Amyotrophic lateral sclerosis (ALS)

Clinical features

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons. Most cases appear to be sporadic, but 5-10% of cases have a family history of the disease.¹ Since the discovery of mutations in gene encoding superoxide dismutase type 1 (SOD1), which account for ∼2% of ALS cases², the understanding of the ALS genetic component and ALS risk has increased significantly, leading to better personalized treatment and revealing the mechanisms that cause motor neuron death².

Approximately 5-10% of ALS is familial (FALS) with a Mendelian pattern of inheritance, suggesting that genetic factors play important roles in the pathogenesis of ALS ^1-3. To date, more than dozen causative genes have been identified in hereditary ALS and more than 30 potential causative or disease-modifying genes have also been identified³. ALS patients carrying specific mutations may exhibit subtly distinct clinical features so that the discovery of the genotype-phenotype correlations has important implications for genetic explanations.

To date, more than 25 chromosomal regions containing 27 identified genes have been linked to ALS⁴. The first causative gene of ALS was identified as SOD1 in 1993 ⁵. Mutations in SOD1 are very common, accounting for about 20 % of FALS and 1-2% of SALS cases ⁵. To date, more than 200 disease-associated mutations have been described, spread throughout all 5 exons of SOD1 ⁵. The majority of SOD1 mutations are missense mutations, while small deletions or insertions are also described ⁵. Among the SOD1 mutations, p.D90A is the most common worldwide. However, regional disparity of SOD1 mutations also exist. For example, the most frequent SOD1 mutation in North America is p.A4V, but in the UK and Japan the most common are p.I113T, and p.H46R, respectively ^{5, 6}.

Mutations in the FUS gene have emerged as the second most common cause of ALS, accounting for about 3-5% of FALS and ~1 % of SALS ⁹. Among the more than 100 FUS mutations reported so far, the majority are clustered in exon 15 which encodes the C-terminus of the protein, and the most common one is p.R521C. Compared to SOD1 patients, FUS-related ALS patients have an earlier age at onset, more frequent bulbar disease, and a more rapid progression. Some FUS mutations are also observed in patients with juvenile-onset ALS, with age at onset younger than 25 years ^{10, 11}. Atypical features such as ALS with mental retardation, essential tremor, Parkinsonism, and dementia were also seen in some patients with FUS mutations ^{10, 11}.

Mutations in ALS2 are responsible for autosomal recessive, early-onset forms of upper motor neuron diseases, such as infantile-onset ascending hereditary spastic paraplegia (IAHSP) and juvenile primary lateral sclerosis (PLSJ) ⁷.

ALS4 is a rare autosomal dominant form of juvenile-onset ALS due to mutations in SETX ⁸. It is characterized by slowly evolving distal muscle weakness and atrophy, pyramidal signs, and sparing of bulbar and respiratory muscles. Recessive SETX mutations are reported to cause ataxia and oculomotor apraxia type 2 (AOA2)⁸.

Mutations in TARDBP encoding TDP-43 account for 4 % of FALS cases and ~1 % of SALS¹³. More than few hundreds mutations have been identified so far, mostly clustered in the C-terminal region encoded by exon 6 of TARDBP. Mutations in TARDBP are predominantly missense with an autosomal dominant inheritance. Although TARDBP mutations are detected in ALS cases worldwide, some regional diversity does exist. For instance, the p.A382T mutation has been found in 28.7 % of all ALS cases in Sardinia ¹³.

Treatment is palliative and many individuals benefit from care by a multidisciplinary team including: a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor ¹².

CENTOGENE´s Amyotrophic lateral sclerosis (ALS) panel includes all relevant genes associated with ALS to date and it can be used for simultaneous testing of many ALS-associated genes, resulting in fast and precise molecular diagnostics of possibly underlying genetic forms of ALS in affected patients. Thus, CENTOGENE offers the ALS panel (genes: ALS2, ANG, CHCHD10, CHMP2B, DCTN1, ERBB4, FIG4, FUS, HNRNPA1, MATR3, NEFH, OPTN, PFN1, PRPH, SETX, SIGMAR1, SOD1, SPG11, SQSTM1, TARDBP, TBK1, TUBA4A, UBQLN2, VAPB, VCP) including full gene sequencing, deletion/duplication analysis of selected genes (SPG11, SETX) and repeat expansion analysis for the genes ATXN2 and C9orf72.

The differential diagnosis of Amyotrophic lateral sclerosis (ALS) disorders – depending on the major symptoms in the initial case – includes the following diseases⁶:

• Spinal and bulbar muscular atrophy (SBMA, Kennedy disease) caused by mutations of AR
• Spinal muscular atrophy (SMA) caused by mutations of SMN
• ALS8 (also known as SMAIV or Finkel type SMA) caused by mutations of VAPB
• Distal hereditary motor neuronopathy type VIIB, caused by mutations of DCTN1
• Primary lateral sclerosis (PLS) caused by pathogenic variants in at least one gene (ALS2)
• Hereditary spastic paraplegia (HSP)
• Hexosaminadase A deficiency, resulting in a group of neurodegenerative disorders caused by intralysosomal storage of the GM2 ganglioside
• BSCL2-related neurologic disorders
• Inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia (IBMPFD) caused by mutation of VCP
• Acquired disorders, including cervical spine disease, brain stem/spinal cord tumors, vitamin B12 deficiency, thyroid disorders, multiple sclerosis, motor neuropathies, myasthenia gravis, myasthenic syndrome, and inclusion body myositis.

To confirm/establish the diagnosis, we offer full Amyotrophic lateral sclerosis (ALS) panel sequencing and deletion/duplication gene testing. We are also offering a broad selection of NGS panels that are designed for the molecular diagnostics of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for Amyotrophic lateral sclerosis (ALS) panel gene testing :

Step 1: Repeat expansion analysis for the Amyotrophic lateral sclerosis (ALS) panel genes ATXN2 and C9orf72.

Step 2: Amyotrophic lateral sclerosis (ALS) panel full gene sequencing –which covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter for all the genes included in the Amyotrophic lateral sclerosis (ALS) panel.

Step 3: Deletion/duplication analysis/mutational scanning of selected Amyotrophic lateral sclerosis (ALS) panel (SPG11, SETX).

Step 4: If no mutation is identified after analysis of the Amyotrophic lateral sclerosis (ALS) panel, we can offer whole exome sequencing based on NGS technology.

The following individuals are candidates for this particular gene testing

• Individuals with a family history of disease and presentation of the most common symptoms
• Individuals without a positive family history, but with symptoms resembling this disease
• Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s amyotrophic lateral sclerosis (ALS) panel can be found in our genetic test catalogue.