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[16]
death by initiating apoptosis . All these perturbations are implicated in mitochondrial dysfunction, hence
strategies to mitigate this may pose an important therapeutic avenue.

CLASSIFICATION OF DEFECTS IN RIBOFLAVIN METABOLISM ASSOCIATED WITH
MITOCHONDRIAL DYSFUNCTION
Simplistically classified in this review, the primary defects of flavocoenzyme metabolism include disorders
of riboflavin or flavocoenzyme transport and enzymes in the synthetic pathway of FMN and FAD.
Secondary flavoproteome defects include FMN- and FAD-dependent reactions resulting in functional
disruption of the cellular flavoproteins, but do not arise as a direct result of defects in the synthesis and
transport of riboflavin, FMN, or FAD.

Secondary flavoproteome defects can be further subcategorized into primary mitochondrial disorders
[17]
(PMD) and secondary mitochondrial dysfunction (SMD) . PMD are genetic disorders that directly impair
OXPHOS proteins or its function by impacting the complex machinery involved in the OXPHOS process.
SMD can be caused by germline mutations in non-OXPHOS genes, accompany various hereditary non-
mitochondrial diseases, or may be acquired secondary to adverse environmental factors which can cause
oxidative stress. A summary of disorders of flavocoenzymes and flavoproteins associated with primary and
secondary mitochondrial dysfunction is presented in Table 1.

PRIMARY DISORDERS OF FLAVOCOENZYME METABOLISM ASSOCIATED WITH
MITOCHONDRIAL DYSFUNCTION
Disorder of Riboflavin Transport
Riboflavin Transporter Deficiency Neuronopathy (OMIM #614707, OMIM# 211500, and OMIM
#211530) – previously known as Brown-Vialetto-Van Laere and Fazio- Londe syndrome
Human riboflavin transporters, RFVT1, RFVT2, and RFVT3, are encoded by their respective genes,
SLC52A1, SLC52A2, and SLC52A3 [18-21] . These transporters with different tissue expressions transport
riboflavin across plasma membranes and maintain the supply of flavins to the cells.

Mutations in the SLC52A2 and SLC52A3 have been reported to cause Brown-Vialetto-Van Laere (BVVL)
and Fazio-Londe (FL) [22,23] . Both conditions are now considered as a single disease entity , with progressive
[24]
sensorimotor and cranial neuropathy in both and absent sensorineural hearing loss in FL as primary
manifestations. A new nomenclature was proposed to clarify the specific disease mechanism and both
[25]
conditions were renamed to riboflavin transporter deficiency (RTD) , with mutations in SLC52A2 and
SLC52A3 causing RTD2 and RTD3, respectively . A recent review identified 109 RTD patients (52 RTD2,
[26]
[26]
56 RTD3, and 1 RTD2/3) . The overall mean age of onset of these patients was 5.3 years (range: 0-5 years).
The predominant clinical features were hearing loss and muscle weakness. Some characteristics of patients
with RTD3 included a later onset of presentation (> 10 years to third decade) and bulbar symptoms. The
[26]
common presenting features of patients with RTD2, on the other hand, was abnormal gait and/or ataxia .
Plasma acylcarnitine profiles prior to riboflavin supplementation was suggestive of multiple acyl-CoA
[22]
dehydrogenase defect (MADD) . Urine organic acids commonly showed ethylmalonic aciduria suggesting
[26]
impaired fatty acid, methionine, and/or isoleucine oxidation . Both plasma acylcarnitine and urine
organic acids, however, have been observed to be normal in nearly half of RTD patients .
[26]
Effective doses of riboflavin varied 10-80 mg/kg/day with over 70% of patients demonstrating
[26]
improvements in muscle strength, motor abilities, respiratory function, and/or cranial nerve deficits .
The pathomechanism of the specific vulnerability of neurons in RTD might be due to mitochondrial
[26]
dysfunction and impairment in the clearance of reactive oxygen species .