. Yoga and Mind-Body Exercises

    • Description: Adapted breathing and stretching postures.

    • Purpose: Promote relaxation, improve flexibility.

    • Mechanism: Modulates autonomic function and muscle tone.

13. Biofeedback

    • Description: Monitoring breathing and muscle activity via screens.

    • Purpose: Teach self-regulation of respiratory patterns.

    • Mechanism: Visual feedback fosters neural control.

14. Cognitive Behavioral Therapy (CBT)

    • Description: Structured sessions targeting coping strategies.

    • Purpose: Manage anxiety related to breathing difficulties.

    • Mechanism: Restructures maladaptive thought patterns.

15. Educational Self-Management

    • Description: Family training on recognizing hypoventilation signs.

    • Purpose: Empower caregivers to intervene early.

    • Mechanism: Knowledge transfer reduces emergency risks.

16. Assistive Communication Devices

    • Description: Speech-generating tablets or picture boards.

    • Purpose: Facilitate communication for nonverbal patients.

    • Mechanism: Replaces speech via alternative input/output pathways.

17. Nutritional Counseling

    • Description: High-calorie, easy-to-swallow meal plans.

    • Purpose: Support growth and prevent aspiration.

    • Mechanism: Ensures adequate caloric intake with minimal effort.

18. Environmental Modifications

    • Description: Air humidifiers and allergen reduction at home.

    • Purpose: Minimize respiratory irritants.

    • Mechanism: Reduces airway inflammation and infection risk.

19. Health Education Workshops

    • Description: Group sessions on rare disease management.

    • Purpose: Build peer support and share best practices.

    • Mechanism: Collective learning enhances adherence.

20. Tele-Rehabilitation

    • Description: Remote monitoring and guided therapy via video calls.

    • Purpose: Maintain continuity of care in remote areas.

    • Mechanism: Digital platforms enable regular follow-up.

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Pharmacological Treatments

Although no drugs reverse ABDS, symptom-targeted medications improve function. Management follows principles for central hypoventilation syndromes Medscape.

Key Symptomatic Medications

1. Baclofen (Muscle Relaxant)

   • Class: GABA_B agonist

   • Dosage: 5–10 mg orally TID

   • Timing: Morning, afternoon, bedtime

   • Side Effects: Drowsiness, weakness, dizziness

2. Diazepam (Spasm Control)

   • Class: Benzodiazepine

   • Dosage: 2–5 mg orally BID–TID

   • Timing: With meals

   • Side Effects: Sedation, ataxia, dependency

3. Levetiracetam (Antiepileptic)

   • Class: SV2A modulator

   • Dosage: 10 mg/kg IV/PO BID

   • Timing: Morning and evening

   • Side Effects: Irritability, fatigue, headache

4. Valproic Acid (Antiepileptic)

   • Class: GABA transaminase inhibitor

   • Dosage: 20–30 mg/kg/day in divided doses

   • Timing: BID

   • Side Effects: Weight gain, tremor, hepatotoxicity

5. Doxapram (Respiratory Stimulant)

   • Class: Central chemoreceptor stimulant

   • Dosage: 1–2 mg/kg IV bolus, then 4–8 mg/kg/hr infusion

   • Timing: Acute respiratory support

   • Side Effects: Hypertension, arrhythmias, agitation

6. Acetazolamide (Respiratory Drive Enhancer)

   • Class: Carbonic anhydrase inhibitor

   • Dosage: 250 mg orally QD

   • Timing: Morning

   • Side Effects: Metabolic acidosis, paresthesia, diuresis

7. Caffeine Citrate (Respiratory Stimulant)

   • Class: Methylxanthine

   • Dosage: 5–20 mg/kg IV/PO once daily

   • Timing: Morning

   • Side Effects: Tachycardia, insomnia, irritability

8. Gabapentin (Neuropathic Pain)

   • Class: Calcium channel modulator

   • Dosage: 10 mg/kg PO TID

   • Timing: With meals

   • Side Effects: Sedation, dizziness, edema

9. Melatonin (Sleep Regulation)

   • Class: Sleep promotor

   • Dosage: 0.5–3 mg orally QHS

   • Timing: Bedtime

   • Side Effects: Drowsiness, headache

10. Omeprazole (Gastroesophageal Reflux)

    • Class: Proton-pump inhibitor

    • Dosage: 0.7 mg/kg PO QD

    • Timing: 30 min before breakfast

    • Side Effects: Headache, diarrhea, long-term osteoporosis risk

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Dietary Molecular Supplements

Ten supplements support neural health and systemic resilience. General benefits of omega-3 PUFAs and micronutrients in brain function are well documented PMCPMC.

1. Docosahexaenoic Acid (DHA)

   • Dosage: 200–500 mg/day

   • Function: Supports neuronal membrane fluidity

   • Mechanism: Enhances synaptic transmission and anti-inflammatory effects

2. Eicosapentaenoic Acid (EPA)

   • Dosage: 200–500 mg/day

   • Function: Modulates neuroinflammation

   • Mechanism: Precursor to anti-inflammatory eicosanoids

3. Vitamin B12

   • Dosage: 500 µg/day

   • Function: Myelin maintenance

   • Mechanism: Cofactor in methylation and DNA synthesis

4. Folic Acid (Vitamin B9)

   • Dosage: 400 µg/day

   • Function: Neurodevelopment support

   • Mechanism: Homocysteine reduction, nucleotide synthesis

5. Vitamin D

   • Dosage: 1,000 IU/day

   • Function: Neuroprotective and immunomodulatory

   • Mechanism: Regulates neurotrophin expression

6. Magnesium

   • Dosage: 200 mg/day

   • Function: Neuronal excitability regulation

   • Mechanism: NMDA receptor modulation

7. Choline

   • Dosage: 250 mg/day

   • Function: Acetylcholine precursor

   • Mechanism: Supports neurotransmission and myelination

8. Vitamin E (α-Tocopherol)

   • Dosage: 200 IU/day

   • Function: Antioxidant defense

   • Mechanism: Protects membranes from lipid peroxidation

9. Coenzyme Q10

   • Dosage: 100 mg/day

   • Function: Mitochondrial support

   • Mechanism: Electron transport chain cofactor, antioxidant

10. L-Carnitine

    • Dosage: 50 mg/kg/day

    • Function: Mitochondrial fatty-acid transport

    • Mechanism: Enhances ATP production and reduces oxidative stress

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Advanced Drug Therapies

While still largely experimental in ABDS, several specialized agents offer potential benefits. Six key therapies span bisphosphonates, regenerative peptides, viscosupplements, and stem-cell drugs:

1. Alendronate (Bisphosphonate)

   • Dosage: 5 mg orally daily (or 35 mg weekly)

   • Function: Prevents osteoporosis from immobility

   • Mechanism: Inhibits osteoclast-mediated bone resorption PMC

2. Zoledronic Acid (Bisphosphonate)

   • Dosage: 5 mg IV infusion over 15 min once yearly

   • Function: Reduces fracture risk in disuse osteoporosis

   • Mechanism: Potent osteoclast inhibition, preserves bone density AAFP

3. Mecasermin (rhIGF-1) (Regenerative)

   • Dosage: 0.04–0.12 mg/kg subcutaneously twice daily

   • Function: Promotes neuronal growth and repair

   • Mechanism: IGF-1 receptor activation enhances neurogenesis Wikipedia

4. Cerebrolysin (Neurotrophic Peptide Mixture)

   • Dosage: 30 mL IV infusion once daily for 10–21 days

   • Function: Delivers exogenous neurotrophic factors

   • Mechanism: Peptide fragments (BDNF, NGF, GDNF) support neuronal survival Wikipedia

5. Hyaluronic Acid (Viscosupplementation)

   • Dosage: 16 mg intra-articular injection weekly for 3 weeks

   • Function: Maintains joint health in immobile patients

   • Mechanism: Restores synovial fluid viscosity, reduces joint pain Medscape

6. Mesenchymal Stem Cell (MSC) Infusion (Stem-Cell Drug)

   • Dosage: 1–2 × 10⁶ cells/kg IV infusion (single dose)

   • Function: Provides immunomodulation and neurotrophic support

   • Mechanism: MSCs secrete growth factors and cytokines that modulate inflammation and promote neural repair BioMed CentralWikipedia

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Surgical Interventions

When structural anomalies compromise function, surgery may help:

1. Tracheostomy Placement

   • Procedure: Surgical airway in neck

   • Benefits: Secure ventilation access, reduces hypoventilation risk.

2. Gastrostomy Tube Insertion

   • Procedure: Endoscopic feeding tube to stomach

   • Benefits: Ensures safe, adequate nutrition if swallowing impaired.

3. Strabismus Correction Surgery

   • Procedure: Eye-muscle repositioning

   • Benefits: Improves gaze alignment, reduces ocular strain.

4. Vocal Cord Medialization

   • Procedure: Injection or implant to bring cords to midline

   • Benefits: Enhances voice quality and protects airway.

5. Cardiac Outflow Tract Repair

   • Procedure: Surgical correction of congenital heart defects

   • Benefits: Normalizes hemodynamics, reduces heart failure risk.

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Prevention Strategies

While ABDS is genetic, these measures reduce complications and recurrence risk:

1. Genetic Counseling for at-risk families

2. Carrier Screening using HOXA1 mutation analysis

3. Prenatal Diagnosis via chorionic villus sampling or amniocentesis

4. Preimplantation Genetic Diagnosis (PGD) in IVF cycles

5. Avoidance of Consanguinity in high-risk populations

6. Early Newborn Screening for hypoventilation signs

7. Vaccination against respiratory pathogens

8. Routine Hearing and Vision Monitoring

9. Nutritional Optimization to support growth

10. Home Safety Evaluations to reduce aspiration and falls

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When to See a Doctor

Immediate medical evaluation is warranted for:

• Recurrent apneic episodes or cyanotic spells

• Seizures or sudden focal neurologic deficits

• Feeding intolerance with choking or aspiration

• Rapid developmental regression

• Cardiovascular symptoms (e.g., syncope, palpitations)

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Lifestyle Guidance: What to Do & Avoid

Do:

1. Adhere to multidisciplinary therapy schedules.

2. Use home pulse-oximetry and capnography as instructed.

3. Maintain upright positioning during and after feeds.

4. Keep immunizations current.

5. Engage in age-appropriate physical play under supervision.

6. Ensure adequate hydration and nutrition.

7. Practice gentle respiratory exercises.

8. Update genetic counseling as new options emerge.

9. Incorporate relaxation techniques to reduce stress.

10. Foster peer and family support networks.

Avoid:

1. Sedative medications without medical clearance.

2. Overheating or hypothermia, which can destabilize breathing.

3. Exposure to respiratory irritants (smoke, strong perfumes).

4. Highly restrictive diets that compromise caloric intake.

5. Unsupervised swimming or water play.

6. Prolonged fasting or skipped feeds.

7. Self-medication with herbal respiratory stimulants.

8. Delayed reporting of fever or respiratory changes.

9. High-altitude travel without ventilatory support plan.

10. Erratic sleep schedules that worsen hypoventilation.

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Frequently Asked Questions (FAQs)

1. Can ABDS be cured?
No; current interventions are supportive to manage symptoms and improve function.

2. Is life expectancy reduced?
With proper ventilatory support, many patients reach adulthood; outcomes vary.

3. Can siblings be tested prenatally?
Yes; genetic testing for HOXA1 mutations is available.

4. Will my child ever breathe normally?
Some older children develop partial respiratory drive; most require lifelong support.

5. How is hearing managed?
Early fitting of hearing aids or cochlear implants improves language outcomes.

6. Can physical therapy worsen hypoventilation?
Therapies are tailored to avoid overexertion; continuous monitoring is used.

7. Are there clinical trials for advanced treatments?
Occasional trials of regenerative therapies exist; enrollment is highly selective.

8. Does early intervention help developmental outcomes?
Yes; starting therapies in infancy maximizes neural plasticity and skill acquisition.

9. How often should cardiac evaluations be done?
At diagnosis and annually thereafter, or sooner if symptoms arise.

10. Is central hypoventilation present at birth?
Often yes, but milder cases may only manifest during sleep or illness.

11. Can exercise be beneficial?
Gentle, monitored exercise aids strength without compromising respiration.

12. Are vaccines safe?
Standard vaccinations are safe; live vaccines require individual risk assessment.

13. What support resources exist?
Rare-disease networks, genetic counseling services, and specialized clinics.

14. How can I prepare for emergencies?
Carry an action plan, oxygen supply, and contact information for specialists.

15. Is ABDS the same as Moebius syndrome?
No; ABDS includes deafness and central hypoventilation, distinguishing it clinically.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: July 14, 2025.

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