Brown-Vialetto-Van Laere Syndrome: A Riboflavin-Unresponsive Patient With a Novel Mutation in the C20orf54 Gene

Abstract

Brown-Vialetto-Van Laere syndrome (Online Mendelian Inheritance in Man number 211530) is a neurodegenerative disorder characterized by pontobulbar palsy affecting cranial nerves (mainly VII-XII). Sensorineural deafness is often the leading sign, followed by other neurologic signs. Inheritance is often autosomal recessive, with mutations in the C20orf54 gene (Online Mendelian Inheritance in Man number 613350). Three previous patients with mutations in the C20orf54 gene and clinical signs of Brown-Vialetto-Van Laere or Fazio-Londe syndrome revealed a metabolic profile suggesting a multiple acyl-coenzyme A dehydrogenase defect. They benefited from riboflavin. We describe a 3-year-old girl with early-onset Brown-Vialetto-Van Laere syndrome and a novel mutation in the C20orf54 gene (c.989G>T). On T₂-weighted imaging, increased signal intensity of the vestibular nuclei bilaterally, the pedunculus cerebellaris superior and the central tegmental tract were observed during acute clinical deterioration. Her metabolic profile was normal. Trials with steroids, immunoglobulins, and riboflavin produced no effect. The patient recovered slowly during subsequent months, with residual deficits. Brown-Vialetto-Van Laere syndrome should be considered in patients with sensorineural hearing loss and pontobulbar palsy. Patients should be screened for riboflavin deficiency and a therapy with riboflavin may provide effective treatment in some affected patients.

Introduction

Brown-Vialetto-Van Laere syndrome (Online Mendelian Inheritance in Man number 211530) is a rare neurodegenerative disorder primarily characterized by pontobulbar palsy affecting the cranial nerves (mainly cranial nerves VII-XII). It was first described by Brown in 1894 [1]. Additional lower motor neuron signs in the limbs were reported in many cases, whereas long tract signs (upper motor neuron dysfunction) such as brisk deep tendon reflexes, clonus, and a positive Babinski sign seem to be less common [2], [3]. The differential diagnosis mainly includes Madras motor neuron disease, which seems to be rare outside India [4], and some atypical variants of autosomal recessive juvenile amyotrophic lateral sclerosis [5]. Diaphragmatic weakness leads to recurrent infections and respiratory distress, causing life-limiting problems [3].

The onset of disease and its clinical course are variable. The diagnosis in most cases is established during the second decade of life, although manifestations during early childhood and adulthood have also been reported [6]. Sensorineural deafness is often an initial sign, and other neurologic abnormalities, such as muscular weakness, slurred speech, or respiratory problems, may also comprise preceding signs [2]. Therapeutic options are limited. Trials of steroids and immunoglobulins only brought mild, temporary abatement [7], [8]. Supportive and symptomatic treatments such as assisted ventilation, gastrostomy, and physiotherapy encompass the mainstay of management [2].

Although many cases are sporadic, about 50% are familial, and most suggest autosomal recessive inheritance [9]. Few affected families have demonstrated an inheritance pattern compatible with autosomal dominant or X-linked inheritance [8]. Therefore, genetic heterogeneity seems a possibility.

Bosch et al. [10] recently reported on mutations in the C20orf54 gene (Online Mendelian Inheritance in Man number 613350) on chromosome 20p13 in three patients with clinical signs of Brown-Vialetto-Van Laere syndrome and of Fazio-Londe syndrome (Online Mendelian Inheritance in Man number 211500), which has been described as a very similar clinical syndrome, but without hearing loss [3].

These patients manifested a metabolic profile suggestive of a multiple acyl-coenzyme A dehydrogenase defect, and demonstrated significant improvement with high doses of riboflavin. Here, we report on a girl with an early and severe onset of Brown-Vialetto-Van Laere syndrome and a novel mutation in the C20orf54 gene.