Brown-Vialetto-Van Laere Syndrome 1

A number sign (#) is used with this entry because Brown-Vialetto-Van Laere syndrome-1 (BVVLS1), a form of progressive bulbar palsy with sensorineural deafness, is caused by homozygous or compound heterozygous mutation in the C20ORF54 gene (SLC52A3; 613350) on chromosome 20p13.

Mutations in the SLC52A3 gene also result in Fazio-Londe disease (211500), a disorder similar to BVVLS but without sensorineural deafness.

Description

Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010).

Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome

See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q.

Clinical Features

The first case of BVVLS was reported by Brown (1894) as a form of familial infantile amyotrophic lateral sclerosis. Familial cases in a pattern consistent with autosomal recessive inheritance were reported by Vialetto (1936), Van Laere (1966), and Boudin et al. (1971). Most familial cases involved affected females.

Gallai et al. (1981) described the clinical features of 2 patients and the clinical and postmortem findings in the sib of one of these. One of these patients was a girl who became deaf at age 2 and developed multiple cranial and spinal nerve palsies at age 14. Her brother died of the condition at age 2. The parents were unrelated. The third case, sporadic, had onset of deafness at age 6 and of other neurologic disturbances at age 12.

Hawkins et al. (1990) reported an affected family. The proband was a healthy, athletic young girl until the age of 12 years when, over the course of a few weeks, she had rapid onset of neurosensory deafness. The following year she developed rapidly progressive weakness with clumsiness of her arms and difficulty in washing, dressing, writing, and combing her hair. At that time she also tended to shake and twitch, particularly at night. She complained of sleepiness during the day and of shortness of breath and was unable to rise from a supine position. Her speech was soft and she had difficulty swallowing. Treatment with steroids for 12 months when she was 13 years old resulted in improvement, but at the age of 15 she began to deteriorate again. She had nocturnal hypoventilation and daytime sleepiness resulting from diaphragmatic weakness, as well as right vocal cord paralysis and increasing difficulty swallowing. She died at the age of 17 years 4 months. A paternal aunt who had had breathing difficulties for 20 years and facial weakness for 2 years showed pallor of the left optic disc and weakness of the facial and neck muscles as well as neurosensory deafness. The tongue was wasted and fasciculating, and the diaphragm was weak. She refused examination of her 10 children. According to the school doctor, 1 of her sons had developed neurosensory deafness in his teens. The paternal grandfather died at the age of 40 years with chronic respiratory problems.

Dipti et al. (2005) reported 4 sibs, born of consanguineous Pakistani parents, with BVVLS. Two presented in the first 16 months of life with stridor and died of respiratory failure by the age of 2 years. Both had normal early psychomotor development before onset of the disorder. Hearing loss was not apparent in these infants, and they were given a diagnosis of Fazio-Londe disease (211500). In contrast, the 2 other sibs showed onset of a bulbar palsy at age 5 and 7 years, followed by onset of deafness and an anterior horn neuropathy with corticospinal tract involvement. Features included dysphagia, facial weakness with ptosis, tongue weakness and fasciculations, muscle weakness, particularly of the upper limbs, hyperreflexia, ankle clonus, and extensor plantar responses. They exhibited a relatively slow but relentless decline over a period of several years, resulting in death at age 10 years in one and severe muscle weakness in the other. Dipti et al. (2005) noted the overlap between BVVLS and Fazio-Londe syndrome, and suggested that both younger children may have developed deafness later. The authors suggested that these disorders may be a single disease entity, which could be considered a form of juvenile amyotrophic lateral sclerosis.

Green et al. (2010) reported 9 patients with BVVLS from 7 families, including 1 reported by Dipti et al. (2005). Members of 4 families showed onset of the disorder before 2 years of age, with bulbar palsy, hypotonia, anterior horn involvement, respiratory insufficiency, and early death in most. Two sisters in another family showed onset of sensorineural deafness at age 12 years and were still alive in their twenties and thirties with muscle weakness and respiratory compromise. The proband from another family showed onset in his early twenties of a peripheral neuropathy, and later developed deafness and ataxia without respiratory compromise. He was alive at age 57 years. Green et al. (2010) noted the variable age at onset and variable severity of this disorder.

Johnson et al. (2010) reported a consanguineous Turkish family in which 3 children had BVVLS. The phenotype was homogeneous, even though there was over 20 years' difference in the age at onset. The proband developed normally until she presented in mid-childhood with acute respiratory distress, stridor, and paralysis of vocal cord abduction, requiring ventilation. She later developed cranial nerve palsies with ophthalmoplegia, dysarthria, dysphagia, tongue fasciculation, facial weakness, and weakness and wasting of the limbs. She died at age 8 years of respiratory failure. Postmortem examination showed replacement gliosis of the cranial nuclei, particularly at the bulbo-pontine level, but only mild anterior horn cell involvement. The proband's affected sister developed rapid onset of hearing loss at the age of 10 years. In the following years she developed similar features as her sister, with progressive bulbar palsy, dysarthria, dysphagia, tongue fasciculation, facial weakness, weakness and wasting of the limbs, and breathing problems. She had a motor neuronopathy and axonal degeneration. She died at age 29 from respiratory failure. A younger niece was also affected, but was in the early stages of the disease with hearing problems and cranial nerve palsies.

Clinical Management

The patient of Bosch et al. (2011) with BVVLS had an acylcarnitine profile suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD; 231680) and was placed on a fat-restricted diet with carnitine, riboflavin (10 mg/kg per day), glycine, and 3-hydroxybutyrate. Her muscle strength improved and from the age of 2 years, artificial ventilation was necessary only during sleep. Acylcarnitine profiles normalized and fat restriction was gradually discontinued. Glycine, 3-hydroxybutyrate, and carnitine supplementation were stopped without problems. However, withdrawal of riboflavin at the age of 4 years resulted in a rapid clinical deterioration with vomiting, progressive fatigue, and elevations of lactate, liver enzymes, and creatine kinase. The acylcarnitine profile became abnormal again. Reintroduction of riboflavin (50 mg twice daily) resulted in clinical improvement and normalization of biochemical abnormalities. However, by age 7 the patient demonstrated the neurologic deterioration frequently observed in untreated BVVLS.

Inheritance

Familial cases of BVVLS in a pattern consistent with autosomal recessive inheritance were reported by Vialetto (1936), Van Laere (1966), and Boudin et al. (1971).

The family reported by Hawkins et al. (1990) raised questions about the genetics of this disorder. The proband, a teenaged girl, had the full syndrome; her father, a paternal uncle, and possibly a paternal first cousin had neurosensory deafness, and a paternal aunt had clinical symptoms indicative of the syndrome. Hawkins et al. (1990) suggested that the disorder may be genetically heterogeneous with autosomal recessive and autosomal dominant forms, or alternatively that it may be caused by a mutant gene on the X chromosome.

Molecular Genetics

By autozygosity mapping followed by candidate gene analysis of a consanguineous Pakistani family with Brown-Vialetto-Van Laere syndrome, Green et al. (2010) identified a homozygous mutation in the C20ORF54 gene (613350.0001) on chromosome 20p13. Analysis of other families with the disorder identified 7 additional homozygous or compound heterozygous C20ORF54 mutations (see, e.g., 613350.0002-613350.0006). One of the families had been reported by Dipti et al. (2005). Green et al. (2010) noted that the C20ORF54 gene is thought to play a role in riboflavin transport. Riboflavin is essential for synthesis of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are involved in energy metabolism. It is plausible that the C20ORF54 protein has a maintenance function in the nervous system, and that the disease is precipitated by defect in a pathway tightly regulated by this protein.

In 3 affected members of a consanguineous Turkish family with Brown-Vialetto-Van Laere syndrome, Johnson et al. (2010) identified a homozygous mutation in the C20ORF54 gene (P28T; 613350.0007). The authors used an exome sequencing technique to identify the candidate gene.

Bosch et al. (2011) identified an additional patient with BVVLS who carried a missense (613350.0009) and a nonsense mutation (613350.0010) in the C20ORF54 gene.

Associations Pending Confirmation

For discussion of a possible association between BVVLS and variation in the UBQLN1 gene, see 605046.0002.