Hereditary spastic paraplegia type 5: a potentially ...

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Jan 10, 2014 - cholesterol (27OHC) in plasma and cerebrospinal fluid. (CSF) [4]. .... (2010) Marked accumulation of 27-hydroxycholesterol in SPG5 patients ...
J Neurol DOI 10.1007/s00415-014-7253-7

LETTER TO THE EDITORS

Hereditary spastic paraplegia type 5: a potentially treatable disorder of cholesterol metabolism Andrea Mignarri • Alessandro Malandrini • Marina Del Puppo • Alessandro Magni • Lucia Monti • Federica Ginanneschi • Alessandra Tessa Filippo Maria Santorelli • Antonio Federico • Maria Teresa Dotti



Received: 28 December 2013 / Revised: 10 January 2014 / Accepted: 15 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Dear Sirs, 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.

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: [email protected] M. Del Puppo  A. Magni Department of Health Sciences, Medical School, University of Milano-Bicocca, Monza, Italy L. Monti Unit of Diagnostic and Therapeutic Neuroradiology, Azienda Ospedaliera Siena, Siena, Italy A. Tessa  F. M. Santorelli Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy

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

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J Neurol Fig. 1 a, b Brain MR spectroscopy (1H MRS) on periventricular and centrum ovale white matter in patient 1 (a) and patient 2 (b) at baseline. A multivoxel technique with SE sequence at TE 30 ms was used. In both subjects, the same areas were evaluated: 1H MRS revealed a mild reduction of the relative ratio N-acetyl aspartate/ creatine (1.80 in patient 1, 1.81 in patient 2) and the presence of a small lipid peak at 1 ppm. c Serum 27OHC assessment over the 9-month follow-up period in patient 1 and patient 2. Normal values = 16 ± 3 lg/dl.

persistently elevated in patient 2 (Fig. 1c). Routine blood tests were unvaried except for reduced cholesterol in patient 1. SPRS scores did not change in both subjects. At month 6, MEPs and neuroimaging studies were repeated. Compared to baseline, CMCTs from right limbs and upper left limb were decreased in patient 1, while in patient 2 all CMCTs were increased. Brain MRI and 1H MRS were substantially unchanged in both patients. SPG5 represents a nice model of neurodegeneration due to defective cholesterol metabolism. Our case reports deserve discussion both on diagnosis and possible treatment. The presence of neonatal jaundice in our patients could be not casual since CYP7B1 mutations have been associated with severe neonatal cholestatic liver disease [7]. Prolonged neonatal jaundice may represent a systemic

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manifestation of SPG5, as observed in other cholesterol metabolism disorders such as cerebrotendinous xanthomatosis [8] and Niemann-Pick disease type c [9]. Serum 27OHC represents an extremely useful diagnostic biomarker allowing differential diagnosis between SPG5 and other autosomal recessive HSPs. Yield of 27OHC assessment in newborns with prolonged unexplained neonatal jaundice should also be considered in light of a possible disease-modifying treatment. Moreover, further studies are needed to establish if a correlation between 27OHC levels and clinical disability or disease duration exists. HMG CoA reductase inhibitors have been hypothesized as a possible treatment option in SPG5 [4], but their administration has not been tried so far. In our patients, the

J Neurol

short follow-up period does not allow for drawing conclusions on statin effects. Occurrence of cramps and hyperCKemia in patient 2 points out the importance of taking into account statin-associated myopathy (SAM). Indeed, early introduction of coenzyme Q10 supplementation may lead to symptomatic improvement in patients with SAM. Findings of moderate reductions of serum 27OHC upon simvastatin administration in patient 1 arouse interesting considerations on possible treatment of SPG5. Since the brain distribution of 27OHC is consistent with an extracerebral origin [10], HMG CoA reductase inhibitors are expected to reduce cerebral accumulation of 27OHC. If further studies will prove 27OHC storage to be responsible for cortico-spinal tract damage, long-term statin administration could be proposed. A double-blind, placebo-controlled cross-over trial will be required to definitively assess the efficacy of statins in SPG5, with these points to be clarified: the best drug and the doses to be preferred, and the possible outcome measures. In this respect, given that 27OHC monitoring in CSF is impractical, MEPs and brain imaging including MR spectroscopy may be useful tools to detect subclinical modifications over time. Acknowledgments The authors would like to thank Gianluca Marangi for excellent nursing and Claudio Salvadori for laboratory assistance. Conflicts of interest We declare that we have no conflicts of interest. Ethical standard This study has been approved by the appropriate ethics committee and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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