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Brown-Vialetto-Van Laere syndrome — Clinical Guidelines

Overview

Brown-Vialetto-Van Laere Syndrome (BVVLS) is a rare, progressive neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. It arises from mutations in the SLC52A2 or SLC52A3 genes, which encode riboflavin transporters, leading to impaired riboflavin metabolism and subsequent neurological dysfunction. Primarily affecting children and young adults, BVVLS manifests with cranial nerve palsies (VII, IX, X, XI, and XII), sensorineural deafness, and motor deficits that can rapidly progress to respiratory failure. Early identification and intervention are crucial due to the debilitating nature of the disease and its potential for significant morbidity and mortality. Understanding BVVLS is essential for clinicians to recognize early symptoms, particularly hearing loss, and initiate timely management to improve quality of life and potentially slow disease progression 1 4 6.

Pathophysiology

BVVLS results from genetic mutations in the SLC52A2 or SLC52A3 genes, which are critical for riboflavin (vitamin B2) transport across cellular membranes. These transporters play a pivotal role in maintaining cellular energy metabolism, particularly in neurons and motor neurons. Mutations disrupt riboflavin uptake, leading to impaired mitochondrial function and energy production within affected cells. This metabolic derangement triggers a cascade of cellular stress responses, including oxidative damage and protein aggregation, ultimately resulting in neuronal degeneration and the characteristic clinical features of pontobulbar palsy and sensorineural hearing loss 1 3 11. The progressive nature of BVVLS underscores the critical dependence of these neurons on efficient riboflavin metabolism for survival and function.

Epidemiology

BVVLS is exceedingly rare, with fewer than 100 cases reported globally over the past century 1. The condition predominantly affects children and young adults, with a slight male predominance noted in symptom onset timelines 1 4. Geographic distribution appears sporadic, with cases reported across various continents, though specific prevalence rates are not well-defined due to the rarity of the syndrome. There are no clear risk factors identified beyond genetic predisposition, and no significant trends in incidence over time have been established in the literature reviewed 4 9.

Clinical Presentation

The clinical presentation of BVVLS typically begins with sensorineural hearing loss, often progressive and severe, preceding other neurological symptoms by months to years 1 4. Common symptoms include:

Sensorineural hearing loss: Usually the initial symptom.

Cranial nerve palsies: Affecting VII (facial), IX (glossopharyngeal), X (vagus), XI (accessory), and XII (hypoglossal) nerves.

Motor deficits: Progressive weakness and atrophy, particularly in bulbar muscles leading to dysphagia, dysphonia, and respiratory compromise.

Reflex changes: Pathological brisk reflexes and Babinski sign.

Autonomic dysfunction: Potential involvement of autonomic nerves leading to dysautonomia.

Red-flag features include rapid progression of neurological deficits, particularly respiratory muscle weakness, which necessitates urgent intervention 1 2 6.

Diagnosis

Diagnosis of BVVLS involves a combination of clinical evaluation and genetic testing. Key diagnostic steps include:

Clinical history and examination: Focus on progressive neurological symptoms, particularly hearing loss and cranial nerve involvement.

Audiological assessment: Essential for early detection of sensorineural hearing loss.

Genetic testing: Sequencing of SLC52A2 and SLC52A3 genes to identify specific mutations.

Imaging: MRI or CT scans may show characteristic brainstem atrophy and other neurological changes.

Electrophysiological studies: Nerve conduction studies and electromyography (EMG) can support the diagnosis by showing denervation patterns.

Specific Criteria and Tests:

Genetic Mutation Identification: Confirmed mutations in SLC52A2 or SLC52A3 genes.

Audiometry: Sensorineural hearing loss with characteristic patterns.

Neurological Examination: Presence of cranial nerve palsies and motor deficits.

Imaging Findings: Brainstem atrophy and other neurological abnormalities on MRI/CT.

Differential Diagnosis: Exclude other causes of progressive neurological disorders such as ALS, mitochondrial disorders, and other genetic neuropathies 1 2 4 6.

Differential Diagnosis

Amyotrophic Lateral Sclerosis (ALS): Distinguished by more widespread motor neuron involvement without characteristic hearing loss.

Mitochondrial Disorders: Often present with additional systemic symptoms and specific metabolic abnormalities.

Hereditary Sensory and Autonomic Neuropathies: Typically involve sensory deficits more prominently without the typical cranial nerve involvement seen in BVVLS 3 9.

Management

First-Line Management

Riboflavin Supplementation: High-dose riboflavin therapy is crucial.

- Dose: Typically 600-1200 mg/day orally 2 8. - Monitoring: Regular assessment of clinical symptoms and serum riboflavin levels. - Contraindications: Assess for any underlying conditions that may affect riboflavin metabolism.

Second-Line Management

Supportive Care: Addressing symptoms and complications.

- Respiratory Support: Mechanical ventilation if respiratory muscles fail. - Nutritional Support: Ensuring adequate nutrition, especially in cases of dysphagia. - Speech and Swallowing Therapy: To manage dysphagia and dysphonia. - Physical and Occupational Therapy: To maintain function and mobility.

Refractory Cases / Specialist Escalation

Multidisciplinary Approach: Involvement of neurologists, geneticists, pulmonologists, and palliative care specialists.

Experimental Therapies: Consider clinical trials for novel treatments targeting riboflavin transport or mitochondrial function.

- Monitoring: Close clinical monitoring and regular reassessment of treatment efficacy.

Complications

Respiratory Failure: Rapid progression to respiratory muscle weakness necessitating mechanical ventilation.

Malnutrition: Due to dysphagia and impaired oral intake.

Infections: Increased susceptibility due to compromised immune function and mechanical ventilation.

Quality of Life Decline: Progressive neurological deficits impacting daily activities and independence.

- Management Triggers: Early detection and intervention in respiratory and nutritional support are critical to mitigate these complications 2 6.

Prognosis & Follow-Up

The prognosis for BVVLS is generally poor, with many patients experiencing rapid progression to severe disability or death, often within a decade of symptom onset 1 4. Prognostic indicators include the rapidity of symptom progression and the extent of initial neurological involvement. Recommended follow-up intervals include:

Monthly: During initial diagnosis and treatment initiation.

Quarterly: For monitoring disease progression and treatment response.

Annually: Long-term follow-up to assess quality of life and manage complications.

Neurological Assessments: Regular evaluations to track cranial nerve function and motor status.

Audiological Monitoring: Periodic audiometry to manage hearing loss 1 6.

Special Populations

Pediatrics: Early intervention with riboflavin therapy can potentially slow disease progression. Close monitoring of developmental milestones is crucial.

Elderly: Less commonly affected, but similar management principles apply with emphasis on supportive care and symptom management.

Ethnic Variants: Cases from diverse ethnic backgrounds, such as the first reported case from sub-Saharan Africa, highlight the global distribution but emphasize the need for genetic testing regardless of ethnicity 10.

Key Recommendations

Genetic Testing: Confirm diagnosis through SLC52A2 and SLC52A3 gene sequencing (Evidence: Strong) 1 4.

Early Riboflavin Supplementation: Initiate high-dose riboflavin therapy (600-1200 mg/day) upon diagnosis (Evidence: Moderate) 2 8.

Comprehensive Audiological Monitoring: Regular audiometry to detect and manage hearing loss (Evidence: Moderate) 1 6.

Multidisciplinary Care Team: Involve neurologists, pulmonologists, nutritionists, and therapists for holistic management (Evidence: Expert opinion) 2 6.

Supportive Respiratory Care: Prepare for potential respiratory failure with early intervention plans (Evidence: Moderate) 2.

Regular Clinical Assessments: Monitor neurological status and adjust treatment based on progression (Evidence: Moderate) 1 4.

Nutritional Support: Implement strategies to manage dysphagia and ensure adequate nutrition (Evidence: Moderate) 2.

Consider Clinical Trials: Evaluate patients for participation in emerging therapies targeting riboflavin transport (Evidence: Weak) 2.

Palliative Care Integration: Early involvement for symptom management and quality of life support (Evidence: Expert opinion) 2.

Long-term Follow-up: Schedule regular follow-ups to assess disease progression and manage complications (Evidence: Moderate) 6.

References

1 Rolim DO, Vicente LC, de Carvalho HAS, Santos RLS, de Amorim RFB, Bahmad F. Audiological findings in Brown Vialetto-Van-Laere Syndrome: A scoping review. Brazilian journal of otorhinolaryngology 2025. link 2 Bashford JA, Chowdhury FA, Shaw CE. Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto-Van Laere syndrome. Practical neurology 2017. link 3 González-Pérez P, Lu Y, Chian RJ, Sapp PC, Tanzi RE, Bertram L et al.. Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. Neurobiology of disease 2012. link 4 Gayathri S, Aravind MK, Gowda VK, Varalakshmi P, Chatterjee C, Matheshwaran S et al.. Brown-Vialetto-Van Laere syndrome patients with unusual phenotypes from Indian ethnicity: Functional analysis of clinical variants in SLC52A2 and SLC52A3 genes. Brain & development 2025. link 5 do Amaral MSA, Massuda ET, Mitikami Fenólio GH, Barbosa Reis ACM, Angelo Hyppolito M. Cochlear Implant in Brown-Vialetto-Van Laere Syndrome Patient. The journal of international advanced otology 2022. link 6 Omar R, Rajput K, Sirimanna T, Rajput S, Pagarkar W. The audiovestibular profile of Brown-Vialetto-Van Laere syndrome. The Journal of laryngology and otology 2021. link 7 Rabbani B, Bakhshandeh MK, Navaeifar MR, Abbaskhanian A, Soveizi M, Geravandpoor S et al.. Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: A novel mutation and in silico analyses. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2020. link 8 Shi K, Shi Z, Yan H, Wang X, Yang Y, Xiong H et al.. A Chinese pedigree with Brown-Vialetto-Van Laere syndrome due to two novel mutations of SLC52A2 gene: clinical course and response to riboflavin. BMC medical genetics 2019. link 9 Woodcock IR, Menezes MP, Coleman L, Yaplito-Lee J, Peters H, White SM et al.. Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome. Seminars in pediatric neurology 2018. link 10 Chaya S, Zampoli M, Gray D, Booth J, Riordan G, Ndondo A et al.. The First Case of Riboflavin Transporter Deficiency in sub-Saharan Africa. Seminars in pediatric neurology 2018. link 11 Malafronte P, Clark HB, Castaneda-Sanchez I, Raisanen J, Hatanpaa KJ. Brown-Vialetto-Van Laere syndrome: clinical and neuropathologic findings with immunohistochemistry for C20orf54 in three affected patients. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2013. link 12 Ciccolella M, Corti S, Catteruccia M, Petrini S, Tozzi G, Rizza T et al.. Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations. Journal of medical genetics 2013. link

Brown-Vialetto-Van Laere syndrome