Description 

Neurodegenerative diseases are characterized by progressive loss of neurons along with deposition of misfolded proteins throughout the body, leading to clinical symptoms such as cognitive decline and movement problems. Conditions that fall within this classification include Parkinson Disease, dystonia, ataxia and more (Kovacs, 2016).

This policy does not address Alzheimer Disease or ataxia due to mitochondrial disorders.

Regulatory Status 
Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). FDA clearance or approval is not currently required for clinical use. 

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. Genetic counseling IS REQUIRED for individuals prior to and after undergoing genetic testing for diagnostic, carrier, and/or risk assessment purposes.

Amyotrophic Lateral Sclerosis (ALS)

2. For diagnosis in individuals with suspected ALS and a first-degree or second-degree relative (see Note 1) with ALS or frontotemporal dementia, genetic testing for ALS, including the genes C9ORF72, SOD1, TARDBP, and FUS,  is considered MEDICALLY NECESSARY.

Ataxias, including Friedreich ataxia

3. For individuals with sporadic ataxia or a family history compatible with an inherited cerebellar ataxia with no known deleterious familial mutation, single gene testing (when a specific ataxia is suspected) or multi-gene panel testing (when a specific ataxia is not suspected)  is considered MEDICALLY NECESSARY.
4. To confirm a diagnosis in individuals with suspected ataxia-telangiectasia, genetic testing for ATM is considered MEDICALLY NECESSARY.

Dystonias

5. Genetic testing of TOR1A (formerly DYT1) is considered MEDICALLY NECESSARY in the following situations:
   1. In individuals with limb-onset, primary dystonia before the age of 30 years.
   2. In individuals with limb-onset, primary dystonia with onset after age 30 when there is a family history compatible with early-onset dystonia.
6. Genetic testing of THAP1 (formerly DYT6) is considered MEDICALLY NECESSARY in the following situations:
   1. In individuals with an early-onset dystonia or familial dystonia with cranio-cervical predominance.
   2. In individuals with early-onset dystonia after exclusion of TOR1A-associated dystonia.
7. To aid in the diagnosis of symptomatic individuals with familial paroxysmal nonkinesigenic dyskinesia (PNKD), genetic testing of PNKD is considered MEDICALLY NECESSARY.
8. In individuals with paroxysmal exercise-induced dyskinesia, genetic testing of SLC2A1 (formerly GLUT1)is considered MEDICALLY NECESSARY if the individual has at least one of the following:
   1. A history of epileptic seizures.
   2. Hemolytic anemia.
   3. A low CSF/serum glucose ratio.
9. In asymptomatic individuals, genetic testing of TOR1Ais considered NOT MEDICALLY NECESSARY.

Hereditary Spastic Paraplegia (HSP)

10. To confirm clinical diagnosis and to determine the genetic type of Hereditary Spastic Paraplegia (HSP), genetic testing for HSP is considered MEDICALLY NECESSARY.

Huntington disease (HD)

11. Genetic testing for Huntington disease is considered MEDICALLY NECESSARY in the following situations:
    1. When an adult patient presents with an otherwise unexplained clinical syndrome of a progressive choreatic movement disorder and neuropsychiatric disturbances.
    2. In an adult patient with a positive family history of the disease.
    3. In a juvenile patient with the following:
       1. A known familial history of HD.
       2. Presenting with two or more of the following:
          1. Declining school performance
          2. Seizures
          3. Oral motor dysfunction
          4. Rigidity
          5. Gait disturbance

Parkinsonism, including Parkinson disease

12. Genetic testing of SNCAis considered MEDICALLY NECESSARY for an individual only if there is a family history with multiple affected members in more than one generation suggestive of dominant inheritance.
13. Genetic testing of LRRK2is considered MEDICALLY NECESSARY in the following situations:
    1. In symptomatic individuals with a positive family history suggestive of dominant inheritance.
    2. In symptomatic individuals belonging to a population with known high mutation frequencies of the LRRK2 gene (i.e., Ashkenazi Jews, Imazighen, and Euskaldunak).
14. Genetic testing of the PRKN (formerly PARK2 or parkin) PINK1, and PARK7 (formerly DJ-1) genes is considered MEDICALLY NECESSARYin the following situations:
    1. In individuals with an onset of disease by the age of 50 years with a positive family history suggestive of recessive inheritance.
    2. In individuals with an onset of disease by the age of 40 years regardless of family history.
15. Genetic testing of the ATP13A2, PLA2G6, and FBXO7 genes is considered MEDICALLY NECESSARY only when all of the following conditions are met:
    1. With onset of disease by the age of 40 years
    2. Prior testing of PRKN, PINK1, and PARK7 genes was negative for known pathogenic variants.

Spinal Muscular Atrophies (SMA)

16. To diagnose individuals suspected of having SMA, genetic testing for SMA (SMN1 deletion/mutation and SMN2 copy number) is considered MEDICALLY NECESSARY.

Wilson disease (WD)

17. Genetic testing of ATP7Bis considered MEDICALLY NECESSARY in the following situations:
    1. To confirm a diagnosis of Wilson disease in a symptomatic individual.
    2. In a first-degree relative (see Note 1) of an individual with known ATP7B mutation to guide potential therapy.

NOTES:

Note 1: First-degree relatives include parents, full siblings, and children of the individual. Second-degree relatives include grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings of the individual.

Note 2: For 2 or more gene tests being run on the same platform, please refer to CAM 235 Reimbursement Policy.

Table of Terminology

Rationale
Neurodegenerative diseases are characterized by progressive loss of neurons along with deposition of misfolded proteins throughout the body. These misfolded proteins have altered biochemical properties, causing dysfunction. Clinical symptoms may include cognitive decline (primarily dementia) and movement problems (cerebellar dysfunction, hyper- or hypo-kinesia, etc.). The molecular spectrum of these disorders may vary, but typically involve oxidative or neuroinflammatory damage (Kovacs, 2016).

Ataxias (including Friedreich ataxia)
Ataxias encompass the set of conditions that are characterized by “motor incoordination resulting from dysfunction of the cerebellum and its connections” (Opal & Zoghbi, 2024b). This policy focuses on progressive and degenerative ataxias, which are further subdivided into autosomal dominant, autosomal recessive, and X-linked forms.

Friedreich ataxia is the most common hereditary ataxia and is inherited in an autosomal recessive manner. Most cases are caused by mutations in the frataxin gene (FXN), which is responsible for transport and management of iron. The frataxin mutation is typically an expanded trinucleotide (van de Warrenburg et al.) repeat in the first intron of the frataxin gene, which reduces expression of frataxin. Severity of phenotype varies with the number of repeats; larger repeats are generally more severe. Impaired iron management leads to a variety of clinical symptoms, such as neurological problems (progressive ataxia, dysphagia, motor weakness, loss of tendon reflexes, etc.), cardiomyopathy, diabetes mellitus, and skeletal deformities. Clinical findings may suggest Friedreich ataxia, but diagnosis is generally confirmed through genetic testing (Opal & Zoghbi, 2023).

Another autosomal recessive ataxia is ataxia-telangiectasia (AT). AT is caused by a defective gene on chromosome 11q22.3, leading to faulty DNA repair mechanisms. This gene (designated AT “M” for mutated) primarily regulates the cell cycle and prevents the cell cycle from progressing if there is DNA damage. When this gene fails, somatic mutations may accumulate. Symptoms such as immune deficiency, cerebellar ataxia, unusual eye movements, and other neurologic abnormalities are characteristic of ataxia-telangiectasia. Ataxia is one of the first clinical symptoms of patients with AT, but other organ systems are usually affected, such as the skin and circulatory system. Similarly, ataxia-telangiectasia-like disorder (ATLD) can affect individuals similarly to AT; however, ATLD is due to mutations within the MRE11A gene involved in double-strand DNA break recognition and repair. The rate of neurodegeneration in ATLD is typically slower than AT. ATLD is more rare than AT; however, “it is estimated that as many as 5 percent of AT cases may be incorrectly diagnosed and actually have ATLD, given the similarity in clinical manifestations and coding sizes of the two affected genes” (Opal, 2024).

Spinocerebellar ataxias (SCAs) are the most common autosomal dominant ataxias. At least 30 types of SCAs with varying phenotypes occur, although, cerebellar ataxia is a primary feature of each type. For example, SCA1 is characterized by dysarthria and bulbar dysfunction whereas SCA2 is characterized by “slow saccadic eye movements.” Several SCA types have a signature CAG repeat beyond what is present in the wildtype; this expansion is pathogenic. As with Friedreich ataxia, larger number of repeats usually lead to more severe symptoms. The four most common SCAs are SCA1, 2, 3, and 6, and each type is caused by a different pathogenic mutation. Below is a table displaying each SCA, its distinguishing features, and its primary associated gene (Opal & Zoghbi, 2024a). 

Jacobi et al. (2015) described the disease progression of SCAs 1, 2, 3, and 6. A total of 462 patients were evaluated on the Scale for the Assessment and Rating of Ataxia (SARA). Annual SARA score increase was 2.11 for SCA1 patients, 1.49 for SCA2, 1.56 for SCA3, and 0.80 for SCA6. The increase of non-ataxia signs plateaued in types 1, 2, and 3. SCA6 symptoms were found to increase more slowly than the other three types. Factors associated with a faster increase of SARA score across all types were short duration of follow-up, older age at inclusion (per additional year), and longer repeat expansions (per additional repeat unit) (Jacobi et al., 2015).

Reetz et al. (2015) examined the effect of the number of GAA repeats in the FXN gene on clinical symptoms of Friedreich’s Ataxia (FA). A total of 592 patients with FA were sequenced and evaluated. The authors found that with every 100 GAA repeats, the age of onset was 2 – 3 years earlier. Disease progression was also found to be faster in patients with more repeats; the annual worsening of the Scale for the Assessment and Rating of Ataxia (SARA) score was 1.04 points per year and 1.37 points per year for early and intermediate onset (≤ 14 and 15 – 24 years, respectively), compared to 0.56 points per year for late-onset patients (≥ 25 years) (Reetz et al., 2015).

Leotti et al. (2021) examined the contribution that the expanded CAG repeat length has on the rate of disease progression in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). Expanded CAG repeat in ATXN3 is the mutation that causes SCA3/MJD, and the length of CAG repeat can determine the age of onset of clinical symptoms. The authors studied 82 patients with SCA3/MJD over 15 years using the International Cooperative Ataxia Rating Scale (ICARS) and found that “The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients.” The authors concluded that the length of CAG repeat in ATXN3 has major influence over clinical symptoms (Leotti et al., 2021). 

Schuermans et al. (2023) performed an observational study to assess the diagnostic value of exome sequencing and multigene panel analysis for adult-onset neurologic disorders, including ataxias. In 2019, 6 diagnostic gene panels were introduced at the center for Medical Genetics of the Ghent University Hospital to diagnose patients with neurologic disorders. One of these panels was for ataxia and spasticity and included 390 genes. While the most common ataxia genes were not included in this panel, only 33% of the diagnosed patients had first been tested for SCAs, Friedrich ataxia, or fragile X tremor/ataxia syndrome. The panels included single nucleotide variants, small indels, and copy number variants. Of the panels and targeted patient populations examined by the authors, the multi-gene panel for ataxia and spasticity had the highest diagnostic yield, identifying the causal pathogenic variant (s) in 19% of the assessed patients (70 of 365) (Schuermans et al., 2023).

Dystonias
Dystonias are a class of movement disorders characterized by “sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both” (Deik & Comelia, 2023). Movements are typically twisting or patterned and are often worsened by voluntary action. The basic neurochemistry of dystonia is unknown (and without consistent findings), and cell degeneration is typically not seen. However, some types of dystonia (particularly early-onset versions) have clear associations with certain genes. For example, TOR1A and THAP1 both carry pathogenic mutations for early-onset dystonia. TOR1A (DYT1) encodes a protein that binds to ATP (torsin A) while THAP1 (DYT6) encodes a transcription regulator for torsin A (Deik & Comelia, 2023).

Dystonias are divided into classes or types. They can be focal (involving a single site), multifocal segmental (involving region(s) of the body), generalized (involving the trunk and at least two additional sites), or hemidystonia (affecting only one side of the body). The etiology of the disorder can be either idiopathic or of known causation. Dystonias can be due to trauma or may be inherited. Those forms of proven genetic origin can be inherited in different inheritance patterns, including autosomal dominant, autosomal recessive, X-linked recessive, or even mitochondrial inheritance. The most common inherited form of dystonia is DYT-TOR1A (or DYT1) dystonia. DYT-TOR1A accounts for approximately 40% – 65% of early-onset generalized dystonia in populations other than the Ashkenazi Jewish population. Within the latter population, DYT-TOR1A is estimated to account for 90% of these cases (Deik & Comelia, 2023). Even though DYT-TOR1A dystonia is inherited in an autosomal dominant pattern, the penetrance is only 30% (Bressman, 2004; Deik & Comelia, 2023; Ozelius & Lubarr, 2016). Paroxysmal dyskinesia with dystonia (PKND) is a special class of dystonia that involves spontaneous episodes of dystonia. Several environmental factors have been proposed to precipitate these episodes, such as stress, caffeine, and fatigue. The primary gene associated with PKND is MR1, or DYT8. Another special class of dystonia is myoclonus-dystonia, which is characterized by short, involuntary movements of the neck or arms in addition to normal dystonia symptoms. The main established type of myoclonus-dystonia is caused by mutations in the SGCE (DYT11) gene (Deik & Comelia, 2023). 

Zech et al. (2017) performed whole exome sequencing on 16 patients with “genetically undefined early-onset generalized dystonia.” Six patients had mutations of known dystonia-related genes. The mutated genes were GCH1, THAP1, TOR1A, ANO3, and ADCY5. The authors noted GCH1, THAP1, and TOR1A as associated with isolated, generalized dystonia and ANO3 and ADCY5 associated with a combined myoclonus-dystonia phenotype (Zech et al., 2017).

Parkinsonism (Parkinson Disease, PD)
Parkinsonism is a constellation of symptoms with “any combination of bradykinesia, rest tremor, rigidity, and postural instability.” The most common form of parkinsonism is Parkinson disease (PD), a progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the brain (Chou, 2024b). The pathogenesis of PD is driven by loss of dopamine from the basal ganglia in the brain; though a number of compensatory mechanisms may mitigate this loss of dopamine, the progression of disease eventually leads to clinical symptoms (Jankovic, 2024). The “cardinal” features of PD are “tremor, bradykinesia, and rigidity”; postural instability is commonly considered a defining feature, yet it typically manifests late in the course of disease. Other motor symptoms such as dysphagia, blurred vision, shuffling, are common; these secondary motor symptoms are commonly derived from the cardinal features. Nonmotor symptoms include cognitive deterioration, dementia, and other mood disorders (Chou, 2024a).

The exact cause of PD is unknown, but several genetic factors have been Identified. These genes do not imply a particular phenotype, and each mutation vary in severity of symptomology. Genes associated with PD are SNCA (PARK1/4), LRRK2 (PARK8), PINK1, PARK2, DJ-1 (PARK7), and GBA (Jankovic, 2024).

GBA- (glucocerebrosidase) associated PD is coupled with the lysosomal storage condition known as Gaucher disease, which is commonly seen in Ashkenazi Jews (Jankovic, 2024). Sidransky et al. (2009) compared PD patients with a GBA mutation to those with PD but without a GBA mutation, and they found that the patients with a GBA mutation had an earlier age of onset and greater chance of cognitive impairment, albeit with less pronounced cardinal features (Sidransky et al., 2009).

SNCA encodes alpha-synuclein. Although its exact role is not well understood, it is thought to function in synaptic plasticity and makes up as much as one percent of total central nervous system protein. Observations suggest a role for mutated alpha-synuclein in the pathogenesis of PD; for example, Lewy bodies, the primary pathologic hallmark of PD, have insoluble, aggregated alpha-synuclein as a major component. It may also be possible for misfolded alpha-synuclein to be transmitted from diseased neurons to healthy ones. PARK1 refers to a missense mutation in SNCA whereas PARK4 refers to a multiplication (Jankovic, 2024).

LRRK2 (leucine-rich repeat kinase-2) encodes a protein called dardarin. Dardarin is thought to function as a kinase for phosphorylation of certain proteins, such as alpha-synuclein and microtubule-associated protein tau. Dardarin may also be implicated in membrane and protein transport. The phenotype of LRRK2 mutations is noted to be less severe than other genotypes of PD; patients have been observed to respond to levodopa, have a later age of onset, and less severe cognitive deterioration (Jankovic, 2024).

PARK2 encodes a protein called parkin. This protein is associated with degradation of certain proteins in wild-type genes; the mutated version of parkin cannot clear proteins, allowing them to aggregate in the neuron. This mutation typically leads to an early-age onset of PD and clinical symptoms, although the severity of these early symptoms does not appear to be significantly worse than other genotypes (Jankovic, 2024).

DJ-1 and PINK1 are both associated with autosomal recessive inheritance and early age of onset (under 50 for PINK1 mutations, under 40 for DJ-1 mutations). PINK1 mutations are possibly associated with mitochondrial dysfunction whereas DJ-1 mutations may lead to increased neuro-oxidative stress (Jankovic, 2024).

Nalls et al. (2014) performed a meta-analysis of genome-wide association studies on PD. A common set of 7,893,274 variants with 13,708 cases and 95,282 controls were evaluated. Thirty-two loci were identified as having genome-wide significant association. These 32 loci were retested in an independent set of 5,353 cases and 5,551 controls, and 24 of these loci replicated their significance. Four loci (GBA, GAK-DGKQ, SNCA, HLA region) were considered to have a “secondary independent risk variant.” The authors noted that the effect of each individual loci was small, but cumulative risk was “substantial” (Nalls et al., 2014).

Maple-Grødem et al. (2021) studied the significance of glucocerebrosidase gene (GBA) carrier status on motor impairment in patients with incident PD. The authors studied 528 patients with PD, using genomic DNA assessment and the Unified Parkinson's Disease Rating Scale (UPDRS). GBA carriers had a faster annual increase in UPDRS score than non-carriers. The authors conclude that “GBA variants are linked to a more aggressive motor disease course over 7 years from diagnosis in patients with PD” (Maple-Grødem et al., 2021).

Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that causes significant motor neuron degeneration all over the body. This causes a variety of neuromuscular problems, such as spasticity, weakness, atrophy, hyperreflexia, cognitive impairment, and eventual death. ALS is divided into two categories: sporadic (90% of cases) and familial (10%) (Elman et al., 2023). 

The primary genes tested in ALS cases are superoxide dismutase (SOD1) and chromosome 9 open reading frame 72 (C9ORF72), both of which lead to familial ALS. The enzyme SOD1 catalyzes toxic superoxide radicals to O2 and H2O2. The mutation thought to be the primary cause of SOD1-mediated toxicity is a gain-of-function mutation, creating many reactive oxygen species. Other hypotheses of SOD1-mediated toxicity include misfolded proteins caused by SOD1 mutations and production of protein aggregates that damage motor neurons (Maragakis, 2023).

C9ORF72 expansions are another common cause of familial ALS. This mutation is a hexanucleotide repeat (GGGGCC) that forms a structure called the G-quadruplex. The exact pathogenic mechanism is unknown, but some hypotheses include creation of defective RNA transcripts and creation of toxic dipeptide proteins that cause RNA processing to falter (Maragakis, 2023).

Chiò et al. (2012) evaluated the genetic landscape of ALS in an Italian cohort. A total of 475 patients were examined, and 51 were noted to carry a mutation associated with ALS. Familial ALS was found in 46 of these patients, and 31 of these 46 were found to have a genetic mutation (leaving 20 mutations in the remaining 429 sporadic cases). After performing a logistic regression, the authors found that the chance to carry a genetic mutation was related to the presence of comorbid frontotemporal dementia by an odds ratio of 3.5 (Chiò et al., 2012).

Vajda et al. (2017) evaluated clinician opinion on genetic testing in ALS. Responses from 167 clinicians in 21 countries were analyzed. Approximately 90.2% of respondents were found to have offered genetic testing to patients they defined as having familial ALS and 49.4% to patients with sporadic ALS. The four main genes tested were SOD1, C9ORF72, TARDBP, and FUS. Further, 42% of respondents did not offer genetic testing to asymptomatic family members of patients with familial ALS (Vajda et al., 2017).

Bandres-Ciga et al. (2019) used publicly available genome-wide association studies to identify shared polygenic risk genetic factors and casual associations in 20,806 ALS cases and 59,804 controls. Positive associations were found with smoking and moderate physical activity levels, and negative associations were found with higher education, cognitive performance, and light physical activity levels. Further, the authors report that “hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest” (Bandres-Ciga et al., 2019). 

Wilson Disease (WD)
Wilson disease (WD) is a condition caused by defective copper transport. This leads to accumulation of copper in several organs, such as the brain, eyes, and liver. Eventually, the liver becomes cirrhotic, while other neurological conditions may develop. The primary gene handling hepatocyte copper transport is ATP7B. Normally, this gene mediates the transport of copper into apoceruloplasmin, which is then secreted into the bloodstream. Mutations in this gene cause impaired binding of copper to the protein, causing copper accumulation in the hepatocyte and eventually the bloodstream (Schilsky, 2024).

Dong et al. (2016) evaluated the genetic spectrum of WD in Chinese patients. A total of 632 patients with WD were compared against 503 controls. Further, 161 variants were found in the WD patents, and 142 were considered pathogenic or “likely pathogenic.” The authors concluded that 569 of the 632 patients (90%) could be diagnosed with two or more “likely pathogenic” or worse variants. Finally, the 14 most common variants were found at least once in 537 of the 569 (94%) genetically diagnosed patients (Dong et al., 2016).

Huntington Disease (HD)
Huntington disease (HD) is a progressive, neurodegenerative disorder characterized by choreiform (brief, abrupt, and involuntary) movements, psychiatric disorders, and eventual dementia. During the early stages of the disease, patients may be able to function day-to-day and perform typical tasks; however, as the disease progresses, patients lose their ability to function independently and require assistance. In the late stages of the disease, patients often become bedridden as cognitive and motor ability continues to decline, with death occurring 10 to 40 years after onset. Currently there is no cure, and the disorder is inherited in an autosomal dominant fashion (Suchowersky, 2023).

Huntington disease is primarily caused by a trinucleotide repeat expansion. A cytosine-adenine-guanine “repeat” encodes for polyglutamine tracts in the huntingtin (HTT) gene, and the “expansion” refers to additional repeats of this trinucleotide side. Approximately 6 – 26 CAG repeats is considered wild-type, 27 – 35 repeats is considered intermediate (i.e., typically do not cause disease but may expand in future generations), and ≥ 36 repeats is considered diagnostic of HD. CAG repeat length is considered to correlate with both rate of disease progression and severity of neurological changes. The CAG repeat expansion leads to a toxic “gain-of-function” of the HTT protein, and although the exact function of this huntingtin protein is unknown, it interacts with several different proteins, implying that it has a function in several cellular events. Mutant huntingtin is seen to disrupt transcription, activation of proteases, synaptic transmission, and more (Zoghbi & Orr, 2023).

Baig et al. (2016) reviewed 22 years of predictive testing performed by the UK’s Huntington Consortium. A total of 9407 predictive tests were performed over 23 testing centers, with 8,441 tests on individuals considered at 50% predictive risk. Of these 8,441, 4,629 were mutation negative and 3790 were mutation positive (with 22 tests as “uninterpretable”). A prevalence figure of 12.3 x 10 - 5 was used to evaluate the “cumulative uptake” of predictive testing at the 50% risk level; this amount was calculated to be 17.4% (the number of individuals at 50% risk that had undergone predictive testing). The authors concluded that the majority of individuals at risk for HD had not undergone predictive testing (Baig et al., 2016).

Spinal Muscular Atrophies (SMA)
Spinal muscular atrophy (SMA) disorders encompass the set of disorders that are characterized by the degeneration of anterior “horn” cells in the spinal cord and motor nuclei in the lower brainstem. This leads to muscle weakness and atrophy, although cognition is unaffected. There are currently five main types of SMA, types 0 to 4. These types are organized by age of onset and clinical presentation, with types 0 and 1 presenting earliest and with the most severe symptoms and type 4 as the least severe phenotype. For example, type 0 presents prenatally and death occurs by six months, whereas type 4 patients usually remain ambulatory and have a normal lifespan (Bodamer, 2023). 

The primary gene mutation occurs in the survival motor neuron 1 (SMN1) gene. This gene encodes a protein that appears to play a role in mRNA synthesis. The most common mutation in SMN1 is a deletion of exon 7, representing up to 94% of SMA patients. Another gene, SMN2, may cause phenotypic changes in SMN1 due to its effect as a gene modifier. SMN2 encodes an extremely similar protein to SMN1 (only one nucleotide difference), and it may compensate for SMN1 loss. Severity of SMA correlates inversely with amount of SMN2 gene copy numbers, which varies from 0 to 8 (Bodamer, 2023).

Zarkov et al. (2015) evaluated the association between clinical symptoms and SMN2 gene copy numbers. Forty-three patients with SMA were examined, and 37 of them had homozygous deletions of SMN1 exon 7. The genetic characterization of these 37 patients were as follows: “One had SMA type I with 3 SMN2 copies, 11 had SMA type II with 3.1 +/- 0.7 copies, 17 had SMA type III with 3.7 +/- 0.9 copies, while 8 had SMA type IV with 4.2 +/- 0.9 copies.” The authors concluded that “a higher SMN2 gene copy number correlated with less severe disease phenotype,” but they noted that potential other phenotype modifiers could not be ignored (Zarkov et al., 2015).

Hereditary Spastic Paraplegia (HSP)
Hereditary spastic paraplegia (HSP) represents a group of genetic neurodegenerative diseases characterized by increased spasticity of the lower limbs over time (Shribman et al., 2019). Spastic gait is often the only, or main, feature of the syndrome; bladder dysfunction is a common clinical finding as well. More than 70 types of HSP have been identified, and are often due to axon degeneration, leading to progressive degeneration of the corticospinal tracts (Fink, 2014; Opal & Ajroud-Driss, 2022). The classification of HSP may be based on age of onset, rate of progression, degree of spasticity, and genetics with more than 55 loci related to the disease (Opal & Ajroud-Driss, 2022). Some of the more common autosomal dominant forms of HSP may be caused by mutations in the ATL1, SPAST, KIAA1096, KIF5A, and REEP1 genes; additional genes are associated with autosomal recessive forms, X-linked forms, and mitochondrial forms of HSP (Opal & Ajroud-Driss, 2022).

Dong et al. (2018) performed next-generation sequencing on 149 genes associated with HSP in a cohort of 99 individuals. A retrospective study on other patients with HSP was also completed. Different genetic mutations cause different subtypes of HSP such as SPG4, SPG3A, and SPG6. The researchers note that “In ADHSP [autosomal dominant HSP], we found that SPG4 (79%) was the most prevalent [subtype], followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). … In ARHSP [autosomal recessive HSP], the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%)” (Dong et al., 2018).

In 2018, GeneReview published an updated overview of HSP. This overview was last updated in 2021. This document states the following regarding genetic testing:

• “Concurrent or serial single-gene testing can be considered if clinical findings and/or family history indicate that involvement of a particular gene or small subset of genes is most likely (see Tables 1, 2, 3, and 4)”
• “A multigene panel that includes some or all of the genes listed in Table 1 is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype”
• “Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic”
• “Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of both parents for the pathogenic variant identified in the proband” (Hedera, 2021)

GeneReviews has published four tables (below) which show the genes associated with autosomal dominant HSP, autosomal recessive HSP, X-linked HSP, and maternal (mitochondrial) HSP.

Table 1: Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – Autosomal Dominant Inheritance (Hedera, 2021)