Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

Abstract

Combined methylmalonic acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials.

Fig. 1

Ophthalmologic complications in patients with cblC disease. Patients with early and late-onset cblC disease with eye exam performed at different ages (years). Proposed classification stages: 1 no alterations found; 2 mild maculopathy, peripheral pigmentary retinopathy; 3 progressive maculopathy, retinal extension of pigmentary changes; 4 legally blind. See details in Supplementary Table 2

Fig. 2

Vascular complications in cblC disease and their relation to plasma total plasma homocysteine (tHcy; normal range 5–15 µM) References: ¹Guigonis et al. 2005; ²Van Hove et al. 2002; ³Tsai et al. 2007; ⁴Kind et al. 2002; ⁵Sharma et al. 2007; ⁶Thauvin-Robinet et al. 2008; ⁷Profitlich et al. 2009a, ; ⁸Brunelli et al. 2002. TMA Thrombotic microangiopathy, HUS hemolytic uremic syndrome, PE pulmonary embolism. tHcy was approximated from plasma-free homocysteine of *23 and **61 µM

Fig. 3

Outcome of patients with cblC disease according to their management. Patients with early-onset (a) and late-onset (b) cblC disease evaluated at different ages (years) and classified according to type of management and severity of disease. Proposed clinical staging: 1 no clinical alterations; 2 mild manifestations not affecting daily quality of life; 3 moderate manifestations including growth impairment, developmental delay, eye disease; 4 severe disease manifestations either affecting daily quality of life or requiring intensive medical care; 5 death. See details in Supplementary Table 2