Brown–Vialetto–Van Laere syndrome

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Brown–Vialetto–Van Laere syndrome
Other namesBVVLS1 [1]

Brown-Vialetto-Van-Laere syndrome (BVVL), is a rare, progressive, inherited neurodegenerative disorder that most often manifests in infancy or early childhood. Since 2010, mutations in the SLC52A1, SLC52A2, or SLC52A3 genes, which encode riboflavin transporters, have been identified as the cause of BVVL. BVVL is now known as Riboflavin transporter deficiency (RTD, OMIM 614707).

Contents

RTD types 2 and 3 are characterized by a diverse phenotypic spectrum encompassing motor, sensory, and cranial nerve neuropathies, leading to sensorineural hearing loss, optic atrophy, sensory ataxia, muscle weakness, ponto-bulbar palsy, and respiratory insufficiency. Without treatment, individuals with RTD types 2 and 3 experience severe disability and a rapidly progressive disease course, often culminating in fatal respiratory failure, particularly in those with early infancy onset.

Oral riboflavin supplementation has emerged as a life-saving treatment, significantly improving outcomes across multiple functional domains and slowing disease progression. Since 2010, approximately one hundred genetically confirmed cases of RTD have been reported in the literature, all of which were treated with high-dose oral riboflavin supplementation.


Symptoms and signs

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. [2] Major features of BVVL include facial and neck weakness, fasciculation of the tongue, and neurological disorders from the cranial nerves. [3] The neurological manifestations develop insidiously: they usually begin with sensorineural deafness, progress inexorably to paralysis, and often culminate in respiratory failure. 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. [3] The first symptoms in nearly all cases of BVVL is progressive vision loss and deafness, and the first initial symptoms are seen anywhere from one to three years. [4]

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 and autonomic dysfunction. [4]

Genetics

BVVL has autosomal recessive pattern of inheritance Autosomal recessive - en.svg
BVVL has autosomal recessive pattern of inheritance

The disorder has been associated with various mutations in the SLC52A2 and SLC52A3 genes. [1] [5] [6] This gene is thought to be involved in transport of riboflavin. [7]

Diagnosis

Diagnosis requires a neurological examination and neuroimaging can be helpful. [8]

BVVL can be differentially diagnosed from similar conditions like Fazio-Londe syndrome and amyotrophic lateral sclerosis, in that those two conditions don't involve sensorineural hearing loss, while BVVL, Madras motor neuron disease, Nathalie syndrome, and Boltshauser syndrome do. Nathalie syndrome does not involve lower cranial nerve symptoms, so it can be excluded if those are present. If there is evidence of lower motor neuron involvement, Boltshauser syndrome can be excluded. Finally, if there is a family history of the condition, then BVVL is more likely than MMND, as MMND tends to be sporadic. [8]

Genetic testing is able to identify genetic mutations underlying BVVL. [6]

Treatment

As of 2017, there were case reports that treatment with high doses of riboflavin 5 phosphate can halt the progress of Brown–Vialetto–Van Laere syndrome and in some cases can improve symptoms. [9] [10]

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 who 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. [11]

Prognosis

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. [3]

The syndrome has previously been considered to have a high mortality rate but the initial response of most patients to the Riboflavin protocol are very encouraging and seem to indicate a significantly improved life expectancy could be achievable. There are three documented cases of BVVL where the patient died within the first five years of the disease. On the contrary, most 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. [4]

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. [12]

Epidemiology

Between 2010 and 2024, the Cure RTD Patient Registry documented over 400 patients with genetically confirmed RTD. This includes, ~200 individuals with RTD type 2 and ~200 individuals with RTD type 3, of which over 200 are reported in the literature. Approximately 59% of reported patients are females.

History

The syndrome was first described by Charles Brown in 1894; [13] further accounts by Vialetto [14] and Van Laere [15] followed in 1936 and 1966, respectively.

See also

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References

  1. 1 2 Online Mendelian Inheritance in Man (OMIM): 211530
  2. ↑ Voudris, KA; Skardoutsou, A; Vagiakou, EA (2002). "Infantile progressive bulbar palsy with deafness". Brain & Development. 24 (7): 732–735. doi:10.1016/S0387-7604(02)00085-2. PMID   12427524. S2CID   7690110.
  3. 1 2 3 Prabhu, HV; Brown, MJ (June 2005). "Brown-Vialetto-Van Laere syndrome: a rare syndrome in otology". The Journal of Laryngology & Otology. 119 (6): 470–2. doi:10.1258/0022215054273179. PMID   15992475. S2CID   28865108.
  4. 1 2 3 Sathasivam, S; O’Sullivan, S; Nicolson, A; Tilley, PJB; Shaw, PJ (2000). "Brown-Vialetto-Van Laere syndrome: Case report and literature review". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 1 (4): 277–281. doi:10.1080/14660820050515106. PMID   11465021. S2CID   42001695.
  5. ↑ Green, P; Wiseman, M; Crow, YJ; et al. (March 2010). "Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54". American Journal of Human Genetics. 86 (3): 485–9. doi:10.1016/j.ajhg.2010.02.006. PMC   2833371 . PMID   20206331.
  6. 1 2 Johnson, JO; Gibbs, JR; Van Maldergem, L; Houlden, H; Singleton, AB (October 2010). "Exome sequencing in Brown-Vialetto-van Laere syndrome". American Journal of Human Genetics. 87 (4): 567–9, author reply 569–70. doi:10.1016/j.ajhg.2010.05.021. PMC   2948797 . PMID   20920669.
  7. ↑ Yamamoto, S; Inoue, K; Ohta, K; Fukatsu, R; Maeda, J; Yoshida, Y; Yuasa, H (2009). "Identification and Functional Characterization of Rat Riboflavin Transporter 2". Journal of Biochemistry. 145 (4): 437–443. doi:10.1093/jb/mvn181. PMID   19122205.
  8. 1 2 Sathasivam, S (17 April 2008). "Brown-Vialetto-Van Laere syndrome". Orphanet Journal of Rare Diseases. 3: 9. doi: 10.1186/1750-1172-3-9 . PMC   2346457 . PMID   18416855.
  9. ↑ Allison, T; Roncero, I; Forsyth, R; Coffman, K; Pichon, JL (May 2017). "Brown-Vialetto-Van Laere Syndrome as a Mimic of Neuroimmune Disorders: 3 Cases From the Clinic and Review of the Literature". Journal of Child Neurology. 32 (6): 528–532. doi:10.1177/0883073816689517. PMID   28116953. S2CID   31769793.
  10. ↑ Bosch, Annet M; Stroek, Kevin; Abeling, Nico G; Waterham, Hans R; IJlst, Lodewijk; Wanders, Ronald JA (2012). "The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives". Orphanet Journal of Rare Diseases. 7 (1): 83. doi: 10.1186/1750-1172-7-83 . PMC   3517535 . PMID   23107375.
  11. ↑ Nemoto, H; Konno, S; Nomoto, N; Wakata, N; Kurihara, T (May 2005). "[A case of Brown-Vialetto-van Laere (BVVL) syndrome in Japan]". Rinsho Shinkeigaku. 45 (5): 357–61. PMID   15960172.
  12. ↑ Dipti, S; Childs, AM; Livingston, JH; Aggarwal, AK; Miller, M; Williams, C; Crow, YJ (September 2005). "Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease". Brain & Development. 27 (6): 443–6. doi:10.1016/j.braindev.2004.10.003. PMID   16122634. S2CID   32223440.
  13. ↑ Brown CH (1894). "Infantile amyotrophic lateral sclerosis of the family type". Journal of Nervous and Mental Disease. 21 (2): 707–716. doi:10.1097/00005053-189411000-00003. S2CID   143353104.
  14. ↑ Vialetto E (1936). "Contributo alla forma ereditaria della paralisi bulbare progressive". Rivista sperimentale di freniatria e medicina legale delle alienazioni mentali. 40: 1–24.
  15. ↑ Van Laere, J (August 1966). "Paralysie bulbo-pontine chronique progressive familiale avec surdité. Un cas de syndrome de Klippel-Trenaunay dans la même fratrie – problèmes diagnostiques et génétiques [Familial progressive chronic bulbo-pontine paralysis with deafness. A case of Klippel-Trenaunay syndrome in siblings of the same family. Diagnostic and genetic problems]". Revue neurologique. 115 (2): 289–95. PMID   5969547.

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