Spastic paraplegia with thinning of the corpus callosum and white matter abnormalities: Further mutations and relative frequency in ZFYVE26/SPG15 in the Italian population

Abstract

Spastic paraplegia with thinning of the corpus callosum (ARHSP-TCC) is a relatively frequent form of complicated hereditary spastic paraplegia in which mental retardation and muscle stiffness at onset are followed by slowly progressive paraparesis and cognitive deterioration. Although genetically heterogeneous, ARHSP-TCC is frequently associated with mutations in the SPG11 gene, on chromosome 15q. However, it is becoming evident that ARHSP-TCC can also be the clinical presentation of mutations in ZFYVE26 (SPG15), as shown by the recent identification of eight families with a variable phenotype. Here, we present an additional Italian ARHSP-TCC patient harboring two new, probably loss-of-function mutations in ZFYVE26. This finding, together with the report of a mutation in another Italian family, provides confirmation that ZFYVE26 is the second gene responsible for ARHSP-TCC in the Italian population.

Introduction

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous Mendelian disorder characterized by weakness, spasticity, and loss of the vibratory sense in the lower limbs [1]. Both pure and complicated forms are recognized depending on whether the spastic paraplegia occurs in isolation or is combined with additional neurological or extraneurological features. Collectively, HSPs account for a large proportion of the motor and cognitive handicaps seen in children and young adults [2]. Whereas considerable advances have been made in understanding of the autosomal dominant types of HSP, which account for approximately 70–80% of cases, less is known about the autosomal recessive forms (ARHSP), which appear to be relatively less common and clinically more complex [3].

Spastic paraplegia with thinning of the corpus callosum (ARHSP-TCC) [MIM 604360] is an autosomal recessive neurological disorder in which the cardinal pathologic features of upper motor neuron degeneration and cognitive deterioration are combined with characteristic brain MRI features, namely a “beaked” anterior corpus callosum and frequent white matter abnormalities (WMAs)[4]. Molecular studies have recently shown that mutations in SPG11 (MIM 610844) account for most ARHSP-TCC cases [5] and occur with a particularly high frequency in the Mediterranean area [6]. We recently identified mutations in ZFYVE26 (SPG15), encoding spastizin [7], in eight families in which 22 patients displayed variable combinations of spastic paraplegia, mental impairment, distal amyotrophy and pigmented maculopathy, sometimes matching the clinical presentation of Kjellin syndrome (MIM 270700). The presence of TCC, often associated with WMAs, in half of the kindred prompted us to investigate the relative frequency of mutations in ZFYVE26 in Italian patients with ARHSP-TCC. We herein report an additional patient harboring two mutations predicting loss-of-function of stastizin.