Disorders of Riboflavin Metabolism

Baby Detect > Metabology > Disorders of Riboflavin Metabolism

Disorders of Riboflavin Metabolism is a new form of classifying all the defects that evolves the Riboflavin (vitamin B2), a water-soluble vitamin, is an essential nutrient in higher organisms, as it is not endogenously synthesised, with requirements being met principally by dietary intake.

This includes nutritional riboflavin deficiency (it is not a genetic disorder, but can impact babies, mimetazing a rare disorder by abnormalities in the biochemical newborn screening. From a different perspective, BabyDetect screening just focuses on the genetic defects of vitamin B2. Also includes defects of transporters and coenzymes involved in the Riboflavin metabolism.

Because riboflavin therapy may be beneficial in a number of primary or secondary disorders of the cellular flavoproteome, early recognition and prompt management of these disorders is imperative.

As most of the Riboflavin deficiencies are considered MADD-like disorders, to make it easier we compiled them in MADD, but we suggest you talk to your metabolic physician to discuss the case of your baby further.

Includes:

– Riboflavin Deficiency (SLC52A1 gene)

Also known as: Riboflavin transporter deficiency 1 (RFVT1)

OMIM#615026 https://omim.org/entry/615026

– Riboflavin Transport Deficiency – SLC52A2 and SLC52A3 gene

Also known as: Brown-Vialetto-Van Laere syndrome 1; Brown-Vialetto-Van Laere syndrome 2; Riboflavin transporter deficiency 2 (RFVT2); Riboflavin transporter deficiency 3 (RFVT3); bulbar palsy, progressive, with sensorineural deafness or pontobulbar palsy with deafness; MADD-like

OMIM#211530 https://omim.org/entry/211530

OMIM#614707 https://omim.org/entry/614707

https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=12856&Disease_Disease_Search_diseaseGroup=riboflavin-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Riboflavin-transporter-deficiency&title=Riboflavin%20transporter%20deficiency&search=Disease_Search_Simple

– Multiple Acyl-Coa Dehydrogenase Deficiency – MADD (ETFA, ETFB and ETFDH genes)

Also known as: Glutaric acidemia II; Glutaric aciduria II; GAII; GA2; Ethylmalonic-adipic aciduria; EMA; Electron Transfer Flavoprotein Dehydrogenase Deficiency; GA IIA – ETFA deficiency; GA IIB – ETFB deficiency; GA IIC – ETFDH deficiency

OMIM#231680 https://omim.org/entry/231680

– Lipid storage myopathy due to Flavin Adenine Dinucleotide Synthetase deficiency (FLAD1 gene).

Also known as: FAD synthase deficiency; MADD-like; Riboflavin deficiency; Riboflavin receptor disorder

OMIM#255100 https://omim.org/entry/255100

– Exercise-intolerance, Riboflavin responsive (SLC25A32 gene).

Also known as: Mitochondrial FAD Transporter deficiency; MADD-like; Riboflavin deficiency

OMIM#255100 https://omim.org/entry/255100

1. The disease:

Multiple acyl-CoA dehydrogenase deficiency (MADD) (including all the MADD-like disorders cited above too) is a disorder of fatty acid and amino acid oxidation and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.

2. The Symptoms:

MADD represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). Lack of early signs or symptoms does not exclude the diagnosis.

  • Individuals with MADD type I or II typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI.
  • Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy.

3. Actions to take in case of early diagnosis:

  • Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in one of these genes) should continue breastfeeding. Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis. Biochemical NBS with acylcarnitines profile shows increased C4-C18 species, although patients may be severely carnitine depleted, which may limit the degree of these abnormalities.
  • The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine (combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates).
  • MADD is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from multidisciplinary approach to care.
  • Routine daily treatment includes limitation of protein and fat in the diet, avoidance of prolonged fasting, high-dose riboflavin (100-300 mg daily, in some cases of transport disorders can be even higher), carnitine supplementation (50-100 mg/kg daily in 3 divided doses) in those with carnitine deficiency, and coenzyme Q10 supplements (60-240 mg daily in 2 divided doses).
  • Further treatments include feeding therapy with consideration of gastrostomy tube for those with failure to thrive, as well as standard treatment for developmental delay, cardiac dysfunction, and sensory neuropathy.
  • Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy depending on the metabolic status.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

 4. For more information

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