Inherited disorders of cholesterol biosynthesis

Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only been recently described and more are likely to follow in the near future. Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. The other recognized defects of cholesterol biosynthesis are due to enzyme defects located distally in the pathway beyond the branching points of nonsterol isoprene biosynthesis and solely affecting cholesterol biosynthesis. Patients with these disorders all present with complex malformation syndromes involving different organ systems. The main characteristics of CHILD syndrome and Conradi-Huenermann syndrome are skeletal defects and ichthyosiform skin involvement. Smith-Lemli-Opitz syndrome and desmosterolosis are generalized malformation syndromes involving many different organs including the central nervous system. The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity, whereas the search for the distally located defects of cholesterol biosynthesis requires sterol analysis in blood or tissues by GCMS. Rational therapeutic approaches have been described for HIDS, MVA and Smith-Lemli-Opitz syndrome.