Genetic characterization of primary lateral sclerosis

Current consensus criteria for PLS state that there is limited or no place for genetic testing in the work-up for PLS [8]. However, a very limited number of studies has been conducted on the genetics of PLS and as a result the data supporting this statement is sparse.

In an attempt to clarify what the contribution of genetics is to PLS susceptibility, Silani and colleagues reviewed the literature [32]. They note that in previous diagnostic criteria (Pringle) a negative family history was required [6], which was mainly meant to differentiate between PLS and HSP. However, in later criteria this requirement was dropped, as rare pedigrees with multiple PLS cases have been reported. This review identified reports of C9orf72 repeat expansions in 3 PLS patients and single cases with mutations in FIG4, UBQLN2, OPTN and DCTN1. They conclude that the finding of ALS mutations in PLS cases is rare, but also acknowledge that study sizes were limited [32].

The largest of these studies was performed by van Rheenen, et al. (n = 110), but only analyzed C9orf72 repeat expansions [25]. The only other relatively large study was performed by Mitsumoto, et al. (C9orf72 and exome sequencing), which included 34 PLS patients with disease duration of > 5 years. This study found 18% of patients to carry a variant in either ALS (C9orf72), Parkinson disease (PARK2, LRRK2) or HSP (SPG7) genes [33]. All other studies had sample sizes smaller than 10 or were case reports on single cases or pedigrees [32]. Therefore, firm conclusions regarding the frequency of pathogenic or likely pathogenic variants in PLS cannot be reached.

In our cohort, which is the largest to date, we found genetic variants in ALS or movement disorder genes in 31 out of 139 cases (22%). It must, however, be noted that a considerable portion of these (n = 21) are variants of unknown significance. It is likely that some of these variants are not clinically relevant, such as the ABCD1 variant we identified.

To provide better interpretation of variants of unknown significance, it remains crucial that they are reported in clinical and scientific reports. Only by doing so, will evidence accumulate over time and therefore allow us to accurately interpret the clinical relevance of these variants. Likely pathogenic or pathogenic variants were found in 7% of our cohort. These findings raise the complicated question of how to diagnostically classify the cases carrying (pleiotropic) ALS and HSP/CMT variants. For example, in case 9 in which a NEFL variant was identified, which is associated with CMT [34], and HSP [35]. This specific patient had bulbar and upper extremity involvement and met the criteria for definite PLS, making the clinical phenotype more compatible with PLS than HSP according to the treating physicians. According to the current consensus criteria genetic testing would not be warranted in this patient, while we believe that based on these genetic results the phenotype should be considered HSP-plus rather than PLS.

The revised El Escorial criteria for ALS state that patients with progressive upper and/or lower motor neuron signs and a family history of a defined pathogenic ALS mutation meet the criteria for “clinically definite familial ALS – Laboratory-supported” [36]. This means only progressive upper motor neuron signs in combination with a mutation in an ALS gene suffices. Therefore, it would seem reasonable to diagnose patients with PLS phenotypes carrying ALS variants as atypical or slow forms of ALS.

The Turner criteria state that testing for HSP genes should only be considered in patients with symmetrical involvement of the lower limbs [8]. Although it is uncommon, HSP patients with one-sided symptoms have been described [14, 15], and this is also seen in 2 of our cases with a (likely) pathogenic variant (“ALS-HSP-CMT overlap group”). It is even relatively common for patients with pure HSP to experience some degree of asymmetry of severity of symptoms in their legs [37, 38]. Apart from asymmetry, arm involvement (so UMN involvement in two regions) has also been documented in HSP patients [13, 39], as well as dysarthria which is reported frequently [39]. A study by Brugman et al. studied whether it was possible to differentiate sporadic HSP from PLS based on clinical presentation and concluded that this is unreliable in most cases [40]. Similarly, it seems reasonable to diagnose patients with PLS phenotypes carrying HSP variants as atypical forms of HSP.

Not all patients with a positive family history for MND or suspect for HSP/CMT in our cohort had a genetic variant identified. Despite the negative genetic findings in these cases, the family history is suggestive of a genetic cause of the disease. Indeed, it is not uncommon that in cases of HSP (also with a positive family history) the disease-causing gene is not found. Mereaux et al. performed genetic testing in a large cohort of HSP cases (1550) and pathogenic/likely pathogenic variants were found in 23.9–54.2% of the familial cases (variating between inheritance) and 26.6% of the isolated cases [16]. 5–15% of the ALS cases is familial and in 60–80% a disease-causing variant can be found (mostly C9orf72, SOD1, FUS and TARDBP) [2]. Therefore, our current knowledge of HSP and ALS genetics is incomplete. However, progress in genetic research is occurring at an ever-increasing pace and it seems highly likely that additional novel HSP and ALS genes will be discovered over the next few years. It also seems highly likely that variants in these genes will also be identified in PLS cases.

The diagnostic yield of genetic testing for HSP and ALS genes in PLS is 7% based on our findings.

We do believe that based on the results of Mitsumoto et al. [33] and our cohort, genetic analyses could have a role in the diagnostic work-up of PLS and should not be limited to patients with only symmetrical involvement of the legs.

Incorporating genetic testing in the work-up of patients with primary pyramidal disorders could lead to clarity regarding the underlying diagnosis for individual patients. Furthermore, it may also provide patients with additional information with regards to their prognosis. There are substantial differences between ALS, PLS and HSP in the rate of disease progression, degree of disability the disease will eventually cause as well as in life-expectancy. Although, this will become apparent over time, in the early stages of the disease this is frequently not clear, causing uncertainty and distress to patients. A desire for pregnancy (among relatives) may also be a reason to have clarity on whether there is a hereditary cause of the disease.

As the prices for DNA sequencing have dramatically dropped over the last couple of years, it is to be expected that genetic testing will become more widely available in the nearby future. DNA testing may, however, also yield results that are difficult to interpret, such as variants of unknown significance, and thereby provide the opposite of clarity. Genetic testing should therefore only be requested by skilled physicians with an up-to-date knowledge of the genetics of motor neuron diseases, who are capable of interpreting and adequately communicating results to patients. An infrastructure to provide genetic counselling to at risk family members should also be in place, to ensure that complicated topics such as mode of inheritance, disease penetrance and prenatal diagnostic testing are discussed appropriately. The decision to perform genetic testing in clinical practice is complex and should, in our opinion always be reached through shared decision making.

This paper offers an in-depth genetic characterization of the largest PLS cohort to date. Our findings show that patients with clinical phenotypes compatible with PLS may carry (likely) pathogenic variants in ALS and/or HSP genes. This raises the question whether PLS is a distinct disease entity or represents endophenotypes within the spectrum of different diseases such as ALS and HSP? The fact that there is no gold standard for PLS complicates this even further.

A limited number of histopathological reports on PLS patients are available, of which some predate the identification of TDP-43. Findings have been heterogeneous and perhaps these publications contain a bias towards unusual cases [41]. Of note, however are recent post-mortem studies by Mackenzie et al. that demonstrated TDP-43 pathology and degeneration of upper motor neurons, with preservation of lower motor neurons and less TDP-43 pathology in seven PLS cases [42]. The addition of a histopathological gold standard to the formal criteria for PLS would constitute a major step forward and should be focused on future efforts.

Similarly prospective data, including genetic results, on larger, international cohorts of PLS patients would also provide additional clarity. Potentially, genome-wide association studies or whole-genome sequencing studies of international PLS cohorts could lead to the identification of novel disease genes or phenotypic modifiers, that are associated with PLS. Understanding the underlying pathophysiology of PLS would be major step forward and could potentially guide therapy development, such as antisense based approaches.

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