Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred

Abstract

BackgroundThe hereditary spastic paraplegias (HSPs) are pleiomorphic disorders of motor pathway and a large number of affected genes have been discovered. Yet, mutations in SPG4/SPAST represent the most frequent molecular etiology in autosomal dominant (AD) patients and sporadic cases. We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5′UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner.Case presentationA 54-year-old woman manifested leg stiffness at age 39 and required a cane to walk at age 50. Neurological examination disclosed mild spasticity and weakness in the legs, hyperreflexia in all limbs, and bilateral Babinski sign. She also complained of urinary urgency, but no additional neurological symptoms or signs were detected at examination. The clinical examination of 24 additional relatives disclosed three further affected individuals, two men and one woman. In the four symptomatic patients the initial manifestations were walking abnormalities and leg stiffness with a mean age at onset (SD) of 46.75 (5.44) years (range 39–51). The mean disease duration was 13.2 (13.4) years (range 6–35), and it correlated well with clinical severity (SPRS score) (r = 0.975, p = 0.005). One patient was confined to bed and displayed knee and ankle contractures, another case needed a cane to walk, and two individuals were able to walk without aids. Interestingly, a patient had also had a miscarriage during her first pregnancy.Gene testing revealed an heterozygous deletion spanning from the 5′-UTR to intron 4 of SPAST in the affected individuals and in one clinically unaffected woman. In three affected patients, the deletion also determined low mRNA levels of SPAST and DPY30, a component of the Set1-like multiprotein histone methyltransferase complex located upstream, head-to-head with SPAST.ConclusionTogether with data described in a Japanese family, our findings seem to suggest that genes close to spastin might be candidates in modulating the clinical phenotype. This report endorses future research on the role of neighboring genes as potential players in SPG4 disease variability.

Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience

“…So far, at least 64 genes (the SPastic Gait/Gene or SPG genes) have been characterized, and further HSP loci have been mapped [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Most autosomal dominant (AD)-HSPs are pure, and SPG4, due to mutations in SPAST , is the most common genetic variant [ 1 , 2 , 3 ] Mutations in ATL1 (SPG3A), REEP1 (SPG31), and KIF5A (SPG10) are also relatively frequent; when combined with SPG4, these forms account for about 50–60% of AD-HSP families [ 8 , 9 , 10 ].…”

“…SPG11, due to mutations in the spatacsin gene, is the most frequent form, including about 20% of all AR-HSP and up to 45% of AR-HSP with a thin corpus callosum (TCC) [ 11 , 12 ]. Additional genes, including CYP7B1 (SPG5), paraplegin (SPG7), and ZFYVE26 (SPG15) [ 7 , 8 , 9 , 10 ], totally account for another 20% of AR-HSP. While X-linked HSPs are extremely rare [ 1 , 2 , 3 ], it is noteworthy that specific HSP genes have been recently associated with both AD and AR forms, depending on the effect of the mutations [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”