Honoring Awareness and Advancing Care on Bardet-Biedl Syndrome Global Day

Recognizing BBS Global Day

October 4th is Bardet-Biedl Syndrome (BBS) Global Day, a day when patients, families, clinicians, and researchers come together worldwide to raise awareness, foster community, and accelerate research. For those affected, BBS is not only a rare genetic diagnosis — it is a lifelong condition with complex impacts on energy, metabolism, vascular health, and neurological function.

What Is Bardet-Biedl Syndrome?

BBS is a rare ciliopathy — a disorder caused by defective cilia, the hair-like projections on cells that function as energy hubs for the autonomic nervous system. When these structures malfunction, signaling pathways are disrupted across multiple organ systems.

Hallmark features include:

• Retinitis pigmentosa (RP) causing blindness, sometimes accompanied by Usher syndrome causing hearing loss and balance disturbance

• Obesity and metabolic dysfunction

• Polydactyly (extra digits)

• Kidney disease

• Learning or cognitive challenges

Secondary Complications and Overlooked Symptoms

Patients with BBS may also face additional neurovascular and metabolic challenges like:

• Intracranial hypertension (IH)

• Venous congestion and impaired cerebral venous outflow

• Headaches, migraines, and facial pain

• Cognitive dysfunction and fatigue

• Glucose instability and hypoglycemia due to inefficient carbohydrate handling

These complications highlight why multidisciplinary care is essential.

MC4R Pathway Disruption: A Shared Mechanism

BBS overlaps mechanistically with MC4R deficiency, as both involve disrupted melanocortin 4-pathway signaling. Key peptides impacted include:

• Alpha-MSH

• Neuropeptide Y

• Agouti-related peptide (AGRP)

• Insulin and glucose pathways

When these signals falter, energy balance and glucose regulation are destabilized.

Therapeutic Developments: Setmelanotide

One of the most hopeful recent developments is setmelanotide, an alpha-MSH agonist approved for BBS-related obesity (Clément et al., 2020). For patients with partial MC4R pathway function, it can restore signaling, reduce hunger, and improve weight regulation.

However, not all BBS variants respond. For example, my own autosomal dominant P299H MC4R deficiency pathogenic mutation leads to complete loss of MC4R function at both the cell surface and intracellularly, making setmelanotide ineffective in my case. This underscores the importance of genotype-specific treatment approaches when it comes to BBS, MC4R deficiency, and other MC4R pathway disturbances.

The Ketogenic Diet: Promise and Risks

The ketogenic diet offers another possible avenue by providing a more stable energy source, beta-hydroxybutyrate (BHB) bypassing unstable glucose metabolism. Some patients report improvements in energy, glucose homeostasis, mood, and cognition.

The ketogenic diet is not universally safe and suitable for all individuals. Risks include metabolic acidosis, fluid and electrolyte disturbance, kidney stones, kidney injury, liver injury, cholelithiasis (gall stones), hyperlipidemia, and nutritional imbalances. A medically necessary ketogenic diet should only be considered under medical supervision, preferably with support from a dietician or nutritionist.

The Importance of Screening

For BBS patients and carriers, proactive monitoring for the following are essential:

• Vision and hearing loss

• Intracranial pressure-related disorders like intracranial hypertension and hypotension, cerebrospinal fluid (CSF) leaks, and venous congestion with venous stenoses

• Headache, migraine, and facial pain

• Secondary cognitive decline from reversible or treatable conditions, such as nutritional deficiency or intracranial pressure-related disorders

• Metabolic screening for obesity, insulin resistance, hypoglycemia, and other endocrine disturbances affecting the hypothalamic-pituitary-thyroid-gonadal axis.

My Personal Connection

In addition to living with autosomal dominant MC4R deficiency due to the P299H variant, I am also a carrier of an MC1R mutation associated with erythropoietic porphyria and oculocutaneous albinism, as well as an MC2R mutation associated with familial glucocorticoid deficiency. Prior to my formal diagnosis with MC4R deficiency, I was concerned I had porphyria due to overlapping symptoms. Typically, carrier states do not yield disease in isolation, but when multiple mutations affect the melanocortin pathway, complex clinical pictures are seen.

Though setmelanotide is not effective in treatment of my MC4R deficiency, all hope is not lost. I have experienced marked improvement in energy, glucose homeostasis, intracranial pressure-related disorders, headache, migraine, facial pain, and cutaneous eruptions or rashes with a medically necessary and supervised ketogenic diet. This, again, highlights the importance of an individualized or genotype-specific approach to treatment.

This lived experience deepens my professional commitment to advancing care, education, and research through Our Neuro Network.

Resources for Patients and Families

On BBS Global Day, I encourage families and clinicians to connect with supportive organizations:

• Bardet-Biedl Syndrome Foundation (US): www.bardetbiedl.org

• BBS UK: www.bbsuk.org.uk

• National Organization for Rare Disorders (NORD): rarediseases.org

• National Eye Institute – Retinitis Pigmentosa: nei.nih.gov

Closing Thoughts

BBS Global Day (October 4th) is a reminder that rare disease advocacy is rooted in both science and community. Advances like setmelanotide, nutritional therapies, and genetic research provide genuine hope, and highlight the importance of tailoring care to individual genetic profiles.

At Our Neuro Network, we remain committed to building bridges between research and lived experience, always guided by honor, homeostasis, and hope.

References

Clément, K., van den Akker, E., Argente, J., Bahm, A., Chung, W. K., Connors, H., De Waele, K., Farooqi, I. S., Gonneau, S., Gordon, G., Hale, P. M., Lam, C., Li, Z., López-Giménez, J. F., Mignot, C., Piening, B. D., Ravussin, E., Rosenbaum, M., Salzano, G., ... Kühnen, P. (2020). Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with Bardet-Biedl syndrome and Alström syndrome: Multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Diabetes & Endocrinology, 8(12), 960–970. https://doi.org/10.1016/S2213-8587(20)30364-8

Forsythe, E., & Beales, P. L. (2013). Bardet-Biedl syndrome. European Journal of Human Genetics, 21(1), 8–13. https://doi.org/10.1038/ejhg.2012.115

Mockel, A., Perdomo, Y., Stutzmann, F., Letsch, J., Marion, V., Dollfus, H., & Dollfus, H. (2011). Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Progress in Retinal and Eye Research, 30(4), 258–274. https://doi.org/10.1016/j.preteyeres.2011.03.001