Hereditary spastic paraplegia type 5: a potentially treatable disorder of cholesterol metabolism

Abstract

Spastic paraplegia type 5 (SPG5) is an autosomal, recessive, hereditary spastic paraparesis (HSP) caused by mutations in CYP7B1, which is responsible for a key step in the alternative pathway of bile acid synthesis [1]. Both pure and complicated clinical forms are possible, and brain magnetic resonance imaging (MRI) might show periventricular and subcortical white matter involvement [2]. Electrophysiology reveals abnormal conduction along the central pathways and peripheral nervous system sparing [3]. SPG5 patients have increased levels of 27-hydroxycholesterol (27OHC) in plasma and cerebrospinal fluid (CSF) [4]. Cerebral accumulation of 27OHC may be an important pathogenetic event in SPG5, with relevant therapeutic implications: indeed, since the substrate availability is a limiting factor for CYP27A1 activity [5], HMG CoA reductase inhibitors might reduce 27OHC, thus preventing neurological impairment. Here we describe two SPG5 patients and report the preliminary follow-up data including evaluation of response to statin therapy in one. Patient 1 was a 29-year-old woman with a 2-year history of gait disturbances, whereas her 24-year-old brother referred walking difficulties and lower limb stiffness since he was age 20. Past medical history revealed prolonged neonatal jaundice in both siblings. Neurological examination disclosed a pure clinical phenotype with spastic paraplegia rating scale (SPRS) [6] values of 15/52 and 10/52 in patients 1 and 2, respectively. Neuropsychological assessment did not detect cognitive impairment. Brain MRI showed slight FLAIR hyper-intense signal in the periventricular and centrum ovale white matter, and spectroscopy (1H MRS) on those areas showed a mild reduction of the relative ratio N-acetyl aspartate/creatine and the presence of a small lipid peak in both patients (Fig. 1a, b). Spinal cord MRI was normal. A motor evoked potentials (MEPs) study uncovered abnormal central motor conduction times (CMCTs) from both upper and lower limbs, and electromyography was normal. Gene analysis detected two compound heterozygous mutations (c.333_334delTC and c.806delA) in CYP7B1. Serum 27OHC levels were elevated 5.5 times in patient 1 (88 lg/ dl) and 10 times in patient 2 (159 lg/dl), respectively (normal 16 ± 3 lg/dl). Both patients underwent clinical, biochemical, and instrumental follow-up over a period of 9 months. Patient 1 was put on oral simvastatin (20 mg/day at months 0–3, 40 mg/day at months 4–6, and 60 mg/day at months 7–9), whereas her younger brother manifested cramps and marked hyperCKemia and discontinued simvastatin 3 days after introduction. When compared to baseline levels, serum 27OHC values were decreased at months 3, 6, and 9 (10, 34, and 33 %, respectively) in patient 1, and A. Mignarri A. Malandrini F. Ginanneschi A. Federico M. T. Dotti (&) Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy e-mail: dotti@unisi.it