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Fazio-Londe syndrome in siblings from India with different phenotypes
Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Fazio-Londe syndrome in siblings from India with different phenotypes Vykuntaraju K. Gowda a,⇑,1, Tamilarasan Udhayabanu b, Perumal Varalakshmi c, Varunvenkat M. Srinivasan a, Balasubramaniem Ashokkumar b,⇑,1 a Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India c Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India b
Received 26 July 2017; received in revised form 14 February 2018; accepted 14 February 2018
Abstract Background: Fazio-Londe syndrome also called progressive bulbar palsy of childhood is a very rare motor neuron disease of pediatric age group characterized by progressive paralysis of lower cranial nerves. Objective: To describe Fazio-Londe syndrome in sibling with different phenotype. Methods: A 6 years old female child presented with inability to close eyes, difficulty in swallowing, respiratory muscle weakness and voice change since 5 yr of age. Examination showed lower motor neuron facial nerve palsy, absent gag reflex, tongue atrophy, fasciculation, limb wasting and exaggerated deep tendon reflexes. An 11 year old boy, elder sibling of the above child presented with similar complaints at 10 years of age, other than later onset and lack of respiratory problem. Genetic testing in both cases confirmed the diagnosis of Fazio-Londe Syndrome. Conclusion: In any child who presents with progressive bulbar palsy with lower motor neuron facial palsy a diagnosis of FazioLonde Syndrome should be considered and family members should also be screened. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Fazio-Londe syndrome; BVVLS; Ponto bulbar palsy; Riboflavin; RFVT-3
1. Introduction Fazio-Londe Syndrome (FLS) and Brown-VialettoVan Laere Syndrome (BVVLS) are progressive disorders affecting motor neurons which are riboflavin dependent and clinically distinguished by deafness in the latter ⇑ Corresponding authors at: Bangalore Child Neurology and Rehabilitation Center, No 8/A, First Cross, First Main, Near Adhichunchanagiri choultry, Vijayanagar, Bangalore 560104, India (V.K. Gowda). E-mail addresses: [email protected] (V.K. Gowda), [email protected] (B. Ashokkumar). 1 Shares equal contribution as corresponding authors.
[1,2]. Fazio-Londe syndrome, characterized by progressive bulbar palsy and respiratory compromise, affects children and young adults [3]. It is inherited in an autosomal recessive manner caused by mutations in SLC52A3 gene that encodes intestinal riboflavin transporter (hRFVT-3) [4]. Here we report siblings with FLS from India having variable age of onset with different severity and without deafness. 2. Case-1 A 6 year old female child born to a second degree consanguineously married couple with normal birth his-
https://doi.org/10.1016/j.braindev.2018.02.010 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
2
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
tory was brought with history of difficulty in breathing and change of voice since 1 year duration. The patient developed pneumonia and respiratory distress for which she required mechanical ventilation and tracheotomy care. The patient had difficulty in closing eyes since 5 years of age. Later she also developed difficulty in swallowing. Developmental milestones were attained up to date. On examination, height, weight and head circumference were appropriate for age. Neurological examination showed bilateral lower facial weakness, absent gag reflex, and wasting of tongue muscles with fasciculation (Fig. 1). Motor system examination showed normal tone, wasting of muscles and exaggerated deep tendon reflexes bilaterally. Sensory and cerebellar systems were normal. Initial baseline investigations including complete hemogram, liver function, renal function, serum electrolytes, and serum creatine kinase were all normal. Motor, sensory and F wave nerve conductions studies were done in bilateral median, ulnar, posterior tibial, common peroneal and sural nerves. Compound muscle action potential, sensory nerve action potential, distal latency, conduction velocity and F wave latency were normal in above tested nerves. Electromyography of facial muscles showed fasciculation (Fig. 2A). MRI of brain and spine was normal. Patient was put on 200 mg of Riboflavin per day. On follow up after 2 years residual facial weakness with some difficulty in swallowing was present. Her respiratory muscle function improved and she is on and off tracheostomy care.
3. Case-2 An 11 year old boy, elder sibling of above child presented with history of difficulty in closing eyes since 10 years of age and difficulty in swallowing. On examination, all anthropometric parameters were normal. There was bilateral lower facial weakness, absent gag reflex, and atrophy of muscles of tongue with fasciculation (Fig. 1). Motor system examination showed normal tone, wasting of muscles with exaggerated deep tendon reflexes. Table 1 shows various clinical features of both siblings. Initial baseline investigations including complete hemogram, liver function, renal function, serum electrolytes, and serum creatine kinase were all normal. Nerve conduction study was normal. Electromyography of facial muscles showed fasciculations (Fig. 2B). MRI of brain was normal. Patient was put on 200 mg of riboflavin and is on regular follow up. His facial muscle power and bulbar muscle weakness improved, and he didn’t develop respiratory muscle weakness. In view of presence of bulbar palsy with facial nerve and upper motor neuron signs, genetic testing for motor neuron disease was performed, which evidenced a pathogenic mutation in SLC52A3 (c.A > 62G; p.Asn21Ser) at homozygous condition in the sibling and thus confirming the diagnosis of Fazio-Londe syndrome (Fig. 3). Genetic testing in parents for carrier status revealed that both the parents were asymptomatic heterozygous carriers of the identified mutation (Fig. 3). Ethical clearance was obtained from institutional review board.
Fig. 1. Clinical photographs of both siblings showing bilateral facial weakness and wasting of facial muscles. Informed consent obtained from parents to publish photograph of face from parents.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
3
Fig. 2. A and B EMG photograph of both siblings showing fasciculations at irregular, slow firing pattern.
Table 1 Showing differences and similarities of clinical manifestation between two siblings. Character
Case 1
Case 2
Age of onset in years Respiratory involvement Mechanical ventilation Tracheostomy care requirement Severity of involvement – requiring nasogastric tube feeding and admission for respiratory care Facial muscle weakness Bulbar Muscle weakness Deafness
5 Yes Yes Yes Required Yes Yes No
10 No No No Not required Yes Yes No
4. Discussion The clinical features of lower cranial nerve palsies with lower and upper motor signs in the limbs prompted us to put forth the following differentials, BVVLS, Fazio-Londe Syndrome, Kennedy disease, cervical myeloradiculopathy, and myasthenia gravis [5]. Cervical myeloradiculopathy excluded as pure motor signs and absent sphincter involvement. In the absence of ocular involvement, pyramidal signs with absence diurnal variation myasthenia gravis unlikely. Kennedy disease excluded based on upper motor signs. The etiology of this condition is documented due to homozygous mutation c.A > 62G (p.Asn21Ser) in SLC52A3 gene. Literature has already documented the same mutation in compound heterozygous state along with c.935C > A (p.Ala312Val) in a BVVLS patient [6]. Recently, we have also reported the same mutation p.Asn21Ser in SLC52A3 along with p.Pro141Thr in SLC52A2 causing Brown-Vialetto-Van Laere Syndrome in an Indian patient [7]. Further, functional examination
of this clinical mutation (p.Asn21Ser) demonstrated drastically reduced riboflavin transport function due to impairment in trafficking and targeting of membranous expression of RFVT-3 protein in the intestinal epithelia [7]. The postulated hypothesis for FLS is progressive death of neurons of cranial nerves without involvement of anterior horn cells. Riboflavin at a dose of 10–15 mg/ kg has been used successfully and the response time may vary from months to years [6]. In the current scenario, case-one has responded well to riboflavin therapy and has been on follow up for 2 years. Other sibling also improved and not developed respiratory muscle weakness. It is noteworthy to mention that a previously reported BVVLS case with same mutation c.A > 62G (p.Asn21Ser) in SLC52A3 responded well to oral riboflavin supplementation with progressive improvement in diaphragmatic function by gaining motor function and muscle strength [7]. However, no improvement upon riboflavin supplementation also has been noted in a BVVLS patient with compound heterozygous muta-
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
4
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
Fig. 3. Mutational analysis in SLC52A3. A) Chromatogram showing the missense mutation c.A > 62G (p.Asn21Ser) in SLC52A3 gene in FLS sibling and parents B) Restriction fragment analysis with TspRI showing allelic pattern of this mutation in the family. The 716-bp PCR amplicon of exon-2 is digested with TspRI in control DNA (lane 3), whereas the mutation present at the homozygous state introduces the cleavage site in the DNA of FLS sibling (lane 4, 6) and mutation present at the heterozygous state of parents (lane 5, 7).
tion in SLC52A3 [8]. This variable or negligible response by the patients harboring defective mutations in RFVT proteins warrant further investigations to underscore the interactions of mutated proteins with riboflavin to understand the benefits of high-dose riboflavin supplementation therapy. In this study, the disease manifested 5 yr earlier and more severe in the younger sibling, compare to elder one and early diagnosis and initiation of riboflavin in the elder sibling prevented progression to severe disease.
Contributions VR: Revised and approved the manuscript for important intellectual content and guarantor of the paper TU: Diagnosis, management, conducted laboratory tests and writing the manuscript PV: Conducted laboratory tests and analyzed the data. VS: Drafted manuscript BA: Supervision of the work and revision of manuscript.
5. Conclusion Funding BVVLS and FLS can be caused by the same mutation in SLC52A3 gene. Moreover, the same mutation in SLC52A3 gene can exert different phenotypes in the same family. If one child is affected in the family, other siblings should be screened for the disease as early initiation of riboflavin prevents further progression of disease.
Informed consent obtained from parents to publish photograph of face from parents.
6. Competing interests
References
None.
None. Consent form
[1] McShane MA, Boyd S, Harding B, Brett EM, Wilson J. Progressive bulbar paralysis of childhood. A reappraisal of Fazio-Londe Syndrome. Brain 1992;115:1889–900.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx [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] Sathasivam S. Brown –Vialtto-Van Laere Syndrome. Orphanet J Rare Dis 2008;3:9. [4] Bosch AM, Strok K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown- Vialetto- Van Laere Syndrome and Fazio-Londe Syndrome revisited: natural history, genetics, treatment and future prospective. Orphanet J Rare Dis 2012;7:83. [5] Varadarajan P, Thayanathi V, Pauline LC. Fazio-Londe Syndrome: A treatable disorder. Ann Indian Acad Neurol 2015;18:87–9.
5
[6] Bosch AM, Abeling NG, Ijlst L, Knoester H, Van der Pol WL, Stroomer AE, et al. Brown-Vialetto-Van Laere 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. [7] Udhayabanu T, Subramanian VS, Teafatiller T, Gowda VK, Raghavan VS, Varalakshmi P, et al. SLC52A2 [p. P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters. Clin Chim Acta 2016;462:210–4. [8] Davis A, Josifova D, Lloyd-Owen S, Radunovic A, Swash M. Brown-Vialetto-Van Laere syndrome: a 28-year follow-up. J Neurol Neurosurg Psychiatry 2016:681–2.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
Case Report
Fazio-Londe syndrome in siblings from India with different phenotypes Vykuntaraju K. Gowda a,⇑,1, Tamilarasan Udhayabanu b, Perumal Varalakshmi c, Varunvenkat M. Srinivasan a, Balasubramaniem Ashokkumar b,⇑,1 a Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India c Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India b
Received 26 July 2017; received in revised form 14 February 2018; accepted 14 February 2018
Abstract Background: Fazio-Londe syndrome also called progressive bulbar palsy of childhood is a very rare motor neuron disease of pediatric age group characterized by progressive paralysis of lower cranial nerves. Objective: To describe Fazio-Londe syndrome in sibling with different phenotype. Methods: A 6 years old female child presented with inability to close eyes, difficulty in swallowing, respiratory muscle weakness and voice change since 5 yr of age. Examination showed lower motor neuron facial nerve palsy, absent gag reflex, tongue atrophy, fasciculation, limb wasting and exaggerated deep tendon reflexes. An 11 year old boy, elder sibling of the above child presented with similar complaints at 10 years of age, other than later onset and lack of respiratory problem. Genetic testing in both cases confirmed the diagnosis of Fazio-Londe Syndrome. Conclusion: In any child who presents with progressive bulbar palsy with lower motor neuron facial palsy a diagnosis of FazioLonde Syndrome should be considered and family members should also be screened. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Fazio-Londe syndrome; BVVLS; Ponto bulbar palsy; Riboflavin; RFVT-3
1. Introduction Fazio-Londe Syndrome (FLS) and Brown-VialettoVan Laere Syndrome (BVVLS) are progressive disorders affecting motor neurons which are riboflavin dependent and clinically distinguished by deafness in the latter ⇑ Corresponding authors at: Bangalore Child Neurology and Rehabilitation Center, No 8/A, First Cross, First Main, Near Adhichunchanagiri choultry, Vijayanagar, Bangalore 560104, India (V.K. Gowda). E-mail addresses: [email protected] (V.K. Gowda), [email protected] (B. Ashokkumar). 1 Shares equal contribution as corresponding authors.
[1,2]. Fazio-Londe syndrome, characterized by progressive bulbar palsy and respiratory compromise, affects children and young adults [3]. It is inherited in an autosomal recessive manner caused by mutations in SLC52A3 gene that encodes intestinal riboflavin transporter (hRFVT-3) [4]. Here we report siblings with FLS from India having variable age of onset with different severity and without deafness. 2. Case-1 A 6 year old female child born to a second degree consanguineously married couple with normal birth his-
https://doi.org/10.1016/j.braindev.2018.02.010 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
2
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
tory was brought with history of difficulty in breathing and change of voice since 1 year duration. The patient developed pneumonia and respiratory distress for which she required mechanical ventilation and tracheotomy care. The patient had difficulty in closing eyes since 5 years of age. Later she also developed difficulty in swallowing. Developmental milestones were attained up to date. On examination, height, weight and head circumference were appropriate for age. Neurological examination showed bilateral lower facial weakness, absent gag reflex, and wasting of tongue muscles with fasciculation (Fig. 1). Motor system examination showed normal tone, wasting of muscles and exaggerated deep tendon reflexes bilaterally. Sensory and cerebellar systems were normal. Initial baseline investigations including complete hemogram, liver function, renal function, serum electrolytes, and serum creatine kinase were all normal. Motor, sensory and F wave nerve conductions studies were done in bilateral median, ulnar, posterior tibial, common peroneal and sural nerves. Compound muscle action potential, sensory nerve action potential, distal latency, conduction velocity and F wave latency were normal in above tested nerves. Electromyography of facial muscles showed fasciculation (Fig. 2A). MRI of brain and spine was normal. Patient was put on 200 mg of Riboflavin per day. On follow up after 2 years residual facial weakness with some difficulty in swallowing was present. Her respiratory muscle function improved and she is on and off tracheostomy care.
3. Case-2 An 11 year old boy, elder sibling of above child presented with history of difficulty in closing eyes since 10 years of age and difficulty in swallowing. On examination, all anthropometric parameters were normal. There was bilateral lower facial weakness, absent gag reflex, and atrophy of muscles of tongue with fasciculation (Fig. 1). Motor system examination showed normal tone, wasting of muscles with exaggerated deep tendon reflexes. Table 1 shows various clinical features of both siblings. Initial baseline investigations including complete hemogram, liver function, renal function, serum electrolytes, and serum creatine kinase were all normal. Nerve conduction study was normal. Electromyography of facial muscles showed fasciculations (Fig. 2B). MRI of brain was normal. Patient was put on 200 mg of riboflavin and is on regular follow up. His facial muscle power and bulbar muscle weakness improved, and he didn’t develop respiratory muscle weakness. In view of presence of bulbar palsy with facial nerve and upper motor neuron signs, genetic testing for motor neuron disease was performed, which evidenced a pathogenic mutation in SLC52A3 (c.A > 62G; p.Asn21Ser) at homozygous condition in the sibling and thus confirming the diagnosis of Fazio-Londe syndrome (Fig. 3). Genetic testing in parents for carrier status revealed that both the parents were asymptomatic heterozygous carriers of the identified mutation (Fig. 3). Ethical clearance was obtained from institutional review board.
Fig. 1. Clinical photographs of both siblings showing bilateral facial weakness and wasting of facial muscles. Informed consent obtained from parents to publish photograph of face from parents.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
3
Fig. 2. A and B EMG photograph of both siblings showing fasciculations at irregular, slow firing pattern.
Table 1 Showing differences and similarities of clinical manifestation between two siblings. Character
Case 1
Case 2
Age of onset in years Respiratory involvement Mechanical ventilation Tracheostomy care requirement Severity of involvement – requiring nasogastric tube feeding and admission for respiratory care Facial muscle weakness Bulbar Muscle weakness Deafness
5 Yes Yes Yes Required Yes Yes No
10 No No No Not required Yes Yes No
4. Discussion The clinical features of lower cranial nerve palsies with lower and upper motor signs in the limbs prompted us to put forth the following differentials, BVVLS, Fazio-Londe Syndrome, Kennedy disease, cervical myeloradiculopathy, and myasthenia gravis [5]. Cervical myeloradiculopathy excluded as pure motor signs and absent sphincter involvement. In the absence of ocular involvement, pyramidal signs with absence diurnal variation myasthenia gravis unlikely. Kennedy disease excluded based on upper motor signs. The etiology of this condition is documented due to homozygous mutation c.A > 62G (p.Asn21Ser) in SLC52A3 gene. Literature has already documented the same mutation in compound heterozygous state along with c.935C > A (p.Ala312Val) in a BVVLS patient [6]. Recently, we have also reported the same mutation p.Asn21Ser in SLC52A3 along with p.Pro141Thr in SLC52A2 causing Brown-Vialetto-Van Laere Syndrome in an Indian patient [7]. Further, functional examination
of this clinical mutation (p.Asn21Ser) demonstrated drastically reduced riboflavin transport function due to impairment in trafficking and targeting of membranous expression of RFVT-3 protein in the intestinal epithelia [7]. The postulated hypothesis for FLS is progressive death of neurons of cranial nerves without involvement of anterior horn cells. Riboflavin at a dose of 10–15 mg/ kg has been used successfully and the response time may vary from months to years [6]. In the current scenario, case-one has responded well to riboflavin therapy and has been on follow up for 2 years. Other sibling also improved and not developed respiratory muscle weakness. It is noteworthy to mention that a previously reported BVVLS case with same mutation c.A > 62G (p.Asn21Ser) in SLC52A3 responded well to oral riboflavin supplementation with progressive improvement in diaphragmatic function by gaining motor function and muscle strength [7]. However, no improvement upon riboflavin supplementation also has been noted in a BVVLS patient with compound heterozygous muta-
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
4
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx
Fig. 3. Mutational analysis in SLC52A3. A) Chromatogram showing the missense mutation c.A > 62G (p.Asn21Ser) in SLC52A3 gene in FLS sibling and parents B) Restriction fragment analysis with TspRI showing allelic pattern of this mutation in the family. The 716-bp PCR amplicon of exon-2 is digested with TspRI in control DNA (lane 3), whereas the mutation present at the homozygous state introduces the cleavage site in the DNA of FLS sibling (lane 4, 6) and mutation present at the heterozygous state of parents (lane 5, 7).
tion in SLC52A3 [8]. This variable or negligible response by the patients harboring defective mutations in RFVT proteins warrant further investigations to underscore the interactions of mutated proteins with riboflavin to understand the benefits of high-dose riboflavin supplementation therapy. In this study, the disease manifested 5 yr earlier and more severe in the younger sibling, compare to elder one and early diagnosis and initiation of riboflavin in the elder sibling prevented progression to severe disease.
Contributions VR: Revised and approved the manuscript for important intellectual content and guarantor of the paper TU: Diagnosis, management, conducted laboratory tests and writing the manuscript PV: Conducted laboratory tests and analyzed the data. VS: Drafted manuscript BA: Supervision of the work and revision of manuscript.
5. Conclusion Funding BVVLS and FLS can be caused by the same mutation in SLC52A3 gene. Moreover, the same mutation in SLC52A3 gene can exert different phenotypes in the same family. If one child is affected in the family, other siblings should be screened for the disease as early initiation of riboflavin prevents further progression of disease.
Informed consent obtained from parents to publish photograph of face from parents.
6. Competing interests
References
None.
None. Consent form
[1] McShane MA, Boyd S, Harding B, Brett EM, Wilson J. Progressive bulbar paralysis of childhood. A reappraisal of Fazio-Londe Syndrome. Brain 1992;115:1889–900.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010
V.K. Gowda et al. / Brain & Development xxx (2018) xxx–xxx [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] Sathasivam S. Brown –Vialtto-Van Laere Syndrome. Orphanet J Rare Dis 2008;3:9. [4] Bosch AM, Strok K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown- Vialetto- Van Laere Syndrome and Fazio-Londe Syndrome revisited: natural history, genetics, treatment and future prospective. Orphanet J Rare Dis 2012;7:83. [5] Varadarajan P, Thayanathi V, Pauline LC. Fazio-Londe Syndrome: A treatable disorder. Ann Indian Acad Neurol 2015;18:87–9.
5
[6] Bosch AM, Abeling NG, Ijlst L, Knoester H, Van der Pol WL, Stroomer AE, et al. Brown-Vialetto-Van Laere 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. [7] Udhayabanu T, Subramanian VS, Teafatiller T, Gowda VK, Raghavan VS, Varalakshmi P, et al. SLC52A2 [p. P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters. Clin Chim Acta 2016;462:210–4. [8] Davis A, Josifova D, Lloyd-Owen S, Radunovic A, Swash M. Brown-Vialetto-Van Laere syndrome: a 28-year follow-up. J Neurol Neurosurg Psychiatry 2016:681–2.
Please cite this article in press as: Gowda VK et al. Fazio-Londe syndrome in siblings from India with different phenotypes. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.010