The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2

Amir, Fatima; Atzinger, Carrie; Massey, Keith; Greinwald, John H.; Hunter, Lisa L.; Ulm, Elizabeth; Kettler, Margaret

doi:10.1177/0883073819893159

Cited by 17 publications

(21 citation statements)

References 35 publications

(94 reference statements)

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“…RTD syndrome, formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, is a rare autosomal-recessive motor neuron disease. Typical clinical features reported include pontobulbar palsy, limb and axial muscle weakness, sensorineural hearing loss, optic atrophy, ataxia, and respiratory compromise [ 24 , 25 ]. The age of onset is variable, and young patients show different phenotypes with variable prognosis, often influenced by the initiation of RF treatment.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Colasuonno

Niceforo

Marioli

et al. 2020

Oxidative Medicine and Cellular Longevity

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Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl β-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Colasuonno

Niceforo

Marioli

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…While sensorineural hearing loss is the most common initial presentation associated with RTD (Bosch et al, 2012), our patient had the unusual initial features of macrocytic anemia and intermittent neutropenia, subsequently determined to be megaloblastic based on bone marrow findings. After excluding the common etiologies of megaloblastic anemia, including vitamin B12 and folic acid deficiencies, the mechanism underlying the megaloblastic anemia related to RTD2 still remains unclear (Amir et al, 2019). Neutropenia associated with RTD or riboflavin deficiency has not been reported before.…”

Section: Discussionmentioning

confidence: 99%

“…Age of onset varies from infancy to adulthood and is often precipitated by intercurrent infections (Bosch et al, 2012). Amir et al recently reported megaloblastic anemia in a patient with RTD type 2 (RTD2) with anemia present in other individuals in their 10 patient cohort (Amir et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency

Pillai

Amin

Gijavanekar

et al. 2020

American J of Med Genetics Pt A

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Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2-year-old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio-exome sequencing detected compound heterozygous variants in SLC52A2 that were classified as pathogenic and a variant of uncertain significance. Bone marrow evaluation demonstrated megaloblastic changes. Notably, his anemia and neutropenia resolved after treatment with oral riboflavin, thus expanding the clinical phenotype of this disorder. We reiterate the importance of starting riboflavin supplementation in a young child who presents with macrocytic anemia and neurological features while awaiting biochemical and genetic work up. We detected multiple biochemical abnormalities with the help of untargeted metabolomics analysis associated with abnormal flavin adenine nucleotide function which normalized after treatment, emphasizing the reversible pathomechanisms involved in this disorder. The utility of untargeted metabolomics analysis to monitor the effects of riboflavin supplementation in RTD has not been previously reported.

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“…Other common clinical features present in RTD2 and RTD3 patients are dysarthria, weakness and hypotonia, whereas the most common differences concern facial weakness which is typical of RTD3 patients and vision loss, characteristic of RTD2 patients [ 103 , 104 ]. RTDs are sometimes responsive to high doses of Rf treatment and characterized by biochemical abnormalities in the acylcarnitine profiles, thus resembling another inborn error of metabolism mainly affecting muscle, named MADD (Multiple Acyl-CoA Dehydrogenase Deficiency) we will discuss later on [ 105 ].…”

Section: Remaining Challenges In Neuronal and Muscular Flavin Homementioning

confidence: 99%

Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy

Tolomeo

Nisco

Leone

et al. 2020

IJMS

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Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of human flavoproteome and, therefore, of cellular bioenergetics. This explains why the interest in studying the “flavin world”, a topic which has not been intensively investigated before, has increased much over the last few years. This also prompts basic questions concerning how Rf transporters and FAD (flavin adenine dinucleotide) -forming enzymes work in humans, and how they can create a coordinated network ensuring the maintenance of intracellular flavoproteome. The concept of a coordinated cellular “flavin network”, introduced long ago studying humans suffering for Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), has been, later on, addressed in model organisms and more recently in cell models. In the frame of the underlying relevance of a correct supply of Rf in humans and of a better understanding of the molecular rationale of Rf therapy in patients, this review wants to deal with theories and existing experimental models in the aim to potentiate possible therapeutic interventions in Rf-related neuromuscular diseases.

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The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2

Cited by 17 publications

References 35 publications

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency

Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy

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