Clinical Neurology and Neurosurgery 128 (2015) 1–3
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Adult onset Brown–Vialetto–Van Laere syndrome with opsoclonus and a novel heterozygous mutation: A case report Jeremy Cosgrove a,∗ , Sayan Datta b , Mark Busby b a b
Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK Department of Neurology, Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
a r t i c l e
i n f o
Article history: Received 16 August 2014 Received in revised form 23 October 2014 Accepted 25 October 2014 Available online 4 November 2014 Keywords: Brown–Vialetto–Van Laere Riboflavin Neuromuscular disease
1. Introduction Brown–Vialetto–Van Laere (BVVL) is a rare neurodegenerative disorder caused by mutations in the human intestinal riboflavin transporter genes, leading to riboflavin deficiency. It is characterised by bulbar palsy, respiratory insufficiency and sensorineural deafness. Some cases of BVVL have been successfully treated with riboflavin supplementation. Although BVVL is most commonly diagnosed in children it may also present in adults. We describe a case of BVVL in a 27-year-old female. 2. Case report A 27-year-old obese woman who had developed progressive hearing loss over the previous six months presented to hospital with a two-month history of progressive dysphonia, dysphagia and intermittent diplopia. Examination revealed bilateral facial weakness, subtle tongue wasting and hypophonic speech (Fig. 1). There were rapid involuntary horizontal and vertical eye movements consistent with opsoclonus as well as variable partial ptosis bilaterally. Nasendoscopy demonstrated bilateral vocal cord paresis and ophthalmological review identified bilateral sectoral optic pallor. She had globally brisk, symmetrical reflexes and subtle left arm
∗ Corresponding author at: Department of Neurology, F Floor, Martin Wing, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. Mobile: +44113 3923339; fax: +44 113 3922244. E-mail address: [email protected] (J. Cosgrove). http://dx.doi.org/10.1016/j.clineuro.2014.10.016 0303-8467/© 2014 Elsevier B.V. All rights reserved.
weakness (4+/5 Medical Research Council scale for muscle strength) but no evidence of ataxia. Family history revealed that her only sibling, a six-year-old sister, had a diagnosis of sensorineural deafness since infancy. Considering the two-month history of progressive bulbar dysfunction, our initial clinical impression included anti-MuSK antibody myasthenia gravis or an immune cranial polyneuropathy, although we were unsatisfied about the lack of a clear explanation for the six-month history of progressive hearing loss. Over the next ten days her respiratory function deteriorated and she developed type-two respiratory failure, requiring non-invasive ventilation (NIV). Her swallowing also worsened, necessitating nasogastric (NG) feeding. Tensilon test was negative, but we treated her with high dose prednisolone and concomitant plasma exchange. She was discharged home after two months using overnight NIV and her NG tube was removed 6 months later. Her prednisolone was gradually tapered and stopped. Testing for acetylcholine receptor, anti-MuSK and antiganglioside antibodies was negative. CSF was normal, as was MR imaging of brain and cervical spine and CT of the chest, abdomen and pelvis. Muscle biopsy of the quadriceps was unremarkable, including investigation for mitochondrial abnormalities. Electrophysiological investigation of the limbs was normal, including repetitive nerve stimulation of abductor digiti minimi. EMG of the right orbicularis oculi demonstrated fast-firing motor units suggestive of neurogenic weakness of the facial muscles. Audiometry confirmed bilateral sensorineural deafness. Genetic testing for BVVL was performed and DNA sequencing identified two mutations in the SLC52A3 gene coding for the human
2
J. Cosgrove et al. / Clinical Neurology and Neurosurgery 128 (2015) 1–3
Fig. 1. The patient’s facial appearance when being asked to smile, demonstrating bilateral facial weakness. Also note the partial right-sided ptosis.
intestinal riboflavin transporter type 2 (hRFT2) – a heterozygous pathogenic mutation (c.1292G>A) in exon 5 and a previously unreported heterozygous variant (c.383C>T) in exon 2 – compatible with compound heterozygosity. The decision to perform a genetic test was based on the patient’s clinical features; we did not perform biochemical testing to look for changes compatible with BVVL. Following the diagnosis of BVVL she was commenced on riboflavin supplementation, which was gradually increased to the current dose of 1500 mg daily (approximately 15 mg/kg). At a recent outpatient review there was continued evidence of improvement of facial and hypoglossal nerve function. Overnight NIV continues but she is now established on a normal diet.
3. Discussion The eponym for this syndrome comes from the original description by Brown (1894) and further reports by Vialetto (1936) and Van Laere (1966) [1]. BVVL is thought to be very rare and only 101 published cases were identified in a review paper in 2012 [1]. In 2010 an area of shared homozygosity between two relatives with BVVL was identified on chromosome 20 [2]. Gene sequencing of this region led to the identification of a homozygous mutation in a gene now known as SLC52A3. Other affected family members were homozygous for this mutation and the parents of an affected child were heterozygous carriers in keeping with an autosomal recessive trait. SLC52A3 shared similarities with a recently identified riboflavin transporter gene in rats. In 2011 three patients with symptoms compatible with BVVL suspected to have a mild form of a condition called multiple acylCoA dehydrogenase defect (MADD) were found to have mutations in the SLC52A3 gene [3]. Riboflavin supplementation improved their metabolic abnormalities as well as producing some improvement in their neurological deficits. Combined with prior knowledge about the role of SLC52A3 in the rat, it was concluded that riboflavin deficiency caused by a defective riboflavin transporter causes BVVL [3]. Numerous mutations causing BVVL have subsequently been identified in the SLC52A3 gene (OMIM 211530) [1].
In BVVL deficiency of the active metabolite of riboflavin, called flavin adenine dinucleotide (FAD), leads to malfunction in a number of dehydrogenase reactions in amino acid catabolism and mitochondrial fatty acid oxidation. The biochemical profile of BVVL is similar to that seen in a mild forms of MADD, characterised by abnormalities in plasma acylcarnitine levels and urine organic acids. Additionally, a number of genetically confirmed cases of BVVL have been found to have low levels of serum riboflavin, FAD and other riboflavin metabolites [1]. Mutations in a gene called SLC52A2, located on chromosome 8, have subsequently been identified as also causing BVVL (OMIM 614707) [4]. This gene codes for a different riboflavin transporter and again the condition is inherited in an autosomal recessive manner. A recent case series of 18 patients with homozygous or compound heterozygous mutations in the SLC52A2 gene has highlighted differences in presentation between the two BVVL subtypes [5]. A third riboflavin transporter gene has been identified but has not yet been directly associated with BVVL. It has been recommend that BVVL should be renamed ‘riboflavin transporter deficiency, types 2 (SLC52A2) and 3 (SLC52A3)’ to recognise the underlying genetic abnormality [5]. BVVL usually presents in children although there are reports of symptom onset in adulthood. The oldest age of onset that we could identify in the literature was a male who developed hearing loss at the age of 30 [6]. Diagnosis has been made as late as the sixth decade but this is many years after initial symptom onset. Hearing loss can precede the development of other symptoms by a number of years but the clinical course of BVVL is extremely varied [1]. Our patient has a younger sister with sensorineural deafness that could be a manifestation of BVVL, but genetic testing has not been performed. The most frequent clinical features in SLC52A3 genetic mutations are bulbar palsy (92%), hearing loss (81%), facial weakness (77%), respiratory compromise (64%) and muscle weakness (55%) [1]. In SLC52A2 mutations a sensorimotor neuropathy and optic atrophy are other common features [5]. A case of BVVL with a reduced range of horizontal eye movements has previously been reported [7] but there is no report of BVVL associated with opsoclonus in the literature. Abnormalities including brainstem atrophy, brainstem nuclei signal change and cerebellar atrophy have been described in BVVL although scans can be normal, as in our patient. Treatment with riboflavin supplementation has led to improvement in some cases of BVVL. The optimum dose is unknown but a starting dose of 10 mg/kg/per day in a child and 1500 mg per day in an adult have been described [1,5]. In a review of treated childhood cases, eight of 13 patients showed some improvement, ranging from stabilisation of neurological deficits to full recovery [1]. A number of questions remain unanswered including why some patients appear to respond to riboflavin whilst others do not and why the time taken for a response is so variable, ranging from days to more than a year. Earlier treatment is likely to be more beneficial and it is recommended to commence treatment with riboflavin supplementation as soon as a diagnosis of BVVL is suspected rather than wait for genetic confirmation [1,5]. In correctly identified patients treatment should be continued for a prolonged period of time before deciding on effectiveness. Medical management is otherwise symptomatic including respiratory and nutritional support. Steroids have been tried in some cases of BVVL and appear to have caused temporary stabilisation. It is possible that the initial improvement in our patient was related to the use of high dose prednisolone. Outcome in BVVL is diverse; some patients plateau or progress slowly over several decades and some show evidence of improvement [6]. Mortality is higher in children than in adults and is as high as 85% in those diagnosed before four years of age [1].
J. Cosgrove et al. / Clinical Neurology and Neurosurgery 128 (2015) 1–3
3
4. Conclusion
References
BVVL is caused by mutations in one of two riboflavin transporter genes leading to defective intestinal riboflavin absorption and subsequent riboflavin deficiency. Opsoclonus has not been described in BVVL before and this, in addition to the unusual age and subacute presentation, could be related to the novel genetic mutation identified in our case. The identification of a potential treatment to what has traditionally been considered an incurable disease highlights the importance of increasing awareness of this rare condition.
[1] Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown–Vialetto–Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis 2012;7:83. [2] Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, et al. Brown–Vialetto–Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am J Hum Genet 2010;86:485–9. [3] Bosch AM, Abeling NG, Ijlst L, Knoester H, Van Der Pol WL, Stroomer AE, et al. Brown–Vialetto–Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis 2011;34:159–64. [4] Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, et al. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 2012;135:2875–82. [5] Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-odaib A, Abrams AJ, et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014;137:44–56. [6] Piccolo G, Marchioni E, Maurelli M, Simonetti F, Bizzetti F, Savoldi F. Recovery from respiratory muscle failure in a sporadic case of Brown–Vialetto–Van Laere syndrome with unusually late onset. J Neurol 1992;239:355–6. [7] De Grandis D, Passadore P, Chinaglia M, Brazzo F, Ravenni R, Cudia P. Clinical features and neurophysiological follow-up in a case of Brown–Vialetto–Van Laere syndrome. Neuromuscul Disord 2005;15:565–8.
Conflict of interest No conflicts of interest. Ethical approval Patient consent obtained.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Adult onset Brown–Vialetto–Van Laere syndrome with opsoclonus and a novel heterozygous mutation: A case report Jeremy Cosgrove a,∗ , Sayan Datta b , Mark Busby b a b
Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK Department of Neurology, Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
a r t i c l e
i n f o
Article history: Received 16 August 2014 Received in revised form 23 October 2014 Accepted 25 October 2014 Available online 4 November 2014 Keywords: Brown–Vialetto–Van Laere Riboflavin Neuromuscular disease
1. Introduction Brown–Vialetto–Van Laere (BVVL) is a rare neurodegenerative disorder caused by mutations in the human intestinal riboflavin transporter genes, leading to riboflavin deficiency. It is characterised by bulbar palsy, respiratory insufficiency and sensorineural deafness. Some cases of BVVL have been successfully treated with riboflavin supplementation. Although BVVL is most commonly diagnosed in children it may also present in adults. We describe a case of BVVL in a 27-year-old female. 2. Case report A 27-year-old obese woman who had developed progressive hearing loss over the previous six months presented to hospital with a two-month history of progressive dysphonia, dysphagia and intermittent diplopia. Examination revealed bilateral facial weakness, subtle tongue wasting and hypophonic speech (Fig. 1). There were rapid involuntary horizontal and vertical eye movements consistent with opsoclonus as well as variable partial ptosis bilaterally. Nasendoscopy demonstrated bilateral vocal cord paresis and ophthalmological review identified bilateral sectoral optic pallor. She had globally brisk, symmetrical reflexes and subtle left arm
∗ Corresponding author at: Department of Neurology, F Floor, Martin Wing, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. Mobile: +44113 3923339; fax: +44 113 3922244. E-mail address: [email protected] (J. Cosgrove). http://dx.doi.org/10.1016/j.clineuro.2014.10.016 0303-8467/© 2014 Elsevier B.V. All rights reserved.
weakness (4+/5 Medical Research Council scale for muscle strength) but no evidence of ataxia. Family history revealed that her only sibling, a six-year-old sister, had a diagnosis of sensorineural deafness since infancy. Considering the two-month history of progressive bulbar dysfunction, our initial clinical impression included anti-MuSK antibody myasthenia gravis or an immune cranial polyneuropathy, although we were unsatisfied about the lack of a clear explanation for the six-month history of progressive hearing loss. Over the next ten days her respiratory function deteriorated and she developed type-two respiratory failure, requiring non-invasive ventilation (NIV). Her swallowing also worsened, necessitating nasogastric (NG) feeding. Tensilon test was negative, but we treated her with high dose prednisolone and concomitant plasma exchange. She was discharged home after two months using overnight NIV and her NG tube was removed 6 months later. Her prednisolone was gradually tapered and stopped. Testing for acetylcholine receptor, anti-MuSK and antiganglioside antibodies was negative. CSF was normal, as was MR imaging of brain and cervical spine and CT of the chest, abdomen and pelvis. Muscle biopsy of the quadriceps was unremarkable, including investigation for mitochondrial abnormalities. Electrophysiological investigation of the limbs was normal, including repetitive nerve stimulation of abductor digiti minimi. EMG of the right orbicularis oculi demonstrated fast-firing motor units suggestive of neurogenic weakness of the facial muscles. Audiometry confirmed bilateral sensorineural deafness. Genetic testing for BVVL was performed and DNA sequencing identified two mutations in the SLC52A3 gene coding for the human
2
J. Cosgrove et al. / Clinical Neurology and Neurosurgery 128 (2015) 1–3
Fig. 1. The patient’s facial appearance when being asked to smile, demonstrating bilateral facial weakness. Also note the partial right-sided ptosis.
intestinal riboflavin transporter type 2 (hRFT2) – a heterozygous pathogenic mutation (c.1292G>A) in exon 5 and a previously unreported heterozygous variant (c.383C>T) in exon 2 – compatible with compound heterozygosity. The decision to perform a genetic test was based on the patient’s clinical features; we did not perform biochemical testing to look for changes compatible with BVVL. Following the diagnosis of BVVL she was commenced on riboflavin supplementation, which was gradually increased to the current dose of 1500 mg daily (approximately 15 mg/kg). At a recent outpatient review there was continued evidence of improvement of facial and hypoglossal nerve function. Overnight NIV continues but she is now established on a normal diet.
3. Discussion The eponym for this syndrome comes from the original description by Brown (1894) and further reports by Vialetto (1936) and Van Laere (1966) [1]. BVVL is thought to be very rare and only 101 published cases were identified in a review paper in 2012 [1]. In 2010 an area of shared homozygosity between two relatives with BVVL was identified on chromosome 20 [2]. Gene sequencing of this region led to the identification of a homozygous mutation in a gene now known as SLC52A3. Other affected family members were homozygous for this mutation and the parents of an affected child were heterozygous carriers in keeping with an autosomal recessive trait. SLC52A3 shared similarities with a recently identified riboflavin transporter gene in rats. In 2011 three patients with symptoms compatible with BVVL suspected to have a mild form of a condition called multiple acylCoA dehydrogenase defect (MADD) were found to have mutations in the SLC52A3 gene [3]. Riboflavin supplementation improved their metabolic abnormalities as well as producing some improvement in their neurological deficits. Combined with prior knowledge about the role of SLC52A3 in the rat, it was concluded that riboflavin deficiency caused by a defective riboflavin transporter causes BVVL [3]. Numerous mutations causing BVVL have subsequently been identified in the SLC52A3 gene (OMIM 211530) [1].
In BVVL deficiency of the active metabolite of riboflavin, called flavin adenine dinucleotide (FAD), leads to malfunction in a number of dehydrogenase reactions in amino acid catabolism and mitochondrial fatty acid oxidation. The biochemical profile of BVVL is similar to that seen in a mild forms of MADD, characterised by abnormalities in plasma acylcarnitine levels and urine organic acids. Additionally, a number of genetically confirmed cases of BVVL have been found to have low levels of serum riboflavin, FAD and other riboflavin metabolites [1]. Mutations in a gene called SLC52A2, located on chromosome 8, have subsequently been identified as also causing BVVL (OMIM 614707) [4]. This gene codes for a different riboflavin transporter and again the condition is inherited in an autosomal recessive manner. A recent case series of 18 patients with homozygous or compound heterozygous mutations in the SLC52A2 gene has highlighted differences in presentation between the two BVVL subtypes [5]. A third riboflavin transporter gene has been identified but has not yet been directly associated with BVVL. It has been recommend that BVVL should be renamed ‘riboflavin transporter deficiency, types 2 (SLC52A2) and 3 (SLC52A3)’ to recognise the underlying genetic abnormality [5]. BVVL usually presents in children although there are reports of symptom onset in adulthood. The oldest age of onset that we could identify in the literature was a male who developed hearing loss at the age of 30 [6]. Diagnosis has been made as late as the sixth decade but this is many years after initial symptom onset. Hearing loss can precede the development of other symptoms by a number of years but the clinical course of BVVL is extremely varied [1]. Our patient has a younger sister with sensorineural deafness that could be a manifestation of BVVL, but genetic testing has not been performed. The most frequent clinical features in SLC52A3 genetic mutations are bulbar palsy (92%), hearing loss (81%), facial weakness (77%), respiratory compromise (64%) and muscle weakness (55%) [1]. In SLC52A2 mutations a sensorimotor neuropathy and optic atrophy are other common features [5]. A case of BVVL with a reduced range of horizontal eye movements has previously been reported [7] but there is no report of BVVL associated with opsoclonus in the literature. Abnormalities including brainstem atrophy, brainstem nuclei signal change and cerebellar atrophy have been described in BVVL although scans can be normal, as in our patient. Treatment with riboflavin supplementation has led to improvement in some cases of BVVL. The optimum dose is unknown but a starting dose of 10 mg/kg/per day in a child and 1500 mg per day in an adult have been described [1,5]. In a review of treated childhood cases, eight of 13 patients showed some improvement, ranging from stabilisation of neurological deficits to full recovery [1]. A number of questions remain unanswered including why some patients appear to respond to riboflavin whilst others do not and why the time taken for a response is so variable, ranging from days to more than a year. Earlier treatment is likely to be more beneficial and it is recommended to commence treatment with riboflavin supplementation as soon as a diagnosis of BVVL is suspected rather than wait for genetic confirmation [1,5]. In correctly identified patients treatment should be continued for a prolonged period of time before deciding on effectiveness. Medical management is otherwise symptomatic including respiratory and nutritional support. Steroids have been tried in some cases of BVVL and appear to have caused temporary stabilisation. It is possible that the initial improvement in our patient was related to the use of high dose prednisolone. Outcome in BVVL is diverse; some patients plateau or progress slowly over several decades and some show evidence of improvement [6]. Mortality is higher in children than in adults and is as high as 85% in those diagnosed before four years of age [1].
J. Cosgrove et al. / Clinical Neurology and Neurosurgery 128 (2015) 1–3
3
4. Conclusion
References
BVVL is caused by mutations in one of two riboflavin transporter genes leading to defective intestinal riboflavin absorption and subsequent riboflavin deficiency. Opsoclonus has not been described in BVVL before and this, in addition to the unusual age and subacute presentation, could be related to the novel genetic mutation identified in our case. The identification of a potential treatment to what has traditionally been considered an incurable disease highlights the importance of increasing awareness of this rare condition.
[1] Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown–Vialetto–Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis 2012;7:83. [2] Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, et al. Brown–Vialetto–Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am J Hum Genet 2010;86:485–9. [3] Bosch AM, Abeling NG, Ijlst L, Knoester H, Van Der Pol WL, Stroomer AE, et al. Brown–Vialetto–Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis 2011;34:159–64. [4] Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, et al. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 2012;135:2875–82. [5] Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-odaib A, Abrams AJ, et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014;137:44–56. [6] Piccolo G, Marchioni E, Maurelli M, Simonetti F, Bizzetti F, Savoldi F. Recovery from respiratory muscle failure in a sporadic case of Brown–Vialetto–Van Laere syndrome with unusually late onset. J Neurol 1992;239:355–6. [7] De Grandis D, Passadore P, Chinaglia M, Brazzo F, Ravenni R, Cudia P. Clinical features and neurophysiological follow-up in a case of Brown–Vialetto–Van Laere syndrome. Neuromuscul Disord 2005;15:565–8.
Conflict of interest No conflicts of interest. Ethical approval Patient consent obtained.
