SPG8 mutations in Italian families: clinical data and literature review
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SPG8 mutations in Italian families: clinical data and literature review Federica Ginanneschi 1 & Angelica D’Amore 2,3 & Melissa Barghigiani 2 & Alessandra Tessa 2 & Alessandro Rossi 1 & Filippo Maria Santorelli 2 Received: 19 July 2019 / Accepted: 25 November 2019 # Fondazione Società Italiana di Neurologia 2019
Abstract Background Spastic paraplegia type 8 (SPG8) is an autosomal-dominant form of hereditary spastic paraplegia (AD-HSP) caused by a mutation in the KIAA0196 gene. SPG8 accounts for 1% of less of all AD-HSP and the genotype–phenotype correlation remains poorly understood. Methods We report the first clinical and genetic description of SPG8 disease in Italian patients. We identified four new mutations in KIAA0196 gene. These variants were identified using a multigene targeted resequencing HSP panel. We took this opportunity to review the pertinent literature. Results Age at disease onset was in the third or fourth decade of life. Stiffness of the lower limb with spastic gait, walking impairment, and decreased vibration sense were common early symptoms. Subjects of two families had bladder control abnormalities. Unlike previous reported cases, Italian SPG8 subjects have pure form of spastic paraparesis without cranial nerve involvement, and onset is in adult life. Discussion By a clinical point of view, it is hard to differentiate SPG8 from the SPG4, in which bladder and vibration sense dysfunctions are frequent signs. The differential diagnosis with other forms of AD-HSPs seems relatively easier if one considers the early-onset manifestations in SPG3A and the peripheral nervous system and cerebellar involvement seen in SPG31. Keywords Hereditary spastic paraparesis . Literature review . KIAA0196 . Strumpellin
Introduction Spastic paraplegia type 8 (SPG8) is an autosomal-dominant form of hereditary spastic paraplegia (AD-HSP) caused by a mutation in the KIAA0196 gene (OMIM no. 603563), which encodes strumpellin, a member of the multiprotein WASH regulatory complex implicated in endosome sorting [1, 2]. SPG8 represents a rare form of HSP and the genotype– phenotype correlation remains poorly understood. It is characterized by progressive lower limb spasticity resulting in walking difficulties. SPG8 is more severe than other types of
* Federica Ginanneschi [email protected] 1
Department of Medical, Surgical and Neurological Sciences, University of Siena, Policlinico Le Scotte. Viale Bracci 1, 53100 Siena, Italy
2
Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy
3
Department of Biology, University of Pisa, Pisa, Italy
HSP and patients become wheelchair bound in the fourth to fifth decade of life [3]. Other features may include upper limb spasticity, impaired vibration sense in the distal lower limbs, and urinary urgency or incontinence, and, occasionally, spastic dysarthria and moderate dysphagia may be caused by upper motor neuron pathology. Unspecific abnormalities at brain magnetic resonance imaging (MRI) have been reported. A complex form has been described,
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