Invitae Hereditary Spastic Paraplegia X-linked Panel

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that is subdivided into complicated (i.e. syndromic) and uncomplicated forms. All forms of HSP, complicated and uncomplicated, share the primary symptom of lower-extremity spastic weakness. Individuals with complicated HSP exhibit additional neurologic features such as intellectual disability, seizures, ataxia, peripheral neuropathy, deafness, cataracts, retinal degeneration, or muscle atrophy, depending on which gene is causative.

X-linked HSP cases are primarily complicated forms of HSP. ABCD1 is associated with adrenoleukodystrophy, which is characterized by symptoms of adrenocortical insufficiency and cerebral demyelination. Adrenoleukodystrophy has been reported to present as HSP in some cases and is included in the X-linked HSP panel due to this phenotypic overlap. Pathogenic variants in L1CAM cause L1 syndrome, which encompasses a range of phenotypes, including hydrocephalus with stenosis of aqueduct of Sylvius (HSAS), MASA syndrome (intellectual disability, aphasia, spastic paraplegia, adducted thumbs), spastic paraplegia with intellectual disability, and corpus callosum agenesis. Pathogenic variants in PLP1 also cause a spectrum of phenotypes, from Pelizaeus-Merzbacher disease (PMD), an early-onset syndrome that causes serious deficits in many aspects of the nervous system, to spastic paraplegia with onset in childhood to adulthood (SPG2). SLC16A2 is associated with MCT8-specific thyroid hormone cell transporter deficiency, also known as Allan-Herndon-Dudley syndrome, which is characterized by hypotonia, intellectual disability, and spasticity. KDM5C is associated with a syndromic form of intellectual disability, termed Claes-Jensen type, which includes spasticity and variable dysmorphic features.

^*Preliminary-evidence gene

Due to the rarity of X-linked HSP, the detection rate for the genes included in this assay is currently unknown.

This test is specific for subtypes of HSP that are inherited in X-linked pattern.

The penetrance of HSP varies depending on the causative gene and the specific pathogenic variant. Pathogenic variants in ABCD1, KDM5C, L1CAM, PLP1, and SLC16A2 are highly penetrant, although these genes are associated with a range of phenotypes. The symptoms associated with these genes typically manifest in early childhood, with the exception of some cases of SPG2 and adrenoleukodystrophy, for which onset may occur in adulthood.

The disorders associated with ABCD1, KDM5C, L1CAM, PLP1, and SLC16A2 are rare. The prevalence of adrenoleukodystrophy is 1 in 20,000, for L1 syndrome it is approximately 1 in 30,000 and for PLP1-associated disorders it is between 1 in 200,000 and 1 in 500,000. AHDS and MRXSCJ are very rare, with a prevalence estimated at less than 1 in 1,000,000.

The clinical presentation of HSP can be variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression or inform family planning.