Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common fatal progressive neurodegenerative disease and has significant effects on functionality, independency, and overall quality of life. It is a non-cell-autonomous disease that targets the motor neurons and the surrounding glia in the brainstem, corticospinal tract, and spinal anterior horn. Characterized by limb weakness, falls, communication, and swallowing difficulties to cognitive and behavioral changes, the severity and range of symptoms differ from case to case. Despite the heterogeneous presentation of symptoms, most cases result in death by respiratory failure, as the lungs and their supporting muscles simply loose optimal vitality to perform their proper function. ALS has an unknown etiology; therefore, its diagnosis becomes a challenge and the commencement of management can be belated. Currently with no cure, symptomatic alleviation is utilized; however, several therapeutic drugs are currently being tested in clinical trials. Modifications to procedural treatment are recommended to ensure the comfort and protection of ALS patients; and multidisciplinary clinical coordination is essential for optimizing health care delivery, increasing survival rate, and enhancing the quality of life of ALS patients.

Background of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive disorder and the most common fatal neurodegenerative disease.¹ It is a non–cell-autonomous disease that targets the motor neurons and the surrounding glia.² Recent studies showed microglia was implicated in the initiation of ALS, wherein the presence of microgliosis directly contributes to neurodegeneration.³ It is characterized by progressive degeneration of the brainstem, corticospinal tract, and spinal anterior horn.⁴

ALS was first described by both Aran and Cruveilhier in 1848 and 1853, respectively. It was not until 1869 that Charles Charcot defined and identified the disease we now know as ALS.¹ Several years later, Charcot stated that ALS was not hereditary; however, in the 1950s Kurland and Mulder established a genetic link to approximately 10% of cases.¹ ALS became a household name in 1939 when American baseball player Lou Gehrig was diagnosed with the disease at 36 years old, putting an end to his illustrious career. Since this time, ALS was also synonymously known as Lou Gehrig disease.¹

ALS sufferers have an extremely poor prognosis, with no cure or viable treatment available. The median survival time postdiagnosis is 3 years, while only 5% can expect to survive 10 years.⁵ ^, ⁶ This poor prognosis is thought to be, in some parts, due to delays in commencement of therapeutic treatments. The average time to commit to a diagnosis is 1 year.⁶ A more noteworthy delay in treatment is the physical manifestations experienced by patients, thought to be considerably downstream to the pathological changes that occur. This leaves an unanswered question: Would early diagnosis and intervention halt the progression or even lead to a cure of ALS?⁶

Description of Amyotrophic Lateral Sclerosis

The characteristic symptoms of ALS include limb weakness, falls, communication, and swallowing difficulties to cognitive and behavioral changes.⁷ ^, ⁸ The severity and range of symptoms differ from case to case.⁷ Despite this heterogeneous presentation of symptoms, most cases result in death by respiratory failure,⁷ as the lungs and their supporting muscles simply loose optimal vitality to perform their proper function.⁹

The onset of symptoms is categorized into bulbar onset (the symptom first noticed is slurred speech) and limb onset (the symptom first noticed is a weakness in the upper or lower limbs).¹ Some phenotypes have only upper or lower motor neurons affected—primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA), both having a better outlook than generalized ALS.¹ The identification of biomarkers upon diagnosis will also give an indication of the rate of progression the patient can expect.¹⁰ These biomarkers are respiratory muscle strength value, esophageal pressure, twitch trans-diaphragmatic pressure, maximal static expiratory mouth pressure, and sniff-trans-diaphragmatic.¹¹

The speed of progression can be predicted by a number of factors. Faster progression is linked with bulbar onset, older age at presentation/diagnosis, the short time frame from symptoms to diagnosis, the genotype, and whether cognitive impairment is already present.¹ Many ALS patients suffer from mental health issues such as depression and anxiety. However, this is thought to be linked to their poor prognosis and experience with the disease rather than a pathological origin.⁸

Epidemiology of Amyotrophic Lateral Sclerosis

Population-based studies of ALS showed 5.1% were familial ALS (FALS) and the remainder were sporadic ALS (SALS),¹² but the distinction between the two was not as clear-cut, as the same gene mutation can be attributed to both.¹³ Studies show that the C9orf72 gene is the most common ALS mutation in European patients for both FALS and SALS, while SOD1 is most common for Asians.¹⁴ It further shows that both Belgium and Greece have a 50% frequency of FALS with the C9orf72 gene mutation, followed by Finland with 46.4%. Koreans have the highest frequency of SOD1 mutations with 54.7%, followed by the Russians and Finnish with 50% and 42.9%, respectively.¹⁴

An overall pooled worldwide ALS crude incidence based on 44 population-based studies shows 1.75 (1.55–1.96)/100,000 person-years of follow-up (PYFU) and 1.68 (1.50–1.85)/100,000 PYFU after standardization on the U.S. population.⁴

Incidence

Studies conducted in the United Kingdom and the United States between multiethnicities highlight heterogeneity of incidence rates. Hispanics, African Americans, and Asian populations display lower crude incidence compared to Caucasians.⁴

Prevalence

In the 1990s the prevalence of SALS in western countries was an average of 5.2 (2.7–7.4)/100,000 and the lifetime risk by the age of 70 was estimated to be 1 in 400 with a male-to-female ratio of 1.5:1.¹⁵ It was noted that prevalence of ALS is 50 to 100 times higher in parts of Japan, Guam, Kii peninsula of Japan, and Guinea than any other part of the world.¹⁵ ^, ¹⁶

Mortality

The estimated mortality rate for ALS was 1.84 (1.54–2.55)/100,000 per year in U.S. population, with the mean age of onset for SALS being between 55 and 65 years and only 5% before the age of 30 years.¹⁵ Bulbar onset is most common in women and in older age groups, with 43% over the age of 70 years compared to 15% below the age of 30.¹⁵ On the contrary, FALS has an onset a decade earlier than SALS and affects male and female equally, in addition to shorter survival.¹⁵

Etiology and Pathogenesis of Amyotrophic Lateral Sclerosis

ALS has a multifactorial pathogenesis with a cellular presentation of “cytoplasmic inclusions containing aggregated/ubiquitinated proteins as well as RNAs.”¹² ^, ¹⁶ The intracellular mechanism involved in the pathogenesis includes protein misfolding with endoplasmic reticulum (ER) stress, impaired autophagy, and damage to the cytoskeleton (Fig. 4.1).¹² It also presents other cellular physiology affecting and contributing to the complexities of the disease. These comprise RNA processing and mitochondrial homeostasis, increased oxidative stress, enhanced excitotoxic pathways, reduced neurotrophic support, glial inflammatory responses oriented toward a harmful side, and many of these encompassed by probable genetic predispositions (Fig. 4.2).¹²

Fig. 4.1 Amyotrophic lateral sclerosis (ALS) nerve disorder.

Fig. 4.2 Pathogenesis mechanisms involved in amyotrophic lateral sclerosis (ALS).

At present, ALS has unknown etiology.¹⁷ In previous years there were very few preexisting genes or symptoms that led to an accurate possible diagnosis.¹⁸ These were classified as sporadic ALS (SALS), with unknown familial history, or familial ALS (FALS), a presence of ALS from first-degree or second-degree relatives.¹⁸ Recently, there has been significant research discoveries that have led to findings of possible genetic malfunctions causing ALS.¹⁹ Meta-analysis studies have identified C9orf72, TARDBP, FUS, and SOD1, as “The Big Four” gene mutations possibly leading to the development of ALS.¹⁴

Genetic Component of Amyotrophic Lateral Sclerosis

SOD1 (Superoxide Dismutase 1 Gene)

The SOD1 gene was the first gene linked to some ALS cases in 1993.²⁰ Its native function is to catalyze the reduction of superoxide (O₂ ⁻) with ambient protons to yield O₂ and hydrogen peroxide (H₂O₂).²¹ The SOD1 gene is an enzyme that works as an antioxidizing agent. A mutation of the SOD1 gene no longer produces the Cu-Zn superoxide dismutase enzyme. This leads to the destruction of the mitochondria and other cellular organelles, leading to a destruction of large groups of cells due to increased free radicals.²² The consensus in the ALS field is that SOD1 mutants acquire a toxic function. In other words, mutations in SOD1 convert this otherwise helpful superoxide radical scavenging enzyme into a toxic protein that causes ALS.²⁰

C9orf72 (Chromosome 9 Open Reading Frame 72)

The C9orf72 (G₄C₂) gene provides instructions for making a protein that is found abundantly in neurons found in the cerebral cortex of the brain. It is likely to also play a role in RNA processing.²³ The diagnosis of C9orf72 in relation to ALS is established by distinguishing a heterozygous pathogenic GGGGCC (G₄C₂) hexanucleotide repeat expansion on genetic molecular testing.¹⁹ The prevalence of ALS is estimated at 4–8:100,000, with an average C9orf72 (G₄C₂) hexanucleotide repeat expansion frequency in ALS patient cohorts of 10%.

TARDBP (TAR DNA-Binding Protein 43)

The TARDBP gene codes for DNA-binding protein 43 (TDP-43). This protein is found within the cell nucleus in most tissues and is involved in many of the steps of protein production.²⁴ The TDP-43 protein regulates DNA transcription. Single protein amino acid changes in the TDP-43 protein regulate most mutations. The majority of these changes affect the region of the protein involved in mRNA processing, potentially obstructing the production of other proteins.²⁴ These changes cause the protein to fold incorrectly, forming proteins found in nerve cells that control muscle movement in some people with ALS. It is unclear whether TDP-43 protein clumps cause the nerve cell death that leads to ALS or if they are a by-product of a dying cell. Frontal-temporal dementia has also been found to exist in patients with ALS from TDP-43 mutations.²⁴

FUS (Fused in Sarcoma)

The FUS gene, similar to TARDP, is found within the cell nucleus in most tissues and is involved in many of the steps of protein production.²⁵ The FUS gene attaches itself to DNA and regulates transcription, also helping in processing mRNA. By cutting and rearranging mRNA molecules in multiple ways, the FUS protein regulates the production of various versions of certain proteins.²⁵ The mutation in the FUS gene may hinder the movement of mRNA out of the cell nucleus, which results in FUS protein and RNA being clumped together. These clumps have been found in nerve cells that control muscle movement in some people with ALS.²⁵

Diagnostic Evaluation of Amyotrophic Lateral Sclerosis

Disease Identification

Identifying and diagnosing ALS can be challenging. To properly identify and correctly diagnose the condition, a thorough review of signs and symptoms must be performed (Fig. 4.3).⁹ ALS is only accurately diagnosed after symptoms worsen, and the disease has matured.⁹ Due to previous lack of knowledge surrounding the origin of the disease, it has become difficult to not only cure but diagnose until very late into its progression.¹ ALS often begins simply as muscle weakness. This condition will worsen over time, eventually leading to a total loss of motor function.⁹ Two main courses of progression generally occur: Limb onset individuals will begin loosing coordination while running or walking; Bulbar onset symptoms include difficulty swallowing or talking.⁹ A further progression leads to a difficulty swallowing (dysphagia), speaking (dysarthria), and loss of motor control (spasticity and hyperreflexia). Another sign of ALS is the weakening of intercostal muscles of the diaphragm leading to decreased lung capacity and severe respiratory problems.⁹

Fig. 4.3 Symptoms of amyotrophic lateral sclerosis (ALS).

A newer alternative diagnostic tool is the identification of genes that are associated with ALS.⁹ SOD1 is one such gene, which is commonly associated with FALS.²² A possible treatment is an experimental therapeutic agent that has the potential to target the SOD1 gene promoting intracellular copper uptake, thus promoting the function of this gene.²⁶ A correlation between individuals with ALS and high levels of glutamate is also a biomarker under observation.²⁷ A diagnosis of ALS from glutamate levels should not be inferred, nor a causation as the link is still being studied.²⁷