30 Inborn Errors of Cholesterol Biosynthesis Dorothea Haas, Richard I

30 Inborn Errors of Cholesterol Biosynthesis Dorothea Haas, Richard I. Kelley 30.1 Introduction Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only recently been described. With the exception of cholesterol supplementation in Smith-Lemli-Opitz syndrome, no therapeutic regimens have yet been proven effective. Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol biosynthesis. Patients affected with these disorders present with recurrent febrile attacks and, in the case of classic MVA,often have malformations, neurological symptoms, and psychomotor retardation (Hoff- mann et al. 1993). Long-term administration of coenzyme Q10 together with vitamin C and E to treat an intrinsic deficiency in the synthesis of coenzyme Q10 and to treat a possible increased sensitivity to reactive oxygen species seems to stabilize the clinical course and improve somatic and psychomotor development (Haas et al. 2001; Prietsch et al. 2003). Dietary supplementation of cholesterol may reduce frequency and severity of febrile attacks in some mildly affected patients, but has further compromised more severely affected patients, similar to the apparent adverse effect of lovastatin in some patients (Hoffmann et al. 1993). In two patients (siblings) followed closely, intervention with corticosteroids was highly beneficial during clinical crises, with resolution ofthecriseswithin24h. The severity of attacks can also be reduced with the leukotriene receptor inhibitors montelukast and zafirlukast (R. I. Kelley, unpublished observations). Despite the apparent adverse effect of lovastatin in classic MVA, a recently completed study has shown a beneficial effect of simvastatin in HIDS (Simon et al. 2004). The main characteristics of CHILD (congenital hemidysplasia, ichthyosiform erythroderma, and limb deficiency) syndrome (König et al. 2000) and Conradi-Hünermann syndrome (Kelley et al. 1999) are skeletal defects, includ- ing, notably, chondrodysplasia punctata and ichthyosiform skin lesions. All reported cases of Greenberg dysplasia (also called hydrops-ectopic calcification- “moth-eaten” skeletal dysplasia, HEM) have had nonimmune hydrops fetalis, short limbs, abnormal severe chondro-osseous calcifications and have been lethal prenatally. This autosomal recessive disorder is caused by a deficiency 322 Inborn Errors of Cholesterol Biosynthesis of sterol-∆14 reductase encoded by the LBR gene (Waterham et al. 2003). LBR was first known to encode for the lamin B receptor. Missense mutations in this gene recently have been reported also to cause Pelger-Huët anomaly, a disorder characterized by abnormally shaped blood granulocytes (Hoffmann et al. 2002) with heterozygous LBR mutations and developmental delay, epilepsy, and skeletal abnormalities in some patients homozygous for specific LBR mutations. Antley-Bixler syndrome is a rare, multiple anomaly syndrome with limb anomalies, craniofacial dysmorphisms and, in some, ambiguous genitalia. In patients with ambiguous genitalia, Kelley et al. (2002) have found increased levels of lanosterol and dihydrolanosterol, suggesting a functional deficiency of lanosterol-14α demethylase, a cytochrome P450 enzyme, encoded by CYP51. Mutation analysis of CYP51, however, discloses no obvious pathogenic mutation. Instead, mutations in the POR gene encoding P450 oxidoreductase, the obligate electron donor for all cytochrome P450 enzymes, have been identified in patients with Antley-Bixler syndrome (Flück et al. 2004). As a general rule, patients with defects in the more proximal steps in cholesterol biosynthesis have normal cholesterol serum levels. Furthermore, the pathology appears to be mostly if not exclusively embryonic, without ev- idence for most precursor sterols that their usually trivial levels are harmful beyond the embryonic period. Therefore, there are few indications for treatment of most of these conditions with cholesterol, unless the level of cholesterol is abnormally low and the level of the precursor sterols is elevated substan- tially more than usual. The principal exceptions among these disorders are the very rare male hemizygote for CDPX2, the occasional unfavorably lyonized CDPX2 heterozygote with hypocholesterolemia and severe skin disease, and patients with CHILD syndrome who have severe, persistent psoriasiform skin lesions. Desmosterolosis and lathosterolosis are malformation syndromes involv- ing many different organ systems (FitzPatrick et al. 1998; Brunetti-Pierri et al. 2002). The total of four patients (two for each disorder) so far reported have clinical characteristics that overlap with SLOS, but serum cholesterol is normal or only marginally diminished in the two patients for whom serum data are available. There currently is no experience with treatment of lathosterolosis. Theoretically, patients with lathosterolosis should require the same cholesterol therapy used for SLOS if the cholesterol level is low and the level of lathosterol is increased. However, unlike SLOS, lathosterolosis is characterized by clinically significant lipid storage, possibly storage of cholesterol esters, which might be aggravated by supplemental cholesterol. Only one patient with desmosterolosis and a borderline low cholesterol level has been treated with cholesterol supplementation (50 mg/kg per day. There was no clinical effect, but a mild reduction in the plasma level of desmosterol was observed. Theoretically, the same criteria for treatment of SLOS should apply to desmosterolosis, with a goal of achieving a normal blood cholesterol level and a concomitant reduction in the level of desmosterol. Introduction 323 Smith-Lemli-Opitzsyndrome,causedbyadeficiencyof7-dehydrocholesterol reductase (DHCR7), is characterized by an accumulation of 7- and 8-dehydrocholesterol (7-DHC and 8-DHC), and, in 90% of patients, a lower-than-normal level of cholesterol in blood and all body tissues (Irons et al. 1993). SLOS has a highly variable phenotype, ranging from lethally affected infants with multiple organ and skeletal malformations to mildly affected patients with moderate mental retardation, mild dysmorphism, and a normal life expectancy. A large proportion of patients may require nasogastric tube feeding or gastrostomy to provide adequate caloric intake. However, it is important not to overfeed the children to archive a better growth. SLOS patients have a genetically determined short stature and, additionally, as a result of their muscle hypoplasia, their normal, well-nourished weight during infancy typically is 1–2 standard deviations less than their length. Trying to achieve arbitrary and inappropriately high weight goals based on age or length alone only increases adipose tissue and thereby limits the availability of cholesterol to the organs. Cholesterol supplementation results in improved growth and behavior in most patients (Irons et al. 1997; Kelley and Hennekam 2000). Treatment with supplements of bile acids has not been effective (Elias et al. 1997) except in severely affected patients with cholestasis or when there is a clinically evident deficiency of bile acids. Unfortunately, an effect of cholesterol supplementation on intrinsic cognitive abilities has been absent or minimal, most likely because cholesterol cannot be transported across the blood-brain barrier and because prenatal developmental insults cannot be reversed. Plasma sterol levels often improve slowly over many months or years after initiation of cholesterol supplementation. However, effects on behavior often are evident after only several days of cholesterol treatment, possibly because of changes in levels of adrenal steroids, many of which, unlike cholesterol, can cross the blood-brain barrier. Treatment of mildly affected SLOS patients with simvastatin, an in- hibitor of HMG-CoA reductase, causes a rapid fall of 7- and 8-DHC and a rise of cholesterol (Jira et al. 2000), probably via augmentation of residual DHCR7 activity, allowing more complete conversion of the abnormal sterols to cholesterol (Wevers et al. 2003). Mental, motor, and social development as well as weight, length, and head circumference reportedly improved in two patients who were not pretreated with cholesterol. However, in several patients with satisfactory improvement on cholesterol treatment, the addition of simvastatin had no mea- surable clinical benefit at the same time that potentially serious side-effects of simvastatin developed in some (Starck et al. 2002a; D. Haas, unpublished observations). Studies in a larger group of patients are needed to evaluate the use of simvastatin. Simvastatin should not be used in severely affected patients (ratio of (7-DHC + 8-DHC) to cholesterol is greater than 0.5) expected to have no or minimal residual DHCR7 activity, because it might further lower cholesterol levels, with severe side-effects (Starck et al. 2002b). 324 Inborn Errors of Cholesterol Biosynthesis 30.2 Nomenclature No. Disorder/ Definition/comment Gene Gene OMIM No. deficiency symbol 30.1a Mevalonic Mevalonate kinase Mevalonate kinase MVK 251170 aciduria deficiency, urinary mevalonate typically >500 mmol/mol creat. 30.1b Hyper-IgD Mevalonate kinase Mevalonate kinase MVK 260920 syndrome deficiency, urinary mevalonate typically <100 mmol/mol creat. 30.2 Desmosterolosis 3β-Hydroxysteroid-∆24 24-Dehydro- DHCR24 602398 reductase deficiency cholesterol reductase 30.3 Antley-Bixler Lanosterol-14α demethylase

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