Introduction

Brown-Vialetto-Van Laere syndrome (BVVL) is a rare, progressive neurodegenerative disorder characterized by sensorineural deafness, bulbar palsy, and respiratory compromise, often presenting in childhood or adolescence. The disorder is primarily associated with mutations in riboflavin transporter genes, notably SLC52A3, which encodes the intestinal riboflavin transporter RFVT3, and less commonly SLC52A2 and SLC52A1. Mutations in SLC52A3 disrupt riboflavin absorption, leading to systemic deficiency and the clinical manifestations of BVVL [1,2,3,4].

High-dose riboflavin supplementation has emerged as a life-saving intervention, with reports documenting dramatic clinical improvement, including reversal of motor deficits and stabilization of disease progression, even in patients with normal baseline riboflavin levels [1,2,3, 5,6,7,8]. Early initiation of riboflavin therapy is strongly recommended due to the potential for rapid and sustained neurological recovery [1, 3, 5, 6]. However, the optimal dosing regimen remains unclear, with reported doses ranging from 7 to 80 mg/kg/day and some cases using up to 1200 mg/day in adults [3, 5, 9]. The variability in response and lack of standardized dosing highlight a significant gap in the literature regarding the most effective and safe riboflavin dose for different age groups and disease severities [3, 9, 10]. There is also a scarcity of literature related to the outcome of the management of presymptomatic individuals identified through family screening or genetic testing. While there are isolated reports of presymptomatic siblings receiving riboflavin and remaining symptom-free, systematic studies on the long-term outcomes, ideal timing, and monitoring strategies for such patients are lacking [6].

This study reports the largest cohort of patients with BVVL diagnosed in the Arabian Peninsula. Twenty-three patients diagnosed with SLC52A3-related BVVL in two tertiary centers from the region were reviewed for demographic and clinical characteristics, in addition to riboflavin doses used. The study reports longitudinal clinical outcomes, including those related to pre-symptomatically diagnosed and treated patients.

Material and method

Study design

All patients with a genetically confirmed diagnosis of BVVL diagnosed between December 2011 and the end of May 2025 with available electronic patient records (EPR) at the two participating sites were enrolled in this retrospective study. The EPR at Sultan Qaboos University Hospital (Oman) and King Fahad Specialist Hospital (Saudi Arabia) were reviewed for demographic, clinical and genetic characteristics as reported in the results section. The study was approved by the Medical Research Ethics Committee at Sultan Qaboos University (MREC# 3203). Written informed consent for participation in this study and for publication was obtained from all subjects or their parents, where applicable.

Clinical evaluation

All subjects reported in this study were clinically evaluated and phenotypically characterized at the two centers collaborating in this study. Multidisciplinary care was conducted as clinically indicated. Patients were clinically followed every 6 months following the diagnosis. Clinical response was assessed through clinical examination, vocal cord function was assessed by indirect laryngoscopy, and hearing assessment was done through audiometry.

Molecular genetic studies

DNA was extracted from blood using a standard technique for all affected. Before the presumed founder variant in this study was encountered, SLC52A3 was sequenced as part of a Next Generation Sequencing Panel outsourced to Prevention Genetics laboratory (USA) or as part of Whole Exome Sequencing outsourced to Centogene Laboratory (Germany). Once the SLC52A3 c.634C>T, p. Arg212Cys variant was identified in more than two unrelated patients, specific primers were designed for amplification and validation of the SLC52A3 identified variant using the restriction fragment length polymorphism technique (https://bioinfo.ut.ee/primer3-0.4.0/). Subsequent patients with overleaping clinical presentation and those evaluated through cascade testing guided by family history, including asymptomatic patients, were screened for the same variant in SLC52A3 by polymerase chain reaction (PCR) using the same primer set, followed by restriction fragment length polymorphism (RFLP) techniques.

Results

A total of 23 patients, 16 females and 7 males, were diagnosed with SLC52A3-related BVVL at the two centers participating in this study up until May 2025, 20 of Omani Arab origin from 6 families and 3 of Saudi Arab origin from 2 families. The family pedigrees related to the patients reported are depicted in Fig. 1. Thirteen out of 23 patients were symptomatic at diagnosis and hence clinically ascertained, while (9/23) patients were diagnosed pre-symptomatically with cascade family testing. All 20 Omani patients were homozygous for SLC52A3: c.634C>T (p.Arg212Cys) variant, and all 3 Saudi patients were homozygous for SLC52A3: c.1325_1326del. Among symptomatic patients in this cohort, the commonest symptoms encountered were facial diplegia (12/13), dysarthria (10/13), hearing loss (10/13), and vocal cord paresis (8/13). Figure 2 shows the frequency of the main symptoms encountered in this cohort. The age of onset of symptoms in patients with the c.634C>T variant ranged between 9 years and 23 years, with a median age of onset of 13 years. The two symptomatic patients with the c.1325_1326del variant presented in infancy. None of the patients reported in this cohort required ventilatory support. However, three patients were admitted for diagnostic evaluation of vocal cord paresis accompanying bulbar symptoms. A total of seven patients from the reported cohort underwent biochemical testing (acylcarnitine profiling and urine organic acids). This was primarily done for the purpose of evaluating whether clinically ascertained patients with BVVL may demonstrate biochemical abnormalities suggestive of multiple acyl-CoA dehydrogenase deficiency. All patients who had an acylcarnitine profiling and urine organic acids analysis showed normal profiles. Patients were treated with riboflavin at a dose range of 20–80 mg/kg/day if symptomatic and 5–10 mg/Kg/day if pre-symptomatic when family history is suggestive of juvenile or young adult onset. Coenzyme Q10 and carnitine were added if the concentrations are low in the blood. The duration of follow-up in patients reported ranged between 6 months and 12 years, with a median of 42 months. 2/13 patients showed complete resolution of symptoms, and the rest had variable residual symptoms with clinical stability and no progression. One of the pre-symptomatically diagnosed patients started to show neurological symptoms, and the family admitted non-compliance with riboflavin. The rest of the pre-symptomatically treated patients have not developed any symptoms so far. No death was reported in this cohort. A full clinical description for all 23 affected individuals is provided in Table 1.

Fig. 1: The family pedigrees related to the patients reported in this cohort.
Fig. 1: The family pedigrees related to the patients reported in this cohort.The alternative text for this image may have been generated using AI.
Full size image

Dotted symbols denote confirmed positive carrier status for the known familial variant. Dark-colored symbols represent affected individuals.

Fig. 2: Major clinical manifestations and morbidities seen in the symptomatic patients reported.
Fig. 2: Major clinical manifestations and morbidities seen in the symptomatic patients reported.The alternative text for this image may have been generated using AI.
Full size image

The numbers displayed adjacent to the horizontal bars represent the number of patients reported to have these morbidities. The most frequently encountered clinical features reported in the 13 clinically ascertained patients.

Table 1 Clinical characteristics of the 13 symptomatic patients with SLC52A3-related Brown-Vialetto-Van Laere syndrome reported in this cohort.
Full size table

Discussion

This study reports the largest cohort of patients with SLC52A3-related BVVL from the Arabian Peninsula. A total of 23 patients from two tertiary hospitals in Oman and Saudi Arabia are reported, the Omani patients being homozygous for SLC52A3 c.634C>T reported initially as a variant of uncertain significance (VUS), while the three patients from Saudi Arabia were homozygous for a previously reported likely pathogenic variant, SLC52A3: c.1325_1326del [11]. Although c.634C>T (p.Arg212Cys) was reported as a VUS, it was previously reported by Manole et al. as a novel homozygous variant in 4 Arab patients with riboflavin-responsive neuropathy [12]. In all families we report here, the variant was perfectly segregated, with all affected individuals in this cohort being homozygous, whereas unaffected individuals were heterozygous carriers or homozygous wild type. The variant has a frequency of 0.000008054 in the GnomAD dataset, and the frequency of this variant in our local database is 0.000379363 (5272 chromosomes). It is highly conserved across various species. This missense variant results in a non-conservative amino acid change, replacing a positively charged arginine with a neutral cysteine at a conserved residue, and is predicted by multiple in silico tools to adversely affect protein structure and/or transporter function. Although no variant-specific functional assays have been published for p.Arg212Cys, biallelic pathogenic variants in SLC52A3 are a well-established cause of riboflavin transporter deficiency type 3, supporting the biological plausibility of functional impairment. We therefore argue that SLC52A3: c.634C>T (p.Arg212Cys) should be classified as likely pathogenic, and it is likely the result of a founder effect given that this otherwise rare variant was shared between six unrelated families from the same region in Oman. The same argument may also apply to the SLC52A3: c.1325_1326del variant described in the Saudi patients reported, given that it was shared between two unrelated families.

From the clinical standpoint, the age of onset of symptoms in the patients with the truncating SLC52A3: c.1325_1326del variant was in infancy, an observation that agrees with the previously reported patients [11]. In contrast, the age of onset in patients with the missense SLC52A3: c.634C>T (p.Arg212Cys) variant was later in childhood or adulthood. The variability in the age of onset in symptomatic individuals (7 to 23 years) overlapping with the age at which the eldest asymptomatic patient was diagnosed (21 years) suggests that the onset of symptoms in patients with this variant is impacted by genetic-environmental interactions or may be subject to genetic modifiers. Despite the variability of the age of onset, this cohort emphasizes the importance of early and preferably pre-symptomatic detection of affected individuals for maximized treatment outcomes in agreement with previously reported cases [1, 6, 9, 12,13,14,15]. Almost none of the patients treated pre-symptomatically developed significant clinical symptoms during the reported durations of follow-up, while almost all symptomatically ascertained patients continued to have some residual symptoms despite the reported significant response to therapy with riboflavin. Given issues implicated for compliance, it is important to answer the question as to whether pre-symptomatically detected patients may be managed with doses lower than those used in patients clinically ascertained when the causative variants are consistently known to be associated with a later age of onset. This study provides longitudinal follow-up for pre-symptomatically treated patients, supporting previously reported success of riboflavin therapy in the prevention of disease morbidities and manifestations. In an agreement with a previously reported patient [14], this study also reports another antenatally treated pregnant lady with an affected pregnancy resulting in the prevention of clinical manifestation in the newborn. The only pre-symptomatically diagnosed patient who developed symptoms was a patient who admitted to non-adherence to the recommended riboflavin therapy.

In conclusion, this study reports the largest cohort of patients with SLC52A3-related BVVL from the Arabian Peninsula. The study highlights the significant intrafamilial and interfamilial variability in this condition, not only in relation to the age of onset and severity of clinical manifestations but also in terms of anticipated therapeutic response to riboflavin therapy on longitudinal follow-up. The study also emphasizes the prognostic and therapeutic value of early diagnosis and early initiation of therapy.