Early use of high-dose riboflavin in a case of Brown–Vialetto–VanLaere syndrome

GEETHA ANAND1 | NADEEM HASAN1 | SATHIYA JAYAPAL1 | ZILLA HUMA2 | TARIQ ALI1 | JEREMY HULL1 |EDWARD BLAIR3 | TONY MCSHANE1 | SANDEEP JAYAWANT1

1 Department of Paediatrics, John Radcliffe Hospital, Oxford. 2 Department of Paediatrics, Wexham Park Hospital, Slough. 3 Department of Clinical Genetics, Churchill Hospital,Oxford, UK.

Correspondence to Dr Geetha Anand, Department of Paediatrics, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: anandgeetha97@gmail.com

PUBLICATION DATA

Accepted for publication 15th August 2011.Published online 18th November 2011.

ABBREVIATIONSBVVLS Brown–Vialetto–Van Laere syndromeNIV Non-invasive ventilation

Brown–Vialetto–Van Laere syndrome (BVVLS) is a genetic condition caused by a mutation in the

C20orf54 gene, which also codes for an intestinal riboflavin transporter. We report the case of a

female who presented at 22 months with acute-onset stridor and generalized muscle weakness,

in whom a genetic diagnosis of BVVLS was made, and whose symptoms improved on therapy with

high-dose riboflavin. She had previously been developing normally and was able to walk at

11 months, then developed progressive muscle weakness at 22 months, and within 2 weeks was

unable to sit without support. She also demonstrated stridor and paradoxical breathing indicating

diaphragmatic weakness, and required continuous non-invasive ventilation (NIV) through a

tracheostomy. After treatment with riboflavin she was able to walk unaided, and her Gross Motor

Functional Classification level improved from level IV to level I, having fully regained the motor

function she showed before symptom onset. There were no longer signs of diaphragmatic

paralysis while on NIV, and she was able to tolerate 10-minute periods off NIV before paradoxical

breathing again became apparent. We therefore recommend that in all cases suspected to be in the

BVVLS or Fazio–Londe spectrum, early treatment with high-dose riboflavin must be considered.

A 22-month-old female born to parents in a consanguineousrelationship presented with acute-onset stridor, difficulty swal-lowing, and progressive generalized weakness. She had previ-ously been developing normally and was able to walk from theage of 11 months. At the age of 22 months she developed stri-dor, difficulty swallowing, and generalized weakness whichwas progressive. She initially stopped walking, and over a per-iod of 2 weeks was needing support to sit. Neurological exam-ination showed ptosis, bilateral vocal cord palsy, and labouredinspiration with paradoxical breathing indicating diaphrag-matic weakness. Laryngoscopy demonstrated pooling withsecretions in the hypopharynx and an unsafe swallow due tobulbar palsy, supported by the finding of fibrillations from thebulbar muscle (tongue) during needle electromyography.There was significant generalized muscle weakness in all mus-cle groups (Medical Research Council classification 3 ⁄ 5), anddeep tendon reflexes were just elicitable.

The patient developed significant breathing difficultiesrequiring non-invasive ventilation (NIV) and a subsequent tra-cheostomy 3 weeks after she first became symptomatic. Shewas given a course of intravenous immunoglobulin on the pre-sumed diagnosis of Guillain–Barre syndrome, which made noimprovement to her symptoms.

Magnetic resonance images of her brain and cervical spinewere normal. She was also extensively investigated for a possi-ble neuromuscular cause for her symptoms. Her creatine

kinase was normal and common spinal muscular atrophymutations were excluded (SMN1 and SMARD1). There wasno evidence of anti-acetylcholine receptor antibodies. Needleelectromyography showed fibrillations from the tongue but noabnormalities in the limb muscles, and nerve conduction stud-ies showed normal motor responses in the upper and lowerlimbs, though sensory responses were marginally attenuated.These findings were consistent with denervation in the bulbarsegment with no evidence for more widespread motorneuronal or neuromuscular junction dysfunction (Table SI,supporting material online). Muscle biopsy was normal.

A homozygous pathogenic mutation was detected in theC20orf54 gene by DNA sequencing, confirming the diagnosisof BVVLS. Visually reinforced audiometry showed moderatehearing loss. A simultaneous plasma acyl carnitine profileshowed moderately increased C4 and C5 carnitine species at0.78lmol ⁄ L (reference <0.4) and 0.81lmol ⁄ L (reference <0.5)respectively, which was suggestive of a riboflavin-responsivedisorder.

She was started on high-dose oral riboflavin (150mgtwice a day, equal to 25mg ⁄ kg ⁄ d) 4 weeks into her illness,after which there was a moderate improvement in her phys-ical activity. She started showing improvement within aweek of riboflavin therapy. Twenty-eight weeks afterpresentation she was completely mobile, could speak afew words, walk up the stairs, and throw and catch a ball.

ª The Authors. Developmental Medicine & Child Neurology ª 2011 Mac Keith Press DOI: 10.1111/j.1469-8749.2011.04142.x 187

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY CASE REPORT

Her Gross Motor Function Classification System (GMFCS)improved from level IV before starting riboflavin (trunksupport required for floor sitting) to level I (walks withoutthe need for any assistive mobility device), having fullyregained the motor function she showed before symptomonset. In terms of her respiratory function, she no longerexhibited paradoxical breathing suggestive of diaphragmaticpalsy while on NIV, but could only tolerate short periods(up to 10min) off NIV, towards the end of which paradoxi-cal breathing was still present.

Both parents were tested and found to be carriers forBVVLS. A few years earlier there had been two brothers inthe extended family who presented with a similar illness to ourpatient, from which they died. No genetic diagnosis was madein them.

Informed consent was obtained from the parents to publishthis case report.

DISCUSSIONBrown–Vialetto–Van Laere syndrome is a rare neurologicaldisorder described by Brown,1 Vialetto,2 and Van Laere.3 It ischaracterized by bilateral sensorineural deafness and progres-sive ponto-bulbar palsy, progressing in some cases to involvespinal motor nerves, upper motor neurons, and lower motorneurons. A similar presentation but without sensorineuraldeafness is seen in Fazio–Londe syndrome, which morerecently has been described as part of the same disease spec-trum as BVVLS.4

A review of the 58 reported cases to 2008 by Sathasivam5

noted a marked variability in age at onset from 6 months to36 years. Approximately half of the cases were sporadic andthe other half familial, with a female to male ratio of 3:1. Ofthe familial cases, most demonstrated autosomal recessiveinheritance, though a much rarer autosomal dominant orX-linked form has also been suggested.6,7

Affected individuals demonstrate progressive ponto-bulbarpalsy, but initial presentation and clinical course are variable.The commonest presenting symptoms are sensorineural deaf-ness followed by limb weakness and respiratory compromise.The disease commonly involves cranial nerves VII to XII, andmay progress to involve lower motor neurons and less fre-quently upper motor neurons. However, the only feature thatis consistent across cases is sensorineural deafness, which dis-tinguishes BVVLS from Fazio–Londe syndrome. Cases withearly-onset disease often have a rapidly progressive coursewith respiratory compromise leading to early death, whereasthose presenting with later-onset disease tend to follow aslower clinical course. Males also tend to be more severelyaffected and die earlier. Some patients have been noted toremain stable for a prolonged period after initial presentation,or even partly improve.7

Bosch et al.8 discussed three patients with progressivemuscle weakness and diaphragmatic paralysis, two of whomwere screened for inborn errors of metabolism with plasmaacylcarnitines and urine organic acids, and were found tohave raised concentrations consistent with a mild form ofmultiple acyl-CoA dehydrogenation defect. On further

testing, these three patients were found to be deficient inplasma flavins, despite a normal dietary intake, suggesting ariboflavin transporter defect. Green et al.9 had concurrentlyidentified the genetic cause of BVVLS as a mutation in theC20orf54 gene, a five-exon gene located on chromosome20p13. They also suggested that the gene may code for anintestinal transporter of riboflavin as the rat orthologue(rRFT2), which shares 83% similarity with C20orf54, hasbeen postulated to perform the same function.10 Accord-ingly, the three patients were treated with parenteral ribo-flavin supplementation (10mg ⁄ kg ⁄ d) and demonstrated amarked improvement in symptoms and biochemistry,though diaphragmatic paralysis was not reversed. Further-more, withdrawal of riboflavin supplementation in one ofthese patients led to rapid deterioration of the disease state,and in another patient led to a recurrence of an abnormalacylcarnitine profile, supporting their hypothesis that ribo-flavin may be an effective therapy for BVVLS and Fazio–Londe syndrome. All three patients were later screened forC20orf54 mutations and were found to be positive, andafter testing for sensorineural hearing loss two patients werediagnosed with Fazio–Londe syndrome and one withBVVLS.

Riboflavin is a precursor of flavin adenine dinucleotide andflavin mononucleotide, which are cofactors involved in oxida-tive phosphorylation, an essential component of energymetabolism. Deficiency normally presents with inflammationof the mouth and tongue, with mouth ulcers, cracked lips, andangular cheilitis, though moderate riboflavin deficiency pre-senting with neurodegenerative disease has been reported.11

Supplementation of riboflavin in this case and in all threepatients presented by Bosch et al.8 led to a rapid improvementin clinical symptoms and corrected the underlying biochemicalabnormalities, consistent with the hypothesis that part of thesymptom complex observed in BVVLS and Fazio–Londesyndrome is caused by a deficiency of riboflavin.

We present here the first case of clinical improvement withearly use of high-dose riboflavin therapy following an earlygenetic diagnosis of BVVLS. The patient was treated with150mg riboflavin twice a day (25mg ⁄ kg ⁄ d), and within a weekstarted showing improvement in motor function from beingable to just sit with support to being completely mobile andable to walk up the stairs. Furthermore, having required NIVfor most of the time, she is now tolerating short periods off itand appears to be following a stable clinical course. However,it appears that she will continue to require NIV through hertracheostomy for ventilatory support, consistent with the find-ing of Bosch et al.8 that diaphragmatic paralysis may beirreversible.

This case further supports the hypothesis that early high-dose riboflavin supplementation represents a potentialtreatment for BVVLS and the Fazio–Londe spectrum and we

What this paper adds• This is the first reported case of high-dose riboflavin used for a primary diagno-

sis of Brown–Vialetto–Van Laere syndrome.• This case supports the very recent hypothesis that riboflavin may be an effec-

tive treatment for Brown–Vialetto–Van Laere syndrome.

188 Developmental Medicine & Child Neurology 2012, 54: 187–189

recommend its use in all cases. In this regard, an early geneticdiagnosis in patients presenting with progressive ponto-bulbarpalsy with or without sensorineural deafness will enable earlyinstitution of therapy and reversal of symptom progression,leading to a better prognosis.

ONLINE MATERIAL ⁄ SUPPORTING INFORMATIONAdditional material and supporting information for this paper may be

found online.

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Case Report 189