Brown–Vialetto–Van Laere syndrome

Overview

Brown–Vialetto–Van Laere syndrome (BVVL) is an extremely rare neurological disorder characterized by progressive cranial nerve palsies and sensorineural deafness, often beginning in childhood or adolescence. The syndrome primarily affects the lower cranial nerves, leading to symptoms such as facial weakness, difficulty swallowing, and respiratory issues. BVVL is part of a broader group of disorders known as riboflavin transporter deficiency disorders and has been linked to impaired cellular transport of vitamin B2 (riboflavin), which is vital for energy metabolism in nerve cells.

Causes

Brown–Vialetto–Van Laere syndrome is caused by mutations in genes responsible for riboflavin transport, primarily:

• SLC52A2 – encodes riboflavin transporter RFVT2

• SLC52A3 – encodes riboflavin transporter RFVT3

These mutations impair riboflavin uptake into cells, leading to mitochondrial dysfunction and progressive neurodegeneration. The syndrome is inherited in an autosomal recessive pattern, meaning both copies of the gene must be mutated for the disease to manifest. Carriers (with one mutated gene) are typically unaffected.

Symptoms

The symptoms of BVVL can vary in severity and age of onset, but common features include:

• Sensorineural hearing loss – often the first symptom, typically bilateral and progressive

• Multiple cranial nerve palsies – particularly affecting nerves VII (facial), IX (glossopharyngeal), X (vagus), and XII (hypoglossal)

• Facial weakness or asymmetry

• Dysphagia (difficulty swallowing)

• Dysarthria (slurred speech)

• Respiratory difficulties – due to diaphragmatic weakness or laryngeal paralysis

• Muscle weakness and hypotonia

• Ataxia – impaired coordination and balance

• Limb paralysis – in advanced stages

Onset is usually in infancy or early childhood, but later onset in adolescence or adulthood has also been documented. Without treatment, the disease can progress rapidly and become life-threatening due to respiratory failure.

Diagnosis

Diagnosing BVVL requires a combination of clinical assessment, genetic testing, and exclusion of other neuromuscular conditions. Diagnostic steps include:

• Clinical evaluation – recognizing the classic pattern of cranial nerve involvement and sensorineural deafness

• Auditory testing – to confirm bilateral sensorineural hearing loss

• MRI of the brain and spinal cord – may reveal cranial nerve enhancement or atrophy

• Genetic testing – identifying mutations in SLC52A2 or SLC52A3

• Riboflavin transporter function studies – in specialized centers

• Electromyography (EMG) and nerve conduction studies – to assess muscle and nerve function

Treatment

The cornerstone of treatment for BVVL is high-dose riboflavin (vitamin B2) supplementation, which can significantly slow or even reverse disease progression in many patients. Other supportive therapies include:

• High-dose oral riboflavin – typically 10–40 mg/kg/day, started as early as possible

• Hearing aids or cochlear implants – for managing deafness

• Speech and swallowing therapy – to improve function and prevent aspiration

• Non-invasive ventilation – for patients with respiratory muscle weakness

• Feeding support – including gastrostomy tubes in severe dysphagia

• Physical therapy – to maintain muscle strength and prevent contractures

Early initiation of riboflavin therapy has been shown to dramatically improve outcomes and may even lead to partial reversal of neurological deficits.

Prognosis

The prognosis of Brown–Vialetto–Van Laere syndrome has improved significantly with the discovery of riboflavin-responsive forms of the disease. While untreated BVVL is progressive and often fatal, especially due to respiratory complications, patients who receive early riboflavin supplementation may experience stabilization or improvement of symptoms. Long-term outcomes depend on the age of onset, severity of symptoms at diagnosis, and response to treatment. Lifelong therapy and multidisciplinary care are typically required.