Riboflavin-responsive exercise intolerance (SLC25A32 deficiency) is a rare disorder caused by mutations of the SLC25A32 gene that encodes the
mitochondrial folate transporter. Patients suffer from exercise intolerance and may have disrupted motor function.
A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency has been observed suggesting that SLC25A32 is in fact a mitochondrial
FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
transporter. In mice studies, besides β-oxidation and amino acid metabolism being impaired by mitochondrial FAD deficiency, Slc25a32 wipeout embryos experienced dysfunction of the glycine cleavage system–
dihydrolipoamide dehydrogenase
Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the ''DLD'' gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.
Dihydrolipoam ...
. This
dihydrolipoamide dehydrogenase
Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the ''DLD'' gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.
Dihydrolipoam ...
dysfunction disrupted folate-mediated one-carbon metabolism, leading a deficiency of 5-methyltetrahydrofolate.
Treatment with
riboflavin
Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in e ...
,
5-formyltetrahydrofolate (Folinic acid) and/or
L-5-methyltetrahydrofolate (5-MTHF) may lead to a drastic improvement of symptoms.
Pyridoxal - 5 - Phosphate (P5P), a cofactor for the enzyme
Serine hydroxymethyltransferase
Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) (Vitamin B6) dependent enzyme () which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine ...
, may also assist with the conversion of
tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is ...
(THF) to
5,10-Methylenetetrahydrofolate
5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF.
As an intermediate in one-carbon metabolism, 5,10-CH2 ...
(5,10-CH
2-THF) a direct precursor to
L-5-methyltetrahydrofolate (5-MTHF).
Symptoms
Patients suffer from
exercise intolerance
Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post ...
and may also have neuromuscular symptoms such as
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...
,
dysarthia and muscle weakness. Staining of skeletal muscle samples with hematoxylin and eosin may reveal the
ragged red fibers
MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the ...
sign indicating disrupted mitochondrial function. In some patients,
hypoketotic hypoglycemia was described.
History
Riboflavin - responsive exercise intolerance was first described in 2016 by Schiff et al.
See also
*
Multiple acyl-CoA dehydrogenase deficiency
Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous ...
- similar in biochemical features; responsive to riboflavin in the majority of late-onset cases.
External links
Exercise intolerance, riboflavin-responsive description in the
OMIM
Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...
compendium.
Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism
References
{{Reflist
Autosomal recessive disorders
Congenital disorders