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Brown–Vialetto–Van Laere syndrome: A rare case report of MND mimic
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.299175
Keywords: Brown–Vialetto–Van Laere syndrome, deafness, motor neuron disease, optic atrophy, riboflavin transporter deficiency, SLC52A2
Brown-Vialetto-Van Laere Syndrome (BVVLS) is a rare neurodegenerative disorder first described in 1894 by Brown later by Vialetto in 1936 and Van Laere in 1966.[1],[2],[3] Mutations causing BVVLS were seen in SLC52A2 (formerly C20orf54, encoding RFVT2) or SLC52A3 (encoding RFVT3).[4],[5],[6] Mutations in both the genes result in riboflavin transporter defect that was at least partially responsive to riboflavin supplementation.[7] The typical clinical features of both forms are progressive axonal neuropathy with predominant upper limb and axial involvement in RFVT2 compared to generalized weakness in RFVT3, and a prominent sensory ganglionopathy and sensory ataxia in RFVT2, optic atrophy, sensorineural hearing loss, bulbar dysfunction, and respiratory insufficiency.[8] At times, the clinical presentation mimics motor neuron syndrome.[7],[8] The following case highlights the clinical features of BVVLS and the identification of novel mutations in SLC52A2.
A 16-year-old boy, a product of nonconsanguineous parentage with normal development and family history, presented with gradually progressive hearing loss of 6 years duration. There is also history of defective vision in both eyes since last five years more on left side. At the time of presentation to our hospital, he could see objects at the distance of 3 m with the left eye and 5 m distance with the right eye. Noticed distal weakness of both upper limbs since two years and thinning of small muscles of hands from eight months. There was no history of proximal weakness in the upper limbs, lower limbs, neck, or trunk. No cranial nerve involvement or history suggestive of sensory, cerebellar, bowel, or bladder involvement was observed. Upon neurological examination, there was bilateral decreased visual acuity, and fundus examination revealed optic atrophy. There was also bilateral sensory neural hearing loss (SNHL), atrophic tongue with fasciculations, wasting of small muscles of hand with split hand sign and distal weakness of both upper limbs with poly-mini myoclonus [Figure 1]. Reflexes were absent in upper limbs and brisk in lower limbs with ankle clonus and plantar reflexes were mute with no sensory deficit. Marfanoid features (wrist and thumb sign) were noted. The rest of the examination was normal.
Routine laboratory tests, peripheral smear, and toxic profile were normal. Magnetic resonance imaging (MRI) scan of the brain and cervical spine were normal [Figure 2] and [Figure 3]. Nerve conduction studies showed diminished amplitudes of compound muscle action poltentials (CMAPs) with normal SNAPs. Electromyography (EMG) revealed a neuropathic pattern with chronic denervation and reinnervation changes in C6 to T1 segments.
Next-generation sequencing revealed homozygous variation in exon 5 of the SLC52A2 gene [chr8: 145584582C>T; c.1245C>T] that resulted in the synonymous amino acid change of glycine at codon 415 [p. Gly415(=)] and was being validated by Sanger sequencing. So, the patient was called for a follow-up and started on 25 mg/kg of riboflavin. There was no significant change in neurological status at 6 months of follow-up.
One study identified 18 patients from 13 families with mutations in SLC52A2.[1] To the best of our knowledge, the c.1245C>T in exon 5 of SLC52A2 found in our patient was not reported in the literature. In our patient, SNHL is the first symptom followed by optic atrophy, amyotrophy of distal upper limbs, atrophic tongue with fasciculations, and a phenotype consistent with SLC52A2 mutation, which was in contrast to generalized weakness in SLC52A3 mutation. Upper motor neuron involvement is less frequent.[5] However, our case had brisk reflexes in lower limbs and ankle clonus. He also had marfanoid features, which were not described previously. Bulbospinal muscular atrophy with deafness was first reported in India as BVVLS in 1996.[9] Phenotypic presentation like an MND with deafness and optic nerve involvement of childhood-onset was well-described.[10] So, BVVLS should be a differential diagnosis of juvenile-onset MND as it was a potentially treatable condition. There were no MRI changes in this patient although others reported atrophy of the brainstem and cerebellum[11] and increased signal on T2 sagittal views of the cervical spinal cord, with subtle changes affecting the dorsal columns.[8] Several conditions closely resemble BVVLS that should always be considered in the differential diagnosis. The most closely related disease is the Fazio–Londe syndrome, where the only distinguishing feature is the absence of deafness.[10] Another differential is the Nathalie syndrome, which is a rare condition characterized by deafness in conjunction with spinal muscular atrophy, cataract, cardiac conduction defects, and hypogonadism. The Boltshauser syndrome, which mimics BVVLS, is characterized by distal muscular atrophy with vocal cord paralysis and SNHL. However, in the former, the brainstem signs are restricted to vocal cord paralysis. The Madras pattern of MND was another close differential presenting with wasting and weakness of limb muscles, sensory neural hearing loss, along with VII, IX and XII cranial nerve involvement.[8],[10] The exact pathophysiology of the neuropathy in BVVLS and the process by which riboflavin deficiency causes sensory and motor neuron degeneration remains to be clarified. Preliminary human tissue studies of the SLC52A2 encoded RFVT2 demonstrate a relatively higher expression in the brain and spinal cord than in the small intestine. Significant clinical and biochemical improvements were observed after the initiation of high-dose oral riboflavin therapy in patients with mutations in SLC52A2.[6],[7],[8] Dramatic improvement of vision has been recently reported even after delayed riboflavin therapy.[12] Our patient did not have any significant recovery with riboflavin therapy after 6 months of follow-up. It is the timely consideration of a diagnosis of a riboflavin transporter deficiency and the rapid initiation of high-dose riboflavin therapy, in any child presenting with a rapidly progressive motor axonal neuropathy particularly in association with optic atrophy, bulbar dysfunction, hearing loss, or respiratory insufficiency might prevent and reverse the progression of this hitherto elusive and relentlessly progressive neurodegenerative condition.
This case identifies a novel mutation for BVVL syndrome and emphasizes the need for early diagnosis and management of symptoms, which can lead to improved clinical outcomes in patients with this disease. This case also highlights the presence of a juvenile-onset MND with deafness. So, BVVLS should be considered as a differential diagnosis in all such cases as it is potentially responsive to high doses of riboflavin. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Acknowledgement We acknowledge the Med Genome Labs, Bangalore for conducting the genetic study of this case at a very concessional price. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
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