Brown-Vialetto-Van Laere Syndrome, a Ponto-Bulbar Palsy with Deafness, Is Caused by Mutations in C20orf54

| Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset-a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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“…99 This syndrome is closely related to Fazio-Londe syndrome, in which auditory function is spared. 3 …”

Section: Als With Deafnessmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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“…Cases of secondary MADD related to riboflavin deficiency have been described in neonates of mothers carrying heterozygous mutations in a riboflavin transporter (deficiency for GPR172B/SLC52A1) and showed a good response to transient riboflavin supplementation (Chiong et al 2007;Harpey et al 1983;Ho et al 2011). A different entity with later presentation, Brown-Vialetto-Van Laere syndrome, is caused by mutations in two related riboflavin transporters SLC52A2 and SLC52A3 (Bosch et al 2011;Green et al 2010;Johnson et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles

et al. 2015

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Classical neonatal-onset glutaric aciduria type 2 (MAD deficiency) is a severe disorder of mitochondrial fatty acid oxidation associated with poor survival. Secondary dysfunction of acyl-CoA dehydrogenases may result from deficiency for riboflavin transporters, leading to severe disorders that, nevertheless, are treatable by riboflavin supplementation. In the last 10 years, we identified nine newborns with biochemical features consistent with MAD deficiency, only four of whom survived past the neonatal period. A likely iatrogenic cause of riboflavin deficiency was found in two premature newborns having parenteral nutrition, one of whom recovered upon multivitamin supplementation, whereas the other died before diagnosis.Four other patients had demonstrated mutations involving ETF or ETF-DH flavoproteins, whereas the remaining three patients presumably had secondary deficiencies of unknown mechanism. Interestingly, six newborns among the seven tested for plasma amino acids had pronounced hyperprolinemia. In one case, because the initial diagnostic workup did not include organic acids and acylcarnitine profiling, clinical presentation and hyperprolinemia suggested the diagnosis. Analysis of our full cohort of >50,000 samples from >30,000 patients suggests that the proline/ alanine ratio may be a good marker of MAD deficiency and could contribute to a more effective management of the treatable forms.

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“…9 Green et al reported that a C20orf54 gene mutation causes Brown-Vialetto-Van Laere syndrome. 10 Although there is no definitive evidence for a causative role of this gene in 12 Riboflavin is a precursor of flavin adenine dinucleotide and flavin mononucleotide, which in turn are electron acceptors important in cell metabolism. Riboflavin is essential for cellular energy generation and DNA repair, and is a plausible candidate for a maintenance role in nervous system function.…”

Section: Discussionmentioning

confidence: 99%

Auditory neuropathy spectrum disorder with Brown–Vialetto–Van Laere syndrome: challenges in hearing rehabilitation

et al. 2015

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Background: Brown-Vialetto-Van Laere syndrome is a rare neurological disorder characterised by pontobulbar palsy and sensorineural hearing loss. Hearing rehabilitation continues to be a challenge because the exact lesion site is unknown.Case report: We examined the clinical and audiological profiles of a case series comprising four siblings with Brown-Vialetto-Van Laere syndrome who had decreased hearing and poor speech discrimination. Audiological investigations revealed normal otoacoustic emissions with absent auditory brainstem responses and middle-ear reflexes in sensorineural hearing loss, suggestive of auditory neuropathy spectrum disorder.Conclusion: The sensorineural hearing loss in Brown-Vialetto-Van Laere syndrome patients is a retrocochlear pathology resembling auditory neuropathy spectrum disorder, with the lesion being most probably of post-synaptic origin. Early cochlear implantation along with high-dose riboflavin represents a possible rehabilitation therapy. However, further research is needed to confirm this. This report emphasises the need for a thorough neurological evaluation of auditory neuropathy spectrum disorder patients.

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Brown-Vialetto-Van Laere Syndrome, a Ponto-Bulbar Palsy with Deafness, Is Caused by Mutations in C20orf54

Cited by 166 publications

References 14 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles

Auditory neuropathy spectrum disorder with Brown–Vialetto–Van Laere syndrome: challenges in hearing rehabilitation

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