Cholestanol and 7αC4 represent important markers for CTX diagnosis and monitoring of therapy. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol, since 7αC4 better mirrors 7α-hydroxylation rate and is thought to be correlated with cholestanol accumulation in the brain. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis at any stage of disease. Lathosterol and plant sterols should be considered as additional markers for diagnosis and monitoring of therapy. Further studies including long-term assessment of bile acid intermediates in cerebrospinal fluid are needed in patients who show clinical progression despite treatment.

BackgroundThe modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols.MethodsWe analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38–79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids).ResultsA significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=−0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age.ConclusionThese data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined.

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Spastic paraplegia type 5 (SPG5) is an autosomal recessive hereditary spastic paraparesis (HSP) associated with pure or complicated phenotypes and mutations in CYP7B1 [1] causing an impairment of the alternative pathway of bile acid synthesis with marked accumulation of 27-hydroxycholesterol (27OHC) in plasma and cerebrospinal fluid [2]. Since brain 27OHC has an extracerebral origin [3], cholesterol-lowering drugs might prevent neurological impairment in SPG5 by reducing circulating 27OHC, which is derived from cholesterol.We previously reported a nine-month follow-up in two ambulant siblings harboring mutations in SPG5/CYP7B1 [4]. At that time, we evaluated the effects of statin therapy in one of the two cases (patient 1) and observed moderate serum 27OHC reduction. Here, we present a 24-month follow-up in patient 1, treated with simvastatin and ezetimibe, and a 12-month follow-up in patient 2, treated with ezetimibe alone.Clinical details, laboratory and instrumental findings, and molecular data in the two patients have been described elsewhere [4]. In the present study, both subjects underwent neurological evaluation including Spastic Paraplegia Rating Scale (SPRS) and Modified Rankin Scale (MRS) clinical scoring, routine blood tests, cholesterol and 27OHC determinations every 3 months, and instrumental follow-up including motor evoked potentials (MEPs), conventional brain magnetic resonance imaging (MRI), and MR spectroscopy every 6 months. Patient 1 received different oral doses of simvastatin (from 20 to 60 mg/day) during the first 12 months, and then oral ezetimibe 10 mg/day was added to simvastatin 40 mg/day for 12 months. Treatments were well tolerated. Serum 27OHC concentration progressively decreased under treatment with simvastatin either alone (reduction ranged from 10 to 45 % compared to baseline) or when in combination with ezetimibe (55 % decrease compared to baseline), and cholesterol tended to decrease in parallel with 27OHC (Fig. 1a). Association of simvastatin and ezetimibe was more effective in reducing 27OHC than the increase of simvastatin dosage up to 60 mg/day. No changes of neurological disability as well as brain MRI and spectroscopic pattern were observed. MEPs revealed a trend toward improvement or stabilization of central motor conduction times (CMCTs).Patient 2, who had not tolerated simvastatin because of cramps and marked hyperCKemia [4], received ezetimibe 10 mg/day for 12 months, and tolerated well this therapy. We observed a persistent decrease of serum 27OHC values (38-50 % reduction compared to baseline), whereas cholesterol levels initially decreased and then returned to baseline (Fig. 1b). Alike his sister, SPRS and MRS scores as well as brain MRI and spectroscopy were unchanged. MEPs showed substantially stable CMCTs values over time.Since chenodeoxycholic acid (CDCA) has been reported to be beneficial in a child with liver disease associated with a missense variant in CYP7B1 [5], we added oral CDCA

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