Fazio-Londe Research Articles

Brown-Vialetto-Van Laere and Fazio-Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance.

Brown-Vialetto-Van Laere syndrome (BVVLS) and Fazio-Londe disease (FLD) are rare neurological disorders presenting with pontobulbar palsy, muscle weakness and respiratory insufficiency. Mutations in SLC52A2 (hRFVT-2) or SLC52A3 (hRFVT-3) genes can be responsible for these disorders with an autosomal recessive pattern of inheritance. The aim of this study was to screen for mutations in SLC52A2 and SLC52A3 among Indian families diagnosed with BVVLS and FLD. SLC52A2 and SLC52A3 were screened in one FLD and three BVVLS patients by exon-specific amplification using PCR and sequencing. In silico predictions using bioinformatics tools and confocal imaging using HEK-293 cells were performed to determine the functional impact of identified mutations. Genetic analysis of a mother and son with BVVLS was identified with a novel homozygous mutation c.710C>T (p.Ala237Val) in SLC52A3. This variant was found to have an autosomal pseudodominant pattern of inheritance, which was neither listed in the Exome Variant Server or in the 1000 Genomes Project database. In silico analysis and confocal imaging of the p.Ala237Val variant showed higher degree of disorderness in hRFVT-3 that could affect riboflavin transport. Furthermore, a common homozygous mutation c.62A>G (p.Asn21Ser) was identified in other BVVLS and FLD patients. Despite having different clinical phenotypes, both BVVLS and FLD can be attributed to this mutation. A rare and peculiar pattern of autosomal pseudodominant inheritance is observed for the first time in two genetically related BVVLS cases with Indian origin and a common mutation c.62A>G (p.Asn21Ser) in SLC52A3 can be responsible for both BVVLS and FLD with variable phenotypes.

Fazio-Londe Syndrome and Patient-centered Nursing Care: A Case Report

Introduction: Fazio-Londe disease is a genetic rare disorder manifesting by acute respiratory distress. This article is a case report of Fazio-Londe syndrome, its comparison with other case reports in the literature, and its patient-centered nursing care. Case presentation: In this study, we reported a case with Fazio-Londe syndrome with respiratory distress, bulbar palsy, muscle weakness, and other symptoms. Management and outcome: The patient was treated with oral riboflavin (100 mg/day), ribavirin (200 mg/day), and intramuscular Vit-B12 (1000 mg/day). She was managed using a patient-centered nursing care model. Discussion: Health care providers should be aware of the new and constant symptoms of this rare disease. A patient-centered nursing care model is suggested to manage the disease.

Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: A novel mutation and in silico analyses

Brown-Vialetto-Van Laere syndrome, a rare neurological disorder is due to SLC52A3 mutations. Here, the SLC52A3 protein and its mutations are in silico structurally and functionally analyzed among all the reported patients and a novel mutation is also reported.After clinical evaluations, SLC52A3 gene was sequenced and segregation analysis of the mutations was also checked. A comprehensive search was performed on the reported mutations of SLC52A3 gene. In silico structural and functional analyses of the mutations and interactome analyses of the protein were done using available software tools.Mutations of 37 affected individuals were identified. Thirty three mutations were determined. c.502A > C was a novel variant that it was segregated within the family. One mutation (c.639C > G) was responsible for 12% of the mutations. Segregation analysis, secondary structure, functional prediction achieved for the novel mutation showed pathogenicity of this variant.BVVL is a very rare disorder; SLC52A3 mutations are distributed among different populations and there might be one frequent mutation in this gene. BVVL should be more considered in Iran. In addition to segregation analysis, computational analyses could accelerate understanding the extent of pathogenicity of the novel variants.

An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown-Vialetto-Van Laere and Fazio-Londe syndromes since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients present with a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal. Considerable progress in the clinical and genetic diagnosis of RTDs has been made in recent years and has permitted the successful lifesaving treatment of many patients with high dose riboflavin supplementation. In this review, we first outline the importance of riboflavin and its efficient transmembrane transport in human physiology. Reports on 109 patients with a genetically confirmed diagnosis of RTD are then summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. Finally, we focus attention on recent work with different models of RTD that have revealed possible pathomechanisms contributing to neurodegeneration in patients.

Bilateral Facial Weakness in a Syndromic Patient: Cadaveric Fascia Lata Graft for Lower Lip Deformity Correction

Fazio-Londe syndrome is a rare neurodegenerative disorder caused by riboflavin transporter deficiency. Clinical presentation includes variable hypotonia or muscle weakness, sensory gait ataxia, optic atrophy, sensorineural hearing loss, and bulbar palsies. We described the case of a 37-year-old patient with a suspected Fazio-Londe syndrome who was referred to us for oral incompetence with dysarthria and drooling and impaired facial expression. First, we provided static sling suspension of the lower lip with Silhouette sutures (Silhouette Lift). Due to recurrent sutures exposure, we had to remove the sutures and insert a bilateral fascia lata graft to resuspend the lower lip. Two months postoperatively, the patient had good oral competence and there were no complications. In our opinion, this is a simple and minimally invasive procedure that can restore the right lower lip position in challenging patients.

Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome in a Brazilian family.

Riboflavin transporter deficiency (formerly known as Brown-Vialetto-Van Laere [BVVL] or Fazio-Londe syndrome) is a neurodegenerative disorder characterized by progressive bulbar palsy with sensorineural deafness or bulbar hereditary neuropathy.1 It is caused by mutations in the riboflavin transporter genes SLC52A2 ( RFVT2 ) or SLC52A3 ( RFVT3 ).2,3 It is a rare syndrome with approximately 70 cases reported worldwide, with molecular diagnoses of RFVT2 or RFVT3 .1,4 We have previously described the first Brazilian family with a clinical diagnosis of BVVL.5 The authors acknowledge the patients who participated in this study.

Case report of patients with Fazio-Londe syndrome

Case report of patients with Fazio-Londe syndrome

Early onset of Fazio-Londe syndrome: the first case report from the Arabian Peninsula

Fazio-Londe syndrome is a rare neurological disorder presenting with sensorineural deafness, bulbar palsy and respiratory compromise that is caused by mutation in the SLC52A3 gene, which encodes the intestinal (hRFT2) riboflavin transporter. We report a patient with early onset of Fazio-Londe syndrome as the first case report in Saudi Arabia with rapid regression to death at 24 months of age.

Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases

Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment.

Recent advances in bulbar syndromes: genetic causes and disease mechanisms.

With advances in next-generation gene sequencing, progress in deep phenotyping and a greater understanding of the pathogenesis of motor neuron disease, our knowledge of the progressive bulbar syndromes has significantly increased in recent years. This group of heterogeneous conditions, in which the primary disorder is focused around degeneration of the lower cranial nerves, can occur in children or adults and form a spectrum of severity, based around the common feature of bulbar dysfunction. Early genetic diagnosis may allow treatment in some bulbar syndromes. Brown-Vialetto-Van Laere and Fazio-Londe syndromes are the most recent childhood forms of progressive bulbar palsy to be genetically defined. The clinical phenotype of this group of childhood disorders was first reported over 120 years ago. Recently, it was demonstrated that in a third of these patients Brown-Vialetto-Van Laere is caused by mutations in the SLC52A2 and SLC52A3 genes, both of which encode riboflavin transporters. Importantly, supplementation of riboflavin can lead to significant clinical improvement if started early in the disease process. Here, we outline the clinical features, management and an update on the disease mechanisms and genetic causes of the progressive bulbar syndromes.

Madras motor neuron disease (MMND) is distinct from the riboflavin transporter genetic defects that cause Brown–Vialetto–Van Laere syndrome

IntroductionMadras motor neuron disease (MMND), MMND variant (MMNDV) and Familial MMND (FMMND) have a unique geographic distribution predominantly reported from Southern India. The characteristic features are onset in young, weakness and wasting of limbs, multiple lower cranial nerve palsies and sensorineural hearing loss. There is a considerable overlap in the phenotype of MMND with Brown–Vialetto–Van Laere syndrome (BVVL) Boltshauser syndrome, Nathalie syndrome and Fazio–Londe syndrome. Recently a number of BVVL cases and families have been described with mutations in two riboflavin transporter genes SLC52A2 and SLC52A3 (solute carrier family 52, riboflavin transporter, member 2 and 3 respectively). Methods and resultsWe describe six families and four sporadic MMND cases that have been clinically characterized in detail with history, examination, imaging and electrophysiological investigations. We sequenced the SLC52A1, SLC52A2 and SLC52A3 in affected probands and sporadic individuals from the MMND series as well as the C9ORF72 expansion. No genetic defects were identified and the C9ORF72 repeats were all less than 10. ConclusionsThese data suggest that MMND is a distinct clinical subgroup of childhood onset MND patients where the known genetic defects are so far negative. The clinico-genetic features of MMND in comparison with the BVVL group of childhood motor neuron diseases suggest that these diseases are likely to share a common defective biological pathway that may be a combination of genetic and environmental factors.

Support your local paediatric neurophysiologist

SIR–The discovery that high-dose riboflavin can treat Brown– Vialetto–Van Leare syndrome is perhaps one of the most exciting developments in paediatric neurology over recent years. This condition, like Fazio–Londe syndrome with which it shares some features, was regarded as an untreatable and relentlessly progressive condition. There have been a series of papers which suggest early treatment may reverse the deterioration although the diaphragm does seem to be stubbornly resistant. 1–3 It was therefore with interest that I read the article by Anand et al. describing a 22-month-old female who responded to high-dose riboflavin. 4 In their concluding comments the authors state that ‘… an early genetic diagnosis in patients presenting with progressive ponto-bulbar palsy with or without sensorineural deafness will enable early institution of therapy and reversal of symptom progression, leading to a better prognosis.’ I do not disagree with the sentiment, but feel that perhaps they have not emphasized the importance of clinical neurophysiology and, in particular, electromyography (EMG) in the early diagnosis of these cases. The studies done by their neurophysiologist were excellent. This neurophysiologist even succeeded with voluntary single-fibre EMG in a 22-monthold child, which is an achievement on its own. Our experience is that there are increasing numbers of referrals of children with suspected bulbar palsy and it is not at all uncommon for a discovery of neurogenic change to be made. In fact, in one of our recent cases of Brown–Vialetto–Van Laere syndrome the discovery of definite neurogenic change in the tongue antedated by several months clinical confirmation of abnormalities in that region. EMG is exquisitely sensitive to denervation and particularly chronic denervation, and it is quite feasible for these changes to be manifest on EMG before clinical appearances such as the tongue fasciculation or wasting confirm the suspicions. It is well-known that effective reinnervation may compensate for muscle fibres which lose their nerve supply with atrophy only occurring when that capacity is exhausted. We are very early on in discovering an effective treatment for this condition but there do appear to be indications that if instituted at the earliest possible point in the disease, rather like pyridoxine dependency, near normalization of the metabolic abnormality may be possible. From what has been said above, EMG of the tongue may give the first indication of abnormality and clinicians should think of this when they have a suspicion of Brown–Vialetto–Van Laere syndrome and encourage their neurophysiologist to assist them. The technique is easily within the reach of any competent clinical neurophysiologist, and if combined with screening for deafness could provide a very quick and effective way to pick up these children early. Otherwise, a great number of children are going to be screened genetically and metabolically with little benefit.

Brown‐Vialetto‐Van Laere and Fazio Londe syndromes: defects of riboflavin transport with biochemical similarities to multiple acyl‐CoA dehydrogenation defects (MADD)

Riboflavin-responsive defects of electron transfer were firstdescribed in the 1980s as mild variant forms of MADD orglutaric acidemia type II (Gregersen et al 1982; Amendt andRhead 1986). Some of these patients were shown to havedefects in ETF and ETF dehydrogenase but a number ofpatients remained in whom the biochemical and moleculardefects remained elusive (Roettger et al 1992). It was pos-tulated that these patients may have defect(s) of riboflavintransport or abnormalities in downstream flavin metabolismto form the active FAD/FMN cofactors required for facili-tating electron transfer. Treatment of some of these patientswith high dose riboflavin tended to normalize the abnormalmetabolite profiles. Treatment with high dose riboflavin wasalso subjectively claimed to improve the clinical phenotype,a difficult judgment given the mild and intermittent natureof the phenotype. The phenotype of most of the cases ofriboflavin-responsive MADD was that of stress-inducedmyopathy (de Visser et al 1986; DiDonato et al 1989).Recently, the genetic basis for Brown-Vialetto-Van Laeresyndrome(BVVLS) wasidentified asapreviouslyunknownopen reading frame C20orf54 (Green et al 2010). This genewas subsequently shown to encode a riboflavin transporterand the gene is now renamed SLC52A3 encoding humanriboflavin transporter 2 (hRFT2). At around the same time, adominantly inherited mutation in SLC52A1encoding humanriboflavin transporter 1 (hRFT1) was identified in theclinically normal mother of a neonate with complex neuro-logical disease and a MADD metabolite profile whichresponded dramatically to riboflavin therapy. It is presumedthat the neonate was riboflavin deficient secondarily to thematernal haploinsufficiency and from increased riboflavindemand during pregnancy (Ho et al 2011). Bosch and cow-orkersandothersextendedthephenotypeofSLC52A3defectsto include patients with Fazio Londe syndrome, which waspreviouslyconsideredtobeanoverlappingclinicalphenotypebut without a molecular basis (Bosch et al 2011). Anand andcoworkers added an additional riboflavin-responsive BVVLScase to the data base (Anand et al 2012). In this volume ofJIMD, Haack et al 2012, demonstrating the power of wholeexome sequencing identified disease-causing mutations in athird riboflavin transporter in an individual with BVVLS.They identified mutations in SLC52A2 and exquisitely dem-onstrate a functional defect of hRFT3, the gene product. Thispresent case also highlights the likely mechanisms of diseasephenotype in BVVLS.The clinical phenotype of BVVLS is not what wewould immediately associate with defects of electrontransfer such as MADD. For this reason, it is importantfor investigators to recognize this phenotype as it wouldappear that these defects of riboflavin transport areeminently treatable with high dose riboflavin therapy.BVVLS is rare and has been reported in about 60patients in total but may be under diagnosed. It presentsprimarily with a severe sensorineural deafness. The ageof onset is from infancy to the third decade. During therelentless progress, lower motor neuron limb signs leadto neuropathy and are accompanied by cerebellar ataxia,optic atrophy, retinal pigmentary changes, mental retar-dation and psychiatric abnormalities. Death is usually aresult of diaphragmatic paralysis (Dipti et al 2005).

Brown–Vialetto–van Laere and Fazio–Londe overlap syndromes: A clinical, biochemical and genetic study

Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17 years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10 years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8 months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease.

Four novel C20orf54 mutations identified in Brown–Vialetto–Van Laere syndrome patients

Brown-Vialetto-Van Laere syndrome (BVVLS) is a very rare neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. Its mode of inheritance in affected families has usually been autosomal recessive, although autosomal dominant inheritance and incomplete penetrance have also been reported. Recently, C20orf54 was identified as a causative gene for BVVLS. Twelve different mutations have so far been identified in 10 patients affected with BVVLS or the related disorder Fazio Londe syndrome. Here, results of screening of C20orf54 in three unrelated BVVLS patients are reported. Four novel mutations that affect amino acid changes, p.Asn21Ser, p.Pro220His, p.Ala312Val and p.Gly375Asp, were identified in the patients. The causative nucleotide variations were not observed in 200 control individuals. One of the patients harbored compound heterozygous mutations, but only one mutated allele was observed in each of the two remaining patients.

Brown-Vialetto-Van Laere Syndrome: A Riboflavin-Unresponsive Patient With a Novel Mutation in the C20orf54 Gene

Brown-Vialetto-Van Laere syndrome (Online Mendelian Inheritance in Man number 211530) is a neurodegenerative disorder characterized by pontobulbar palsy affecting cranial nerves (mainly VII-XII). Sensorineural deafness is often the leading sign, followed by other neurologic signs. Inheritance is often autosomal recessive, with mutations in the C20orf54 gene (Online Mendelian Inheritance in Man number 613350). Three previous patients with mutations in the C20orf54 gene and clinical signs of Brown-Vialetto-Van Laere or Fazio-Londe syndrome revealed a metabolic profile suggesting a multiple acyl-coenzyme A dehydrogenase defect. They benefited from riboflavin. We describe a 3-year-old girl with early-onset Brown-Vialetto-Van Laere syndrome and a novel mutation in the C20orf54 gene (c.989G>T). On T(2)-weighted imaging, increased signal intensity of the vestibular nuclei bilaterally, the pedunculus cerebellaris superior and the central tegmental tract were observed during acute clinical deterioration. Her metabolic profile was normal. Trials with steroids, immunoglobulins, and riboflavin produced no effect. The patient recovered slowly during subsequent months, with residual deficits. Brown-Vialetto-Van Laere syndrome should be considered in patients with sensorineural hearing loss and pontobulbar palsy. Patients should be screened for riboflavin deficiency and a therapy with riboflavin may provide effective treatment in some affected patients.

Brown-Vialetto-Van Laere syndrome: A riboflavin-unresponsive patient with a novel mutation in the C20orf54 gene

Aims: Brown-Vialetto-Van Laere syndrome (BVVLS) is a neurodegenerative disorder characterized by pontobulbar palsy and sensorineural deafness. Other symptoms are motor neuron signs, epilepsy or breathing difficulties. Inheritance is often autosomal recessive with mutations in the C20orf54 gene. Bosch A et al described 3 patients with mutations in the C20orf54 gene and BVVLS or Fazio Londe syndrome and a multiple acyl-CoA dehydrogenase deficiency. They benefitted from the substituion of riboflavin.

Update on clinical aspects and treatment of selected vitamin‐responsive disorders II (riboflavin and CoQ10)

Riboflavin and ubiquinone (Coenzyme Q(10), CoQ(10)) deficiencies are heterogeneous groups of autosomal recessive conditions affecting both children and adults. Riboflavin (vitamin B(2))-derived cofactors are essential for the function of numerous dehydrogenases. Genetic defects of the riboflavin transport have been detected in Brown-Vialetto-Van Laere and Fazio-Londe syndromes (C20orf54), and haploinsufficiency of GPR172B has been proposed in one patient to cause persistent riboflavin deficiency. Mutations in the electron tranferring fravoprotein genes (ETFA/ETFB) and its dehydrogenase (ETFDH) are causative for multiple acyl-CoA dehydrogenase deficiency. Mutations in ACAD9, encoding the acyl-CoA dehydrogenase 9 protein were recently reported in mitochondrial disease with respiratory chain complex I deficiency. All these conditions may respond to riboflavin therapy. CoQ(10) is a lipid-soluble component of the cell membranes, where it functions as a mobile electron and proton carrier, but also participates in other cellular processes as a potent antioxidant, and by influencing pyrimidine metabolism. The increasing number of molecular defects in enzymes of the CoQ(10) biosynthetic pathways (PDSS1, PDSS2, COQ2, COQ6, COQ9, CABC1/ADCK3) underlies the importance of these conditions. The clinical heterogeneity may reflect blocks at different levels in the complex biosynthetic pathway. Despite the identification of several primary CoQ(10) deficiency genes, the number of reported patients is still low, and no true genotype-phenotype correlations are known which makes the genetic diagnosis still difficult. Additionally to primary CoQ(10) deficiencies, where the mutation impairs a protein directly involved in CoQ(10) biosynthesis, we can differentiate secondary deficiencies. CoQ(10) supplementation may be beneficial in both primary and secondary deficiencies and therefore the early recognition of these diseases is of utmost importance.

The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives

The Brown-Vialetto-Van Laere syndrome is a rare neurological disorder which may present at all ages with sensorineural deafness, bulbar palsy and respiratory compromise. Fazio-Londe syndrome is considered to be the same disease entity. Recently it was demonstrated that in some patients the disease is caused by mutations in the SLC52A3 gene which encodes the intestinal (hRFT2) riboflavin transporter. In these patients riboflavin deficiency is the cause of the BVVL/FL syndrome and supplementation of riboflavin proved a life saving treatment. Mutations in the SLC52A2 gene and the SLC52A1 (GPR172B) gene, coding for human riboflavin transporters hRFT3 and hRFT1 have been associated with the BVVL syndrome as well. We performed a review of the literature, with emphasis on the natural history and the effects of treatment in these patients. A total of 35 publications were traced reporting on the clinical presentation of 74 patients who presented before age 18. The most prevalent symptoms were bulbar palsy, hearing loss, facial weakness and respiratory compromise. Death was reported in 28 of the 61 untreated patients, with a very low survival in patients presenting before age 4. All 13 patients who were treated with riboflavin survived, with a strong clinical improvement after days to months of treatment in eight patients. Three patients demonstrated a stable clinical course and treatment was stopped early in two patients. Abnormalities in plasma flavin levels and/or plasma acylcarnitine profiles were observed in some but not in all patients, and also patients with normal plasma flavin levels and acylcarnitine profiles demonstrated a striking clinical improvement on riboflavin supplementation. It is now clear that proper diagnosis requires mutation analysis of all three transporter genes and treatment should be started immediately without first awaiting results of molecular analysis. Clinical improvement may be rapid or gradual over a period of more than 12 months.

P3.1 Brown–Vialetto–Van Laere and Fazio Londe overlap sindromes: A clinical, biochemical and genetic study in 6 patients

Myofibrillar myaopathy (MFM) is a group of genetically heterogeneous disorders characterized by protein aggregates in muscle fibers associated with markedly disorganized myofibrils. To date, 7 causative genes were identified including DES, CRYAB, ZASP, MYOT, FLNC, BAG3, and FHL1. To know the character of Japanese patients with MFM. We performed mutation screening in 114 Japanese patients with MFM. Clinical and pathological findings were analyzed. In our series, number of patients with mutations in DES, ZASP, MYOT, FLNC, BAG3, and FHL1 were 6, 6, 4, 6, 2, and 6, respectively. No patient with CRYAB mutation was identified. Clinical and pathological characterization of these patients was performed. We further screened VCP mutation and identified 5 patients in our series. One patient show cerebellar signs, but the remaining four patients show no clinical symptoms for Paget’s disease of bone and front-temporal dementia. From the pathological points of view, VCP could also include a causative gene for MFM. Clinical features of MFM patients are quite variable. Frequency of each causative gene was different from the previous reports. In our series, no mutation was identified in 69% of the MFM patients. Additional responsible genes should be identified.