Tuesday, March 21, 2023

Riboflavin transporter deficiency

Inspired by a patient

Colasuonno F, Marioli C, Tartaglia M, Bertini E, Compagnucci C, Moreno S. New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement. Biomedicines. 2022 Jun 6;10(6):1329. doi: 10.3390/biomedicines10061329. PMID: 35740351; PMCID: PMC9219947.


Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.

Bulas S, Bedoukian EC, O'Neil EC, Krantz ID, Yum SW, Liu GT, Aleman TS. Ocular Biomarkers of Riboflavin Transporter Deficiency. J Neuroophthalmol. 2023 Mar 1;43(1):110-115. doi: 10.1097/WNO.0000000000001678. Epub 2022 Aug 2. PMID: 35921603.


Background: To describe the clinical presentation with a focus on ocular manifestations and response to riboflavin supplementation of 3 patients with riboflavin transporter deficiency (RTD) caused by mutations in SLC52A2 ( SLC52A2- RTD).

Methods: This is a retrospective review of records of 3 children (aged 18, n = 2 and age = 8, n = 1) with SLC52A2- RTD. Patients underwent comprehensive ophthalmic evaluations including color vision testing, pattern visual-evoked potentials (pVEPs, 1 patient) and spectral domain optical coherence tomography (SD-OCT) imaging. Patients received riboflavin supplements from the time of the molecular diagnosis of RTD.

Results: Two unrelated 18-year-old patients with SLC52A2- RTD had a symptomatic onset with sensorineural hearing loss and auditory neuropathy/dys-synchrony since age 3 and 11, respectively. On examination 7 years after symptomatic onset, they showed subnormal visual acuities (20/30 and 20/60, both eyes, respectively), preserved color vision, and a thin but measurable retinal ganglion cell layer (GCL) and nerve fiber (RNFL). The inner and outer nuclear layers were normal. The asymptomatic SLC52A2- positive brother of one of these patients started riboflavin supplementation right after the molecular diagnosis and had normal vision and SD-OCTs 7 years later. Onset of riboflavin supplementation in one of the 2 symptomatic cases resulted in acute improvement of the pattern visual-evoked potential and vision.

Conclusions: Retinal ganglion cells and their axons are uniquely susceptible to RTD compared with other highly energy-dependent retinal neurons, such as photoreceptors, raising the possibility for alternative mechanisms of disease or protection. Riboflavin supplementation results in acute functional improvement of vision and long-term preservation of GCL and RNFL if initiated early.

Sanchez JA, Traub R, Trau SP, Howard JF Jr. Electrodiagnostic Findings in Riboflavin Transporter Deficiency Type 2. J Clin Neuromuscul Dis. 2022 Jun 1;23(4):205-209. doi: 10.1097/CND.0000000000000390. PMID: 35608644.


We present the electrodiagnostic findings in a case of a 3-year-old girl presenting with sensory ataxia, gait disturbance, and visual-auditory disturbance with a genetically confirmed diagnosis of riboflavin transporter deficiency type 2 (RTD2). She carries a homozygous mutation in the SLC52A2 gene, c.1016T>C (p.Leu339Pro). Her testing demonstrates a non-length-dependent axonal sensorimotor polyneuropathy affecting predominantly the upper extremities with active denervation of the distal muscles of both arms. It is important to highlight these findings because most genetic neuropathies have a length-dependent pattern of involvement, affecting the distal legs before the arms. The electrodiagnostic findings in RTD2 have not been previously well described. These electrodiagnostic findings are in agreement with the typical clinical phenotype of RTD2, which affects the upper limbs and bulbar muscles more than the lower extremities.

Frederick AL, Yang JH, Schneider S, Quade A, Guidugli L, Wigby K, Cameron M. To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler. Child Neurol Open. 2021 Aug 5;8:2329048X211030723. doi: 10.1177/2329048X211030723. PMID: 34395718; PMCID: PMC8361551.


We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.

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