Fighting against neurotoxic oxysterols: new insights from cerebrotendinous xanthomatosis and spastic paraplegia type 5 (SPG5)

Chapter 1 Cerebrotendinous xanthomatosis (CTX) and spastic paraplegia type 5 (SPG5) are autosomal recessive bile acid disorders characterized by accumulation of neurotoxic oxysterols which leads to central nervous system damage causing significant disability if the disorders are not early treated. CTX patients are treated with chenodeoxycholic acid (CDCA), while SPG5 subjects may benefit from a cholesterol lowering-therapy. Chapter 2 Since CTX is a chronic disorder leading to progressive deterioration and premature death if not treated, all authors agree on the need for early diagnosis and timely introduction of CDCA therapy. However, as there is considerable variation in disease onset, systemic involvement and neurological impairment, its recognition at an initial stage may be challenging in the clinical setting. This prompted us to develop a simple practical diagnostic algorithm for early identification of CTX patients.We reviewed the largest available series of CTX cases analyzed together, and we developed a suspicion index to achieve early diagnosis of this treatable metabolic disorder. Our results show that the present suspicion index could allow early diagnosis of CTX, so that treatment can be started before disability occurs. We therefore propose its use in clinical practice. Chapter 3 We evaluated the serum profile of bile acids intermediates (cholestanol and its precursor 7αC4, 27-OHC, 24S-hydroxycholesterol), cholesterol, lathosterol, and plant sterols (campesterol, sitosterol) in a significantly large CTX population: we performed a baseline assessment and a long-term follow up during therapy with oral CDCA, comparing biochemical data with neurological outcome. Our metabolic evaluation of CTX patients allowed us to clarify some pathogenetic aspects of the disease, to specify the role of the various biochemical parameters in the diagnostic setting, and to better assess the effects of CDCA treatment on cholesterol metabolism, also in the light of clinical evolution. Chapter 4 We report the clinical and MRI findings of 38 CTX patients, and the follow up data of 16 of them who were untreated at baseline. Our detailed description of the complex spectrum of MRI abnormalities in CTX brains should contribute to the earlier recognition. Infratentorial lesions involving the dentate nuclei and surrounding white matter, and less frequently the brainstem, should lead to suspect CTX. However, this finding is not invariably present, since cerebellar signal alterations can be subtle or absent in some patients. The variable appearance of cerebellar abnormalities seems to provide a snapshot into the neuropathology underlying CTX. Notably, patients showing MRI evidence of cerebellar vacuolation should be monitored more strictly over time and could be the ones to select for additional or experimental therapies. Chapter 5 We report a case of a child presenting with neonatal cholestasis and diagnosed as CTX in the first year of life. She was promptly treated with CDCA and presented a normal neurological development. The early beginning of the therapy with CDCA, with the declining of the toxic bile acid intermediates, prevented clinical deterioration. Our long term experience, with an early beginning of the treatment with CDCA, not only confirms the efficacy of the drug in preventing neurologic damage, but also demonstrates its total safety. Chapter 6 SPG5 patients have increased levels of 27-hydroxycholesterol (27OHC), and its accumulation in the brain may be the key pathogenetic event, with relevant therapeutic implications. We describe four SPG5 patients and report the follow up data including evaluation of response to therapy with cholesterol-lowering drugs. Therapy of HSPs essentially focuses on symptomatic treatment. In this regard, SPG5 may represent the first form with an available disease-modifying therapy. In our patients simvastatin and ezetimibe strongly reduced serum levels of 27OHC. Our findings support the use of this drugs in SPG5, which however should be further evaluated with a double-blind, placebo-controlled clinical trial.