Brown-Vialetto-Van Laere Syndrome

What is Brown-Vialetto-Van Laere syndrome?

Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological condition affecting infants, children and young adults. It affects the body’s nervous system. BVVL is a motor neuron disorder: it attacks and progressively destroys motor neurons (the cells that control muscle activity including breathing, speaking, swallowing, and general movement of the body), causing paralysis of the cranial nerves. BVVL is degenerative, which means that many of the body’s activities such as breathing, hearing, talking, movement, balance and heart function will deteriorate over a period of time, causing progressive disability.

BVVL is sometimes referred to as bulbar palsy because it involves the brainstem – the bulb-shaped region containing lower motor neurons that control swallowing, speaking, chewing, and other functions. One of the characteristics of this syndrome is sensorineural hearing loss. Sensorineural hearing loss occurs from damage to the inner ear, the nerve that runs from the ear to the brain (auditory nerve), or the brain. Progressive bulbar palsy without hearing loss is referred to as Fazio-Londe syndrome and this and BVVL are considered to be the same disease entity.

The name Brown-Vialetto-Van Laere comes from the doctors and researchers who described some of the first reported cases (Brown in 1894; Vialetto in 1936; and Van Laere in 1966).

How common is Brown-Vialetto-Van Laere syndrome?

BVVL is an extremely rare condition. Only 58 cases had been reported in the medical literature, worldwide, by 2008; but now that this condition is better recognised, the numbers keep growing.

What causes Brown-Vialetto-Van Laere syndrome?

BVVL is a genetic disorder: it is caused by alterations, or ‘mutations’, in an individual’s genes.

As of March 2010, at least one gene has been identified as the cause of BVVL, this gene is called SLC52A3. In 2011 it was demonstrated that this gene encodes the intestinal (hRFT2) riboflavin transporter and that in these patients riboflavin deficiency is the cause of BVVL syndrome. Treatment with riboflavin supplements has proved a life-saving treatment for some young patients.

Recently, mutations in the SLC52A2 gene coding for another human riboflavin transporter (hRFT3) have been associated with BVVL syndrome as well, and in these cases oral riboflavin supplements have again proved beneficial.

BVVL follows an autosomal recessive pattern of inheritance. Autosomal means that the altered gene is located on an autosome – a chromosome that is not a sex chromosome.

Recessive diseases occur only when an individual carries two malfunctioning copies of the relevant gene. Most frequently, for this to happen, both parents carry one faulty gene each and are said to be ‘carriers’, but they are not affected themselves.

When both parents carry one altered gene, there’s a 50 per cent chance that a child will also be a carrier; a 25 per cent chance that a child will have received one altered gene from the mother and one altered gene from the father, and thus have the disorder; and a 25 per cent chance that a child will neither be a carrier nor have the disorder.

Several BVVL cases that have yet to be linked to this gene are being further investigated.

What are the symptoms of Brown-Vialetto-Van Laere syndrome?

Symptoms may appear at any time and the age of onset varies from infancy to adulthood. In many cases, children are healthy and develop normally for years before showing the first symptoms.

Typically, the first symptom of nerve degeneration is sensorineural hearing loss. Sensorineural hearing loss often manifests itself as follows:

  • Difficulty following conversations when two or more people are talking
  • Difficulty hearing when there is background noise
  • Difficulty with high-pitched sounds – making it easier to hear men’s voices than women’s voices
  • Other people’s voices sound mumbled
  • Certain sounds seem too loud

Other examples of nerve degeneration include:

  • Facial weakness, or facial palsy
  • Slurred speech
  • Vocal cord paralysis
  • Droopy eyelids
  • Difficulty swallowing
  • Visual impairment caused by damage to the optic nerve
  • Neck and shoulder weakness
  • Weakness in the arms and legs
  • Breathing difficulties
  • Anomalies in any of the involuntary functions in the body: these are controlled by the autonomic nervous system (part of the nervous system that regulates the organs). They include heart rate, blood pressure, sweating and digestive tract peristalsis (contraction of the muscles that help move food along through the digestive tract), amongst others.

How is Brown-Vialetto-Van Laere syndrome diagnosed?

In any child where there is evidence of muscle weakness with cranial nerve problems and/or respiratory problems (such as facial paralysis or vocal cord paralysis), BVVL should be considered a possible cause. Some children will present with obvious hearing loss but the disorder may also occur without obvious hearing loss, especially in younger children.

The child or teenager must be referred to a paediatric neurologist who can test for other treatable conditions which may cause the same symptoms as BVVL.

Some tests used in the diagnosis of BVVL are:

  • Hearing tests: these will show evidence of sensorineural hearing loss
  • Brainstem auditory evoked potentials (BAEP): this test involves placing electrodes on the head to measure and record the electrical activity coming from the brainstem – the part of the brain adjoining the spinal cord. All the nerve connections from the main part of the brain to the rest of the body pass through the brainstem. A BAEP helps evaluate the cause of symptoms such as loss of balance, hearing loss, headaches, vision problems, weakness, or numbness.
  • Electromyography (EMG): this test evaluates and records the electrical activity produced by the muscles cells, when activated. It can confirm the denervation of muscles. There are two kinds of EMGs: surface EMG (where a surface electrode is used to monitor the general picture of muscle activation) and intramuscular EMG (involving a needle electrode inserted through the skin into the muscle tissue, to record the activity of a few muscular fibres).
  • There is at least one genetic test available to confirm the presence of BVVL, for the genetic mutation(s) of SLC52A3. (See above, ‘What causes Brown-Vialetto-Van Laere syndrome?’)

What is the prognosis for Brown-Vialetto-Van Laere syndrome?

The rate of progression of the disease varies from person to person. Some affected individuals will gradually get worse, while for others there may be periods during which the progression seems to slow down or even stop. Untreated BVVL is a severe and often fatal disorder; however, new treatments with riboflavin supplements are now proven to improve outcomes for some patients.

Is there a treatment for Brown-Vialetto-Van Laere syndrome?

Since November 2010, Dr Bosch and her team in the Division of Metabolic Disorders at University Hospital of Amsterdam, Netherlands, have reported some very promising results in BVVL patients who were given high doses of riboflavin (vitamin B2) supplements. [1]

There was evidence of stabilisation, and even reversal of degeneration, in some of the patients treated with riboflavin. Similar results were observed in people affected by Fazio-Londe syndrome (a condition very similar to BVVL).

Not all patients treated with riboflavin reported an improvement, and more patients are needed to keep measuring the effects of this therapy.

Awareness of the therapeutic options among health professionals is essential, especially since treatment appears to be lifesaving. Where BVVL is suspected but not yet diagnosed, it is important to start riboflavin treatment immediately without awaiting results of gene mutation analysis. Some patients show improvement quickly whereas others take longer to respond and show improvement over a much longer term. Treating physicians should continue trials of riboflavin supplements over a longer period if the initial treatment seems unsuccessful. [1]

Links to further information

BVVL International was created in June 2008. The result of a collaborative effort among physicians and researchers in the UK, the USA and other countries, it is the first web-based resource tool for physicians, researchers, and families interested in learning more about BVVL syndrome.

Brown Vialetto Van Laere UK (BVVL) is the first UK website set up specifically to provide information, offer support and consolidate information on Brown-vialetto-Van-Laere syndrome.

References

1. Bosch A, Stroek K, Abeling N, Waterham H, IJlst L, Wanders R: The Brown-Vialette-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives.
www.ojrd.com/content/7/1/83

Last reviewed: 01-07-2016    ||    Next review due: 01-07-2018