Riboflavin Therapy Research Articles

Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on MADD that describes the phenotypic and genetic features of a Malaysian cohort. Among the >2,500 patients in a local muscle biopsy database, patients with LSM were identified and their genomic DNA were extracted from muscle samples and peripheral blood. All 13 exons of the electron-transfer flavoprotein dehydrogenase gene (ETFDH) were subsequently sequenced. Fifty controls were included to determine the prevalence of identified mutations in the normal population. Fourteen (82%) of the 17 LSM patients had MADD with ETFDH mutations. Twelve (86%) were Chinese and two were Malay sisters. Other unrelated patients reported that they had no relevant family history. Nine (64%) were females. The median age at onset was 18.5 years (interquartile range=16-37 years). All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. Three patients experienced a metabolic crisis at their presentation. Sanger sequencing of ETFDH revealed nine different variants/mutations, one of which was novel: c.998A>G (p.Y333C) in exon 9. Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China. All of the patients responded well to riboflavin therapy. Most of our Malaysian cohort with LSM had late-onset, riboflavin-responsive MADD with ETFDH mutations, and they demonstrated phenotypic and genetic features similar to those of cases reported in southern China. Furthermore, we report a novel ETFDH mutation and possibly the first ever MADD patients of Malay descent.

Benefit of high-dose oral riboflavin therapy in riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short-term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease-modifying therapies.

Photodynamic antibacterial and antibiofilm activity of riboflavin against Xanthomonas oryzae pv oryzae: an ecofriendly strategy to combat bacterial leaf blight (BLB) rice disease.

Bacterial leaf blight (BLB), caused by Xanthomonas oryzae pv oryzae (Xoo), is one of the most damaging rice diseases, causing severe production losses depending on the rice variety. The purpose of this study was to develop an antibacterial photodynamic treatment (aPDT) using riboflavin for the treatment of BLB disease. Combining light and riboflavin (RF) therapy significantly reduced bacterial planktonic cells compared to RF alone. Photoactivated riboflavin also decreased biofilm biomass by reducing the number of viable sessile cells and the production of extracellular polymeric substances (EPS). Reactive oxygen species (ROS) levels in Xoo cells treated with photoactivated riboflavin were found to be significantly higher than in cells treated with riboflavin and light individually. Malondialdehyde (MDA) increased greatly in photoactivated riboflavin treated cells, indicating that severe oxidative damage was induced. Subsequently, a reduction in lactate dehydrogenase (LDH) activity in photoactivated riboflavin treated Xoo cells indicates that oxidative stress has disrupted the respiratory system, leading to bacterial cell death. In an ex vivo aPDT assay, photoactivated riboflavin successfully eradicated Xoo on the surface of rice leaves. Photoactivated riboflavin had no side effects on rice seed germination in subsequent trials, indicating that it is safe for agricultural applications. Therefore, all these findings suggest that aPDT is a potential alternative management strategy for BLB disease.

Clinical, pathological and genetic features and follow-up of 110 patients with late-onset MADD: a single-center retrospective study.

To observe a long-term prognosis in late-onset multiple acyl-coenzyme-A dehydrogenation deficiency (MADD) patients and to determine whether riboflavin should be administrated in the long-term and high-dosage manner, we studied the clinical, pathological and genetic features of 110 patients with late-onset MADD in a single neuromuscular center. The plasma riboflavin levels and a long-term follow-up study were performed. We showed that fluctuating proximal muscle weakness, exercise intolerance and dramatic responsiveness to riboflavin treatment were essential clinical features for all 110 MADD patients. Among them, we identified 106 cases with ETFDH variants, 1 case with FLAD1 variants and 3 cases without causal variants. On muscle pathology, fibers with cracks, atypical ragged red fibers (aRRFs) and diffuse decrease of SDH activity were the distinctive features of these MADD patients. The plasma riboflavin levels before treatment were significantly decreased in these patients as compared to healthy controls. Among 48 MADD patients with a follow-up of 6.1 years on average, 31 patients were free of muscle weakness recurrence, while 17 patients had episodes of slight muscle weakness upon riboflavin withdrawal, but recovered after retaking a small-dose of riboflavin for a short-term. Multivariate Cox regression analysis showed vegetarian diet and masseter weakness were independent risk factors for muscle weakness recurrence. In conclusion, fibers with cracks, aRRFs and diffuse decreased SDH activity could distinguish MADD from other genotypes of lipid storage myopathy. For late-onset MADD, increased fatty acid oxidation and reduced riboflavin levels can induce episodes of muscle symptoms, which can be treated by short-term and small-dose of riboflavin therapy.

Singlet oxygen formation during accelerated and hyperaccelerated corneal cross-linking: in vitro study.

To evaluate the singlet oxygen (1O2) production of oxygen assisted %0.1 riboflavin and ultraviolet-A (UVA) crosslinking therapy (with and without oxygen assistance), in combination with standard, accelerated and hyper-accelerated procedures via an important quantitive marker of 1O2 which is the photo-oxidation of 1,3 diphenylisobenzofuran (DPBF). %0.1 riboflavin-containing wells were irradiated with UVA light (365-nm wavelength) with or without 2-4-6-8 L/min oxygen flow assistance. Measurements of decrease in absorbance of DPBF were made in 30 mW (hyper-accelerated), 9 mW (accelerated), and 3 mW UV-A (standard) applications, and with additional 2-4-6-8 L/min oxygen flow in 30 mW and 2 L/min oxygen flow in 9 mW. A total of 8 different UV-A irradiance with and without oxygen supplementation groups were formed. 2 L/min oxygen assisted accelerated UV-A irradiance group has shown a greater decrease in DPBF absorbance compared to Dresden protocol. (p = 0.014) Also, Dresden protocol has shown a greater decrease in DPBF compared to all groups except accelerated crosslinking with 2 L/min oxygen. (p < 0.001) Oxygen assisted hyper-accelerated crosslinking groups were showed greater reduction in DPBF absorbance compared to standard crosslinking without oxygen groups. (p < 0.001). Oxygen supplementation may increase the singlet oxygen generation to the similar levels of Dresden Protocol's in accelerated group. Also, more singlet oxygen generation with oxygen supplementation compared to standard UV-A application might be considered to be promising in terms of shortening the crosslinking therapy.

Effectiveness of low-dose riboflavin as a prophylactic agent in pediatric migraine

BackgroundRiboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines. MethodsWe retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response. ResultsThe frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3–7) vs. 4.0 (2–5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%–50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27–13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16–12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04–0.73; p = 0.013). No adverse effects of riboflavin were identified. ConclusionsLow-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types.

Disorders of riboflavin metabolism

Riboflavin (vitamin B2), a water-soluble vitamin, is an essential nutrient in higher organisms as it is not endogenously synthesised, with requirements being met principally by dietary intake. Tissue-specific transporter proteins direct riboflavin to the intracellular machinery responsible for the biosynthesis of the flavocoenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These flavocoenzymes play a vital role in ensuring the functionality of a multitude of flavoproteins involved in bioenergetics, redox homeostasis, DNA repair, chromatin remodelling, protein folding, apoptosis, and other physiologically relevant processes. Hence, it is not surprising that the impairment of flavin homeostasis in humans may lead to multisystem dysfunction including neuromuscular disorders, anaemia, abnormal fetal development, and cardiovascular disease. In this review, we provide an overview of riboflavin absorption, transport, and metabolism. We then focus on the clinical and biochemical features associated with biallelic FLAD1 mutations leading to FAD synthase deficiency, the only known primary defect in flavocoenzyme synthesis, in addition to providing an overview of clinical disorders associated with nutritional deficiency of riboflavin and primary defects of riboflavin transport. Finally, we give a brief overview of disorders of the cellular flavoproteome. Because riboflavin therapy may be beneficial in a number of primary or secondary disorders of the cellular flavoproteome, early recognition and prompt management of these disorders is imperative.

Successful treatment of a genetic childhood ataxia due to riboflavin transporter deficiency

BackgroundRiboflavin transporter deficiency (Brown-Vialetto-Van Laere syndrome) is a rare recessive neurodegenerative disorder that can present with gait ataxia, primarily due to sensory neuropathy as well as cerebellar involvement. Although sensorineural hearing loss, bulbar palsy, and optic atrophy are typical, presentation may be variable and an atypical condition may be difficult to recognize clinically.Case presentationHere we report a patient presenting at age 8 with progressive ataxia since the age of 2.5 years with cerebellar atrophy and peripheral polyneuropathy. Whole exome sequencing identified a known pathogenic mutation in the SLC52A2 gene consistent with a diagnosis of Brown-Vialetto-Van Laere syndrome despite the absence of common symptoms including motor neuropathy, bulbar palsy, optic atrophy, and sensorineural hearing loss. High-dose riboflavin therapy was initiated, symptoms stabilized, metabolic abnormalities resolved, and the patient is doing well with a near-normal examination at age 15.ConclusionsRiboflavin transporter deficiency can be fatal if left untreated. The excellent outcome of this case illustrates the importance of identifying this potentially treatable neurologic condition. In this patient, clinical diagnosis was limited by an atypical presentation lacking several common features which was overcome through the use of genomic sequencing identifying the pathogenic mutation enabling correct diagnosis and subsequent treatment. Riboflavin transporter deficiency should be considered early in the diagnostic evaluation as a treatable form of ataxia in children, even if patients lack typical features.

Patient with multiple acyl-CoA dehydrogenase deficiency disease and ETFDH mutations benefits from riboflavin therapy: a case report

BackgroundLipid storage myopathy (LSM) is a diverse group of lipid metabolic disorders with great variations in the clinical phenotype and age of onset. Classical multiple acyl-CoA dehydrogenase deficiency (MADD) is known to occur secondary to mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene. Whole exome sequencing (WES) with clinical correlations can be useful in identifying genomic alterations for targeted therapy.Case presentationWe report a patient presented with severe muscle weakness and exercise intolerance, suggestive of LSM. Diagnostic testing demonstrated lipid accumulation in muscle fibres and elevated plasma acyl carnitine levels. Exome sequencing of the proband and two of his unaffected siblings revealed compound heterozygous mutations, c.250G > A (p.Ala84Thr) and c.770A > G (p.Tyr257Cys) in the ETFDH gene as the probable causative mutations. In addition, a previously unreported variant c.1042C > T (p.Arg348Trp) in ACOT11 gene was found. This missense variant was predicted to be deleterious but its association with lipid storage in muscle is unclear. The diagnosis of MADD was established and the patient was treated with riboflavin which resulted in rapid clinical and biochemical improvement.ConclusionsOur findings support the role of WES as an effective tool in the diagnosis of highly heterogeneous disease and this has important implications in the therapeutic strategy of LSM treatment.

P.367 - A case of childhood onset of treatable sensory neuronopathy caused by mutations in riboflavin transporter RFVT2 presenting as pure sensory ataxia with excellent response to riboflavin – a five year follow up

Childhood onset neuronopathies are a clinically heterogeneous group of disorders. Its original description is known as Brown-Vialetto-Van Laere syndrome and characterized by motor neuronopathy with early onset of bulbar palsy, hearing loss and respiratory failure. Sensorimotor neuronopathy was described later. No treatment was available for this neurodegenerative disorder until recent discovery of riboflavin transporters RFVT3 and RFVT2. We report a case of early childhood onset of RFVT2 related disorder due to compound heterozygous mutation p.S52F and p.L339P in the SLC52A2 gene presenting as a pure sensory ataxia associated with sensorineural hearing loss, respiratory dysfunction, optic atrophy and retinitis pigmentosa. The patient is a 2-year-old girl at the onset of her condition. Initial presentation consisted of isolated sensory ataxia. Lack of clinically evident muscle weakness and electrodiagnostic studies ruled out motor neuronopathy. 3T high resolution MRI of the brain showed abnormal T2 signal in the reticulospinal tracts. There was biochemical evidence for abnormal acylcarnitine profile. A year later patient developed hearing loss, optic nerve atrophy and retinitis pigmentosa. Polysomnogram revealed central apnea with reduced O2 concentration. We followed prospectively clinical, neurophysiological and biochemical parameters starting at baseline and after initiation of therapy with high doses of riboflavin. We report overt response to high-dose of oral riboflavin therapy in our patient. The clinical and biochemical responses in our patient consistent with reports in the literature that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated early in the course and can be lifesaving. In addition, this case further broadened knowledge of this rare disorder including never reported before findings of abnormal MRI, retinitis pigmentosa and detailed characterization of respiratory dysfunction.

Prophylaxis of migraine headaches with riboflavin: A systematic review.

Migraine headache is a relatively common, debilitating condition that costs our healthcare system over 78 billion dollars per year. Riboflavin has been advocated as a safe, effective prophylactic therapy for the prevention of migraines. The purpose of this study was to provide a systematic review of the current role of riboflavin in the prophylaxis of migraine headache. A MEDLINE literature search inclusive of the dates 1966-2016 was performed using the search terms: riboflavin and migraine disorders. Excerpta Medica was searched from 1980 to 2016 using the search terms: riboflavin and migraine. Additionally, Web of Science was searched using the terms riboflavin and migraine inclusive of 1945-2016. Bibliographies of all relevant papers were reviewed for additional citations. We utilized the PRISMA guidelines to select English language, human, clinical trials of riboflavin as a single entity or in combination, review articles, and supporting pharmacokinetic and pharmacogenomic data assessing the efficacy and mechanism of riboflavin therapy in the prophylactic treatment of migraine headache. A total of 11 clinical trials reveal a mixed effect of riboflavin in the prophylaxis of migraine headache. Five clinical trials show a consistent positive therapeutic effect in adults; four clinical trials show a mixed effect in paediatric and adolescent patients, and two clinical trials of combination therapy have not shown benefit. Adverse reactions with riboflavin have generally been mild. Riboflavin is well tolerated, inexpensive and has demonstrated efficacy in the reduction of adult patient's migraine headache frequency. Additional data are needed, however, to resolve questions involving pharmacokinetic issues and pharmacogenomic implications of therapy.

Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy

Multiple acyl-CoA dehydrogenation deficiency is genetically heterogenous metabolic disease with mutations in genes involved in electron transfer to the mitochondrial respiratory chain. Disease symptoms vary from severe neonatal form to late-onset presentation with metabolic acidosis, lethargy, vomiting, muscle pain and weakness. Riboflavin therapy has been shown to ameliorate diseases symptoms in some of these patients. Recently, mutations in FAD synthase have been described to cause multiple acyl-CoA dehydrogenation deficiency. We describe here the effect of riboflavin supplementation therapy in a previously reported adult patient with multiple acyl-CoA dehydrogenation deficiency having compound heterozygous gene variations in FLAD1 (MIM: 610595) encoding FAD synthase. We present thorough clinical history including laboratory investigations, muscle MRI, muscle biopsy and spiroergometric analyses comprising of a follow-up of 20 years. Our data suggest that patients with adult-onset multiple acyl-CoA dehydrogenation deficiency with FLAD1 gene mutations also benefit from long-term riboflavin therapy.

Remarkable motor recovery after riboflavin therapy in adult-onset Brown—Vialetto—Van Laere syndrome

The clinical diagnosis of Brown—Vialetto—Van Laere syndrome in this woman with rapidly progressive pontobulbar palsy led to empirical high-dose oral riboflavin (1200 mg/day) therapy. This resulted in a dramatic improvement...

Auditory neuropathy in Brown-Vialetto-Van Laere syndrome due to riboflavin transporter RFVT2 deficiency.

Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown-Vialetto-Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy. We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual. Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual. Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation.

Sustained therapeutic response to riboflavin in a child with a progressive neurological condition, diagnosed by whole-exome sequencing.

One of the most promising outcomes of whole-exome sequencing (WES) is the alteration of medical management following an accurate diagnosis in patients with previously unresolved disorders. Although case reports of targeted therapies resulting from WES have been published, there are few reports with long-term follow-up that confirm a sustained therapeutic response. Following a diagnosis by WES of Brown–Vialetto–Van Laere Syndrome 2 (BVVLS2), high-dose riboflavin therapy was instituted in a 20-mo-old child. An immediate clinical response with stabilization of signs and symptoms was noted over the first 2–4 wk. Subsequent clinical follow-up over the following 8 mo demonstrates not just stabilization, but continuing and sustained improvements in all manifestations of this usually fatal condition, which generally includes worsening motor weakness, sensory ataxia, hearing, and vision impairments. This case emphasizes that early application of WES can transform patient care, enabling therapy that in addition to being lifesaving can sometimes reverse the disabling disease processes in a progressive condition.

Muscle pain, fatigue and night hypothermia in association with mitochondrial dysfunction

In case of non-specific and relatively mild muscle symptoms, the diagnosis of an inborn error of metabolism could be easily missed. Muscle pain can be the first sign of a mitochondrial disorder, especially in combination with motor developmental delay or associated organ dysfunction. Here we report on six children with a distinctive pattern of symptoms in association with variable, suboptimal mitochondrial dysfunction. This pattern exists of early onset exercise intolerance, fatigue, feeding difficulties and concentration problems associated with recurrent episodes of nocturnal hypothermia, muscle pain and mild motor retardation. No endocrine, cardiac, immunologic, neurodegenerative or psychiatric causes were found to explain these complaints. Based on the presence of muscle pain, multisystem involvement and mild lactic acidemia a mitochondrial disorder was suspected. We found decreased oxidation capacity in muscle, confirming a suboptimal mitochondrial function in our patients. Four out of five patients benefited from high dose riboflavin therapy. We think pediatricians should be aware of the possibility of a mitochondrial dysfunction in children presenting with a combination of diverse but relatively mild, “aspecific” symptoms. We advise to use the Mitochondrial Disease Criteria to evaluate the possibility of mitochondrial disease in these children.

Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter

ObjectiveBrown–Vialetto–Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. MethodsAxonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10–21years) at baseline and after 12months of riboflavin (1000mg daily) therapy. ResultsAt baseline, depolarizing and hyperpolarizing threshold electrotonus was ‘fanned out’ and superexcitability was increased, while the resting current–threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. ConclusionsThe present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. SignificanceThis study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients.

Riboflavin in Brown-Vialetto-Van Laere Syndrome

Investigators at Great Ormond Street Hospital, London, UK, and multiple centers internationally report the response to high-dose oral riboflavin therapy in 18 patients from 13 families with mutations in SLC5ZA2, encoding riboflavin transporter RTVT2, a new causative gene for Brown-Vialetto-Van Laere syndrome (BVVLS), a progressive neurodegenerative disorder leading to death in childhood.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Ultraviolet A and Riboflavin Therapy as an Adjunct in Corneal Ulcer Refractory to Medical Treatment

To present a case of corneal ulcer unresponsive to medical treatment, successfully treated with the use of ultraviolet (UV) A and riboflavin collagen crosslinking (CXL) administered twice. A 68-year-old diabetic male patient was diagnosed with unilateral severe corneal ulcer. Gram and Giemsa stains and corneal culture results were performed twice, but no specific pathogen could be detected. The clinical presentation suggested fungal infection. The ulcer was unresponsive to extensive medical treatment administered for 10 days. There was an initial response to topical and intrastromal voriconazole administration; however, this was followed by reactivation. Therefore, UVA-riboflavin treatment was performed when the patient was still on medical therapy. The stromal infiltrate appeared inactive 1 week after UVA-riboflavin CXL treatment. However, reactivation was noticed on the second week, and a second UVA-riboflavin treatment was planned and performed 3 weeks after the first one. The epithelial defect disappeared, and the stromal infiltrate stayed inactive starting from the first week of the second UVA-riboflavin treatment until the last follow-up examination at month 6. The UVA-riboflavin CXL may be considered in the management of corneal ulcers unresponsive to medical management.