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The biotin cycle
Free biotin enters the cycle from dietary sources or from the cleavage of biocytin or biotinyl-peptides by the action of biotinidase. The free biotin is then covalently attached to the various apocarboxylases, propionyl-CoA carboxylase (PCC), beta-methylcrotonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), and acetyl-CoA carboxylase (ACC) by the action of biotin holocarboxylase synthetase, thereby forming active holocarboxylases. The holocarboxylases are subsequently proteolyzed to biocytin and/or biotinyl-peptides which are then further cleaved by biotinidase, thus recycling the biotin. The liberated biotin can then enter the free biotin pool. Isolated deficiencies of each of the carboxylases and deficiencies of both holocarboxylase synthetase and biotinidase can occur.

NBIA Types
PKAN = pantothenate kinase-associated neurodegeneration
PLAN = PLA2G6-associated neurodegeneration
MPAN = mitochondrial membrane protein-associated neurodegeneration
BPAN = beta-propeller protein-associated neurodegeneration
Minor forms include those associated with pathogenic variants in ATP13A2, FA2H, FTL, CP, and DCAF17. Frequencies are based on 850 families worldwide collected over 25 years in a repository of neurodegeneration with brain iron accumulation.

Metabolic pathway. Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol. Deficiency of PCC results in propionic acidemia (PA) and accumulation of 3-OH propionate, methylcitrate, and glycine, among other metabolites. PCC, located inside the mitochondrion, is a heterododecamer (α6β6) comprising six α-subunits (orange) and six β-subunits (purple). Biotin (blue), bicarbonate, and ATP have binding sites in the α-subunit. The β-subunits form a central core.

A. Left axial image shows high brain iron in the globus pallidus (see arrow) on T₂-weighted MRI.
B. Right sagittal image shows cerebellar atrophy (see arrow).

T₂-weighted brain MRI of PKAN (A) and non-PKAN NBIA (B)
A. Arrow indicates the "eye of the tiger" change characteristic of PKAN.
B. MRI shows globus pallidus hypointensities only, consistent with iron deposition and supporting a diagnosis of non-PKAN NBIA.

T₂-weighted imaging in MPAN
A. Typical eye-of-the-tiger sign seen in PKAN
B. Iron accumulation in globus pallidus without an eye-of-the-tiger sign, as observed in MPAN and other forms of NBIA
C. Isointense streaking of the medial medullary lamina between the hypointense signal regions in globus pallidus externa and interna, observed in most persons with MPAN; may be mistaken for an eye-of-the-tiger sign

T₂-weighted sequences demonstrating globus pallidus hypointensity (A) and hypointensity of the substantia nigra (B). In BPAN, the substantia nigra is usually more hypointense relative to the globus pallidus, indicating higher levels of iron. Note: The illustrated findings are not typically present in early childhood, when imaging may be normal or show only hypomyelination, a thin corpus callosum, or cerebral/cerebellar volume loss.

Brain MRI findings in a child with the late-infantile form of GM1 gangliosidosis
A. At age 3 years 6 months: T₂-weighted axial view showing minimal atrophy
B and C. At age 6 years 10 months: T₂-weighted axial view showing progressive atrophy as evidenced by enlarged ventricles (black arrows) and T₂-weighted axial view showing extensive brain iron accumulation within the globus pallidus (white arrows)

Brain MRI of individuals with WSS. Arrows indicate the following findings:
A. Sagittal T₁-weighted image, showing small pituitary gland and partially empty sella.
B-C. Fluid-attenuated inversion recovery (FLAIR) demonstrating variable degrees of white matter signal intensities at different stages of the disease.
D. T₂*-weighted MRI showing iron deposition in the globus pallidus.
E-F. Diffusion-weighted imaging (DWI) showing diffusion restriction involving the splenium of the corpus callosum.