Carbonic anhydrase deficiency (Type II) is a rare, autosomal recessive disease that is commonly found in individuals from the Middle East and Africa. It is caused by a mutation of the carbonic anhydrase II gene (CA2) localized to chromosome 8q22, although several different mutations have been identified in different populations. Carbonic anhydrase II is a cytoplasmic enzyme that is found in a wide variety of cells in the body, and is involved in electrolyte, water and pH homeostasis, CO2 and HCO3 transport, CSF production, metabolic pathways, and more.
Specifically, the enzyme plays an important role in bicarbonate reabsorption in the kidneys, along with osteoclast acidification in the bone resorption process; thus, resulting in the cardinal features we commonly see on presentation. The cardinal features include osteoporosis, renal tubular acidosis (mixed), and brain calcifications. Almost all patients that present with osteoporosis and renal tubular acidosis have a carbonic anhydrase II deficiency. Developmental delay, short stature, craniofacial abnormalities, mental retardation, and neuro-ophthalmological features may be observed, among others. However, it’s important to note that there is variability in cerebral calcification, cognitive impairments and optic nerve involvement, which may imply other genetic and/or epigenetic influences on the disease course.
On imaging, variable optic canal sizes are commonly seen, and are almost always smaller on the side with more severe optic nerve disease. Thickened skulls compatible with osteoporosis, small or absent paranasal sinuses, and unilateral or bilateral optic atrophy may be seen. On T2-weighted MRI, one optic nerve may appear smaller than the other when looking at the pre-chiasmatic portion.
Brain calcification is typically seen with a distinct symmetrical distribution involving the basal ganglia, the posterolateral and anteromedial areas of the thalami. Calcifications may also be seen in an asymmetric distribution involving the grey-white matter junctions, most commonly found in the frontal lobes, followed by the parietal and temporal lobes. Calcifications are typically progressive over time, and may be present as early as 2 years of age; however, calcifications may be absent in older children. Besides the areas of brain calcification, the parenchyma is unremarkable on routine MRI sequences, including diffusion-weighted images (DWI).
References:
1. Thomas M. Bosley, Mustafa A. Salih, Ibrahim A. Alorainy, M. Zahidul Islam, Darren T. Oystreck, Omer S. M. Suliman, Salem al Malki, Adel H. Suhaibani, Hattan Khiari, Sigri Beckers, Liesbeth van Wesenbeeck, Bram Perdu, Abdulmajeed AlDrees, Salah A. Elmalik, Wim Van Hul, Khaled K. Abu-Amero; The neurology of carbonic anhydrase type II deficiency syndrome, Brain, Volume 134, Issue 12, 1 December 2011, Pages 3502–3515, https://doi.org/10.1093/brain/awr302
2. Shah, G. N., Bonapace, G. , Hu, P. Y., Strisciuglio, P. and Sly, W. S. (2004), Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): Novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype‐phenotype correlation. Hum. Mutat., 24: 272-272. doi:10.1002/humu.9266