Abstract
The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally.
Highlights
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of monogenic neurodegenerative diseases characterised by progressive spasticity of the lower limbs, with a pooled global prevalence of 1.8/100,000 [1]
We present our genetic and clinical findings of PTPN23-related complex HSP identified in a Palestinian community, alongside a review of recently published candidate PTPN23 sequence alterations which together define biallelic PTPN23 sequence alterations as a cause of complex HSP associated with microcephaly
Eight individuals affected by a microcephalic form of complex HSP were identified from a single extended pedigree
Summary
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of monogenic neurodegenerative diseases characterised by progressive spasticity of the lower limbs, with a pooled global prevalence of 1.8/100,000 [1]. HSPs are subclassified into either (i) uncomplicated (or pure) when neurologic impairment is limited to progressive lower-extremity spastic and weakness, hypertonic urinary bladder disturbance, and mild diminution of lower-extremity vibration sensation or (ii) complicated (or complex) when these features are accompanied by other neurological or non-neurological signs [2]. Advancements in our understanding of the genetic architecture of HSP have led to it being recognised as one of the most genetically heterogeneous of inherited disorders, with pathogenic sequence alterations in affected families identified in at least 72 genes in molecules associated with a plethora of cellular roles [3]. The specific cellular roles of PTPN23 include interactions with mitogen-activated protein kinase signalling (MAPK) pathways [9], ciliogenesis [10], and regulation of splicing through regulation of survival of motor neurone (SMN) [11]. We present our genetic and clinical findings of PTPN23-related complex HSP identified in a Palestinian community, alongside a review of recently published candidate PTPN23 sequence alterations which together define biallelic PTPN23 sequence alterations as a cause of complex HSP associated with microcephaly
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