Abstract
Spastic paraplegia type 64 (SPG64; OMIM 615683) is a complicated form of hereditary spastic paraplegia (HSP) recently identified in individuals diagnosed with suspected neurodegenerative disease. Affected patients carry homozygous mutations in the ectonucleoside triphosphate diphosphohydrolase 1 gene (ENTPD1). Although they share common characteristics, affected individuals show slight discrepancies in some clinical aspects. At present, only two different cases of SPG64 have been diagnosed. More findings of genetic variation would be helpful to better understand the effect of mutations in the ENTPD1 gene on the neurological condition of affected individuals. In this study, we examined a family with an individual diagnosed with suspected HSP based on clinical findings. DNA samples from the proband, her affected sister, and both parents were analyzed using next-generation sequencing. We used an in-house automated pipeline to detect potential neuromuscular disease-causing variants. Variants were confirmed by Sanger sequencing. After cosegregation analysis, the variant NM_001776.5:c.401T>G (p.M134R) of the ENTPD1 gene was identified as a novel missense mutation linked to the phenotype of SPG64 in the proband and her sister, who showed similar and distinct clinical features compared with the two cases previously described in the literature.
Highlights
Hereditary spastic paraplegias (HSPs) are a group of rare and heterogeneous genetic neurodegenerative diseases
HSPs are a group of heterogeneous genetic neurodegenerative diseases
In terms of amino acid structure, this variant leads to a single change, p.M134R, in the extracellular domain of ENTPDase-1 [UniProtKB—P49961 (ENTP1_HUMAN); https://www.UniProt.org/UniProt/ P49961]
Summary
Hereditary spastic paraplegias (HSPs) are a group of rare and heterogeneous genetic neurodegenerative diseases. They are characterized by length-dependent distal axonal degeneration, which causes a loss of function of the corticospinal tract, resulting in progressive lower limb spasticity. HSPs are classified into two broad categories, uncomplicated and complicated, based on the manifestation of additional features, such as ataxia, delayed psychomotor development, dysarthria, mental retardation, and visual defects[1]. It is very difficult to make a reliable diagnosis of a specific HSP based solely on individual history, physical and physiological examinations, and magnetic resonance imaging (MRI). Like many other hereditary neurodegenerative disorders, the final diagnosis of HSP is usually made after genetic testing confirms the presence of a mutation known to be linked to the suspected specific type of the disease
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