Brown–Vialetto–Van Laere syndrome
|Brown–Vialetto–Van Laere syndrome|
|Classification and external resources|
Brown-Vialetto-Van-Laere syndrome (BVVL), sometimes better known as Brown's Syndrome, is a rare degenerative disorder that is characterized by progressive sensorineural deafness (Voudris 2002). BVVL is marked by a number of cranial nerve palsies including those of the motor components involving the 7th and 9th-12th cranial nerves, spinal motor nerves, and upper motor neurons (Voudris 2002). The neurological manifestations develop insidiously: they usually begin with sensorineural deafness, progress inexorably to paralysis, and often culminate in respiratory failure. The syndrome affects children, adolescents, and younger adults; the age at onset of symptoms in the reported cases has ranged from infancy to the third decade of life. The prognosis is poor—most patients diagnosed with the syndrome die within 10 years. There is no cure.
The syndrome was first described by Charles Brown in 1894; further accounts by Vialetto and Van Laere followed in 1936 and 1966, respectively. There are fewer than 60 cases reported in the medical literature over the 100 odd years since its first description.
Worldwide, there are thirty-eight known cases of Brown-Vialetto-Van-Laere syndrome (Voudris 2002). BVVL was first described in a Portuguese family, and has since been described in a number of ethnic groups. Reports have shown that BVVL infects females more than males at a rate of 5:1 respectively. However, males usually exhibit more severe symptoms, an earlier onset of deafness and a tendency to die earlier in life (Voudris 2002).
The etiology of BVVL is unknown (Prahbu 2005). Since about half of the 38 BVVL patients have no recognized symptoms in parents or relatives, it is thought that BVVL might be of autosomal recessive inheritance (Prahbu 2005). However, several cases of BVVL have suggested that the syndrome may be autosomal dominant or X linked (Sathasivam 2000).
Megarbane et al. reported for the first time a consanguineous Lebanese family (Nair 2006). This family demonstrates the autosomal recessive inheritance of the disorder. The family had three affected children that all presented the same severe symptoms, however, the parents and other siblings had no signs of the disease. The first case involved an eight-year-old boy, whose hearing and walking impairment started at two years of age. Upon examining the boy, it was found that he was weak, completely deaf, and hypotonic. Neurological examination showed low muscle tone; dorsal scoliosis; tongue contractions; a small number of spontaneous movements; neck, shoulder and upper arm muscular weakness; clawed hands; absent deep tendon reflexes; and no Babinski response. Upon radiological examination, the patient showed left curved scoliosis and thin diaphyses of the long bones. The patient died at five, most likely due to respiratory failure. The patient’s younger brother suffered from the same disease, and demonstrated limited speech and vocalization by the age of seven. He also showed similar neurological symptoms as his brother, and died four months after the onset of symptoms. The third case in the immediate family was the two patients’ sister who died at the age of four with symptoms similar to her brothers. Finally, the patients had a cousin whose neurological features were identical to his cousins. All of these patients had symptoms indicative of BVVL. It is thought that identification of the gene responsible for the family’s disorder would be a major step in knowing the etiology of this disease (Nair 2006).
The gene defective in at least some patients with BVVL has been identified by a team of British researchers: C20orf54. This gene is thought to be involved in transport of riboflavin It has been proposed that Fazio–Londe disease and Brown-Vialetto–Van–Laere syndrome are a phenotypically associated condition.
Major features of BVVL include facial and neck weakness, fasciculation of the tongue, and neurological disorders from the cranial nerves (Prahbu 2005). Most mortality in patients has been from either respiratory infections or respiratory muscle paralysis. Pathological descriptions of BVVL include injury and depletion of 3rd-7th cranial nerves, loss of the spinal anterior horn cells, degeneration of Purkinje cells, as well as degeneration of the spinocerebellar and pyramidal tracts (Prahbu 2005). The first symptoms in nearly all cases of BVVL is progressive deafness, and the first initial symptoms are seen anywhere from one to three years (Sathasivam 2000). Most cases of deafness are followed by a latent period that can extend anywhere from weeks to years, and this time is usually marked by cranial nerve degeneration. Neurological symptoms of BVVL include optic atrophy, cerebellar ataxia, retinitis pigmentosa, epilepsy, mental retardation, and autonomic dysfunction (Sathasivam 2000). Non- neurological symptoms can include diabetes, auditory hallucinations, respiratory difficulties, color blindness, and hypertension.
To date, there is no test of confirmation for BVVL, although as of 2008, BVVL researchers are searching to isolate the responsible gene(s) for both BVVL and Fazio-Londe syndromes, as it has been proposed that Fazio-Londe disease and Brown-Vialetto-Van-Laere syndrome are a phenotypically associated condition.
Differential diagnosis of BVVL includes Boltshauser syndrome, Madras disease, progressive bulbar paralysis of Fazio Londe, Nathalie syndrome and ALS (Nair 2006)
The first report of BVVL syndrome in Japanese literature was of a woman that had BVVL and showed improvement after such treatments. The patient was a sixty-year-old woman that had symptoms such as sensorineural deafness, weakness, and atrophy since she was 15 years old. Around the age of 49 the patient was officially diagnosed with BVVL, intubated, and then attached to a respirator to improve her CO2 narcosis. After the treatments, the patient still required respiratory assistance during sleep; however, the patient no longer needed assistance by a respirator during the daytime (Hiroshi 2005).
The clinical course of BVVL can vary from one patient to another. There have been cases with progressive deterioration, deterioration followed by periods of stabilization, and deterioration with abrupt periods of increasing severity (Prahbu 2005).
BVVL syndrome is often found in late childhood and adolescents, however, seven cases have been found with symptoms starting within the first five years (Voudris 2002).
The youngest case of BVVL was documented by Voudris (Voudris 2002). The patient was a male infant who had a normal birth and neonatal period, healthy parents and no family history of neurological disorders. This male was the youngest patient in literature who featured severe symptoms of BVVL syndrome. At twelve months, the patient developed an upper respiratory infection and demonstrated both stridor and harshness of voice. Three weeks later, the child showed apnea, suspension of external breathing, and was artificially ventilated for three days. However, aside from slight bilateral facial weakness the patient showed a relatively normal neurological examination with normal motor and sensory nerve conduction. At fourteen months, the child developed dysphagia, or difficulty swallowing, and was then fed with a catheter. Between fifteen and eighteen months, the patient showed progressive neurological degeneration with symptoms such as paralysis of extraocular muscles responsible for eye movements, bilateral facial palsy, weakness of jaw muscles and tongue, and sever weakness of upper extremities with disappearance of tendon reflexes. Between eighteen and twenty-one months, the child became lethargic and unresponsive, lost interchange between sleep and awakening, and no longer reacted to any visual or auditory stimulation. The patient died at twenty-one months of respiratory failure. This particular case of BVVL syndrome differs from others in that the patient had severe symptoms at an unusually early age. While no autopsy on the child was performed, researchers are hoping that the unusual symptoms in this case and other similar cases can be used to provide a link between BVVL syndrome and Fazio-Londe disease (Voudris 2002).
The syndrome can be fatal or protracted for a longer period. There are three documented cases of BVVL where the patient died within the first five years of the disease. On the contrary, at least fourteen patients have survived more than 10 years after the onset of their first symptom, and several cases have survived 20–30 years after the onset of their first symptom (Sathasivam 2000).
Families with multiple cases of BVVL and more generally, multiple cases of Infantile Progressive Bulbar Palsy, can show variability in age of disease onset and survival. Dipti and Childs described such a situation in which a family had five children that had Infantile PBP. In this family, three siblings showed sensorineural deafness and other symptoms of BVVL at an older age. The other two siblings showed symptoms of Fazio-Londe disease and died before the age of two (Dipti 2005).
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