Brown-Vialetto-Van Laere syndrome: two siblings with a new mutation and dramatic therapeutic effect of high-dose riboflavin

Abstract

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.

Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience

“…After exclusion of duplicates 70 reported patients (42/70 (60 %) females and 28/70 (40 %)males) with either compound heterozygous or homozygous mutations in SLC52A2 or SLC52A3 were included in the review. Of these, 37 patients (53 %) were diagnosed with a RFVT2 deficiency (SLC52A2) (Johnson et al 2012; Haack et al 2012; Ciccolella et al 2012; Foley et al 2014; Srour et al 2014; Menezes et al 2016) and 33 (47 %) with a RFVT3 deficiency (SLC52A3) (Green et al 2010; Johnson et al 2010; Bosch et al 2011; Anand et al 2012; Koy et al 2012; Dezfouli et al 2012; Ciccolella et al 2013; Bandettini Di Poggio et al 2014; Spagnoli et al 2014; Cosgrove et al 2015; Davis et al 2015; Horoz et al 2015; Spagnoli and De Sousa 2012). …”

“…Respiratory problems were reported in 21/37 (57 %) patients with RFTV2 deficiency and in 25/33 (76 %) patients with RFVT3 deficiency (Green et al 2010; Johnson et al 2010; Bosch et al 2011; Anand et al 2012; Koy et al 2012; Dezfouli et al 2012; Johnson et al 2012; Ciccolella et al 2012; Ciccolella et al 2013; Foley et al 2014; Spagnoli et al 2014; Cosgrove et al 2015; Davis et al 2015; Horoz et al 2015). Respiratory symptoms developed during the course of the disease in most patients but were a presenting symptom in two and eight RFVT2 and RFVT3 deficient patients respectively.…”

“…Mean age between onset of symptoms and death was 7.11 years (range 0.6-19.0 years). In 39 (RFVT2: 27; RFVT3: 13) patients treatment with oral riboflavin was started in a dosage ranging from 7 to 60 mg/kg/ day (Bosch et al 2011;Anand et al 2012;Koy et al 2012;Haack et al 2012;Foley et al 2014;Spagnoli et al 2014;Cosgrove et al 2015;Menezes et al 2016;Davis et al 2015;Horoz et al 2015). Side effects were reported in three patients and included gastrointestinal symptoms.…”

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

“…Generally the most positive responses are reported in patients that receive riboflavin supplementation shortly after disease onset . Of note, a newly born sibling of an RTD3 patient harboring the same pathogenic mutations has been administered riboflavin since birth and remains asymptomatic after 1 year, while patient 2 from the first report of RTD3 who was symptomatic and treated from 3 months of age is now still asymptomatic at 8 years of age.…”

“…An article in this journal 3 years ago 15 summarized reports of 70 genetically confirmed RTD patients that had been published at that time. 13,[18][19][20][21][24][25][26][27][28][29][30][31][32][33][34][35][36] There have since been a further 10 publications reporting on 23 newly diagnosed RTD2 cases, 37-46 and 12 reporting on 27 newly diagnosed RTD3 cases. 41,43,[46][47][48][49][50][51][52][53][54][55] A patient harboring a heterozygous pathogenic mutation in SLC52A3 and heterozygous SLC52A2 variant of unknown significance has been described, 37 which will be considered as a RTD3 case here.…”