Spastic Paraplegia 73 via the CPT1C Gene

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by bilateral lower extremity spasticity (rigid muscles) and weakness (Fink et al. 2014. PubMed ID: 25192507; Hensiek et al. 2015. PubMed ID: 25480570; Hedera. 2018. PubMed ID: 20301682). HSP is classified as “pure” or “uncomplicated” when symptoms are confined to lower extremity spasticity and weakness and hypertonic urinary bladder. In contrast, HSP is classified as “complex” or “complicated” if the impairments in the lower limbs are also accompanied by other systemic or neurologic abnormalities such as seizures, ataxia, intellectual disability, dementia, peripheral neuropathy, and vision and hearing impairment (Fink. 2014. PubMed ID: 25192507; Hedera. 2018. PubMed ID: 20301682). The incidence of all forms of HSP is estimated to be less than one in 10,000 individuals or 0.01% (Hensiek et al. 2015. PubMed ID: 25480570).

Symptoms of the disease may begin at any age, with early onset HSP starting in early childhood and often resembling spastic diplegic cerebral palsy and late onset HSP beginning later in childhood or early adulthood (Fink. 2014. PubMed ID: 25192507; Hedera. 2018. PubMed ID: 20301682). In addition to variation in the age of onset, the severity and rate of progression are highly variable among different subtypes of complex HSPs, and even within a specific subtype (Tesson et al. 2015. PubMed ID: 25758904).

Spastic paraplegia 73 (SPG73) is characterized by adult-onset spasticity and weakness of the lower limbs resulting in walking abnormalities, hyperreflexia with extensor plantar responses, and decreased vibratory sensation. Additional features may include muscle atrophy, urinary dysfunction, foot deformities, and motor delay (Rinaldi et al. 2015. PubMed ID: 25751282; D'Amore et al. 2018. PubMed ID: 30564185; Hong et al. 2019. PubMed ID: 30911584). SPG73 has been reported in a small number of patients. In addition to the adult-onset form of HSP, a congenital-onset form of HSP has been reported recently in a SPG73 family (Hong et al. 2019. PubMed ID: 30911584). Variable expressivity is documented even among family members who carry the same variant (Hong et al. 2019. PubMed ID: 30911584).

Advantages of genetic testing for HSP include confirmation of diagnosis, identification of other health risks associated with complicated HSP, targeted testing of other family members, and assistance with reproductive planning (Hedera. 2018. PubMed ID: 20301682).

To date, more than 90 genetic loci and over 70 genes have been shown to be involved in HSP (Tesson et al. 2015. PubMed ID: 25758904; de Souza et al. 2017. PubMed ID: 27271711). HSP may be inherited in an autosomal dominant (AD) (75% to 80% of cases), autosomal recessive (AR) manner (25% to 30%); or X-linked (XL) (1% to 2%) manner (Hensiek et al. 2015. PubMed ID: 25480570; Hedera et al. 2018. PubMed ID: 20301682). The genotype-phenotype correlation is poor, and some genes are associated with both complex and pure HSP (Fink. 2013. PubMed ID: 23897027).

SPG73 is inherited in an AD manner and is caused by pathogenic variants at the 19q13.33 locus in the CPT1C (carnitine palmitoyltransferase 1C) gene. To date, four variants (2 missense, 1 nonsense, and 1 splicing) in CPT1C have been reported in patients with SPG73 (Rinaldi et al. 2015. PubMed ID: 25751282; D'Amore et al. 2018. PubMed ID: 30564185; Hong et al. 2019. PubMed ID: 30911584). The exact mechanism of disease remains to be elucidated, although loss-of-function and dominant negative mechanisms have been proposed (Rinaldi et al. 2015. PubMed ID: 25751282; Hong et al. 2019. PubMed ID: 30911584). No definitive instances of de novo pathogenic variants have been reported.

An Italian study which conducted molecular screenings on 239 consecutive HSP index cases identified two patients with missense variants in CPT1C (D'Amore et al. 2018. PubMed ID: 30564185). Both missense variants were reported in few individuals in control population databases, which may be explained by the adult-onset conditions in SPG73 or incomplete penetrance.

The CPT1C gene encodes a carnitine palmitoyltransferase, which is localized to the endoplasmic reticulum. It was reported that CPT1C regulates late endosome/lysosome anterograde transport and axon growth in neurons (Palomo-Guerrero et al. 2019. PubMed ID: 31868590). CPT1C has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). Studies in homozygous knockout mice showed muscle weakness, ataxia, dyscoordination, spatial learning deficits, and impaired body energy homeostasis (Carrasco et al. 2012. PubMed ID: 22539351; Carrasco et al. 2013. PubMed ID: 23973755; Rodríguez-Rodríguez et al. 2019. PubMed ID: 30448371). Heterozygous knockout mice have not been characterized in the literature.

Pathogenic variants in CPT1C appear to be a rare cause of spastic paraplegia. Approximately 40% of AD HSPs are caused by pathogenic variants in SPAST (Shribman et al. 2019. PubMed ID: 31377012), while variants in ATL1, KIF5A, and REEP1 make up another 20% of HSPs (Schlipf et al. 2010. PubMed ID: 20461110). It is expected that clinical sensitivity for SPG73 will be low.

Analytical sensitivity should be high as all reported pathogenic variants are detectable by sequencing.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CPT1C gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).