Biotin Deficiency Workup

Updated: Oct 22, 2018
  • Author: Gratias Tom Mundakel, MBBS, DCH; Chief Editor: Jatinder Bhatia, MBBS, FAAP  more...
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Approach Considerations

Work up for biotin deficiency should be considered if the clinical presentation raises a suspicion of biotin deficiency or the patient is at risk for biotin deficiency (e.g. chronic alcoholism)

Profound and partial biotinidase deficiency are identified by newborn screening; however, newborn screening became available in developed countries only in the eighties, and is not routinely available in many developing nations. [42]  

Nutritional biotin deficiency, biotinidase deficiency as well as HCLS deficiency all respond to biotin treatment. However, isolated carboxylase deficiencies do not respond to biotin.  

Once biotin deficiency has been established, further evaluation is recommended to determine the extent and severity of disease, and may include:

  1. detailed neurologic exam, to look for hypotonia, ataxia, evaluate seizure activity, evaluation of psychomotor deficits
  2. vision and hearing tests to evaluate for optic atrophy and sensorineural deafness.




Laboratory Studies

In healthy individuals, serum biotin ranges from 133-329 pmol/L and urinary excretion of biotin is 18-127 nmol/24 hours.

Decreased urinary excretion of biotin and its catabolites is an early indicator of biotin deficiency. [3]

Biotin deficiency leads to decreased activity of biotin-dependent carboxylases. Reduced activity of pyruvate carboxylase leads to lactic acidosis. Reduced levels of the carboxylases may also affect levels of various intermediary metabolites and provide additional diagnostic clues. Organic aciduria may occur. For example, reduced activity of β-methylcrotonyl-CoA carboxylase leads to shunting of β-methylcrotonyl-CoA (MCC) to alternative pathways, leading to increased production of 3-hydroxyisovaleric acid and its excretion into urine. However, urinary organic acids may be not be elevated in all cases. 

Adults who consume raw egg whites for 14-21 days demonstrate decreased biotin levels in serum and urine and excrete large amounts of β-hydroxyisovalerate in the urine.

The levels of biotinylated MCC and propionyl-CoA carboxylase in white blood cells are considered to be one of the most reliable indicators of biotin status and are decreased in even those with marginal biotin deficiency. In contrast, serum biotin levels do not reliably indicate individuals with marginal biotin deficiency.

In individuals with suspected biotinidase deficiency, enzyme activity can be measured. Testing for biotinidase deficiency is included as part of newborn screening in all US States and in many developed countries.  [26, 43, 44, 42]

Individuals with profound biotinidase deficiency have serum enzyme activity of less than 10% of mean normal activity. [26] Children with biotinidase deficiency commonly become symptomatic if caregivers do not administer biotin. Children who have partial biotinidase deficiency have 10-30% of mean normal serum biotinidase activity and usually develop clinical manifestations of biotinidase deficiency only during times of stress, such as infection or a systemic illness. False positive newborn screening tests for biotinidase deficiency may occur in premature infants [45]  as well as neonates with jaundice.    [46]

When biotinidase deficiency has been identified, testing for the responsible mutation may be helpful.  [47] Dobrowolski et al noted that, in the United States, the 4 mutations most commonly associated with complete biotinidase deficiency are c98:d7i3, Q456H, R538C, and the double mutation D444H:A171T. [48]  Partial biotinidase deficiency is almost universally attributed to the D444H mutation.

Prenatal testing and preimplantation genetic diagnosis are possible for biotinidase deficiency as well as holocarboxylase synthetase deficiency. [24, 38]



Imaging Studies

MRI changes have been described in individuals with biotinidase deficiency. [49, 50]

A 3-year-old male with biotinidase deficiency presented with skin eruption, ataxia, paraparesis, and MRI findings of myelopathy; all of which resolved with treatment.

Desai et al noted MRI findings in 4 patients and found (1) encephalopathy, low cerebral volume, ventriculomegaly, and widened extracerebral cerebrospinal fluid (CSF) spaces were common; (2) caudate involvement and parieto-occipital cortical abnormalities were uncommon; (3) a single patient had restricted diffusion; (4) 2 patients manifested with subdural effusions, and (5) 1H-magnetic resonance (MR) spectroscopy revealed decreased NAA peaks, elevated lactate levels, and reversal of the choline-to-creatine ratio. With use of biotin, a total reversal of imaging findings occurred in 2 patients.

Both antenatal and postnatal abnormal CNS findings have been described in individuals with holocarboxylase synthetase deficiency and include subependymal cysts, ventriculomegaly and intraventricular hemorrhage. [38]