New research details some of the clinical and genetic changes and imaging features seen in patients with amyotrophic lateral sclerosis type 4 (ALS4), a subtype of juvenile amyotrophic lateral sclerosis. This information could help clinicians quantify disease severity and track its progression in patients.
The data were presented by Christopher Grunseich, MD, at the 2019 American Academy of Neurology (AAN) annual meeting in Philadelphia.
ALS4 is caused by a mutation in the senataxin gene (SETX). It is an autosomal dominant condition, which means that only one copy of the mutated gene is needed for the disease to develop. ALS4 usually starts early in life, and symptoms include muscle weakness and abnormally sensitive reflexes (hyperreflexia), a sign of upper motor neuron damage.
“We evaluated a cohort of ALS4 patients to identify features of disease that could be used to quantify severity and track progression,” the researchers wrote.
A total of 31 patients with ALS4 were evaluated. All the patients had the same mutation in SETX: the nucleotide C instead of T at position 1166 in the gene, called 1166 T>C (or p.Leu389Ser, which denotes the change in the protein the gene codes for, the amino acid serine instead of leucine at the 389th amino acid position). Of note, a nucleotide is a building block of DNA.
The group of patients had an average age of 42 years old and 55% were female. Average age of disease onset was 17, and 90% presented with hyperreflexia.
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All the patients underwent neurological examinations and had their muscle strength tested. In addition, levels of various components in the blood, such as some types of hormones, were assessed.
Additionally, imaging — MRI [magnetic resonance imaging] and dual-energy X-ray absorptiometry (DXA), which can measure fat and bone density — was performed on the thighs of some of the patients.
Compared to data from age- and sex-matched control patients, ALS4 patients had significantly higher levels of a protein called creatine kinase. This protein, found in the muscles, is necessary for proper muscular function. High levels in the blood are often indicative of muscle injury; this can be thought of as the protein “leaking” out of damaged muscles and into the blood.
Additionally, male (but not female) ALS4 patients had significantly lower levels of creatinine, a waste product produced by muscles, when compared to controls. This might be indicative of a significant loss of muscle mass in these patients.
From the imaging studies, the reduction of muscle mass in patients’ thighs correlated with disease duration. ALS4 patients also had lower appendicular (in appendages) lean body mass adjusted by height — essentially, less muscle based on height than control subjects without ALS.
The patients were followed, on average, for just over three years. In that time, there was an average decrease of 30% in ankle dorsiflexion strength (a measurement of leg muscle strength).
In the AAN presentation, the effects of the mutation also were discussed. Senataxin is an enzyme (an helicase) that resolves R-loops and is involved in maintaining the integrity of DNA and RNA. R-loops are regarded as a double-edged sword; while persistent formation may risk genome stability, these structures also are seen as potential regulators of gene expression (protein production).
Here, the researchers noted that the mutation leading to ALS4 results in fewer R-loops in patients (gain of function mutation). This reduction also was seen for E385K, a previously unreported mutation seen in one patient.
The scientists noted that the quantification of these R-loops may be useful, namely for diagnostic purposes and to differentiate between benign and pathogenic mutations.
The researchers noted that more studies — in particular, studies that follow patients for longer periods of time — might be able to shed light on how these factors, namely the amount of R-loops, interact and affect disease progression. A better understanding of this may lead to better care for ALS4 patients.
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