Written by Dr. Brenda Toscano Márquez  Edited by Dr. Ray Truant

ARSACS researchers develop a better “measuring stick”, or disease severity index that can help better assess the progression of motor symptoms and compare different groups of ARSACS patients.

How does your doctor know you are sick? In short: measurements. Doctors record your weight, blood pressure, temperature, glucose levels, etc. The complex relationship between these biomarkers should indicate if you are healthy, or if not, to what degree you deviate from the healthy range.

Of course, each disease has a unique set of symptoms and characteristics. Performing the right measurements, with the right scales, is key to determining the type of disease, the course of treatment and most importantly, to know if the treatment is working. It would be careless and even dangerous if, for example, your doctor weighed you with a scale that could only detect a change of 10 kilograms. Even worse would be to focus on this measurement when you are actually suffering from high blood pressure.

Patients with cerebellar ataxia also need physicians to perform the right measurements that take into account their particular type of ataxia. Proper measurements show how fast symptoms are progressing and if treatments and therapies are having an effect. Cynthia Gagnon and colleagues published a paper in the journal of Neurology this past year in which she and her collaborators designed a new set of measurements or “disease severity index” to track the symptoms better. The new index is designed for adult patients with a type of cerebellar ataxia called ARSACS. The researchers hope that this new index which they call DSI-ARSACS will help clinicians better assess how the disease is progressing, and will provide the means to compare different groups of patients.

ARSACS, which stands for autosomal recessive spastic ataxia of Charlevoix-Saguenay is the second most common recessive-inherited ataxia in the world¹. It was first described in the region of Charlevoix-Saguenay of Quebec, Canada, but now, cases of ARSACS have been described in countries all around the world¹. It is caused by mutations in the SACS gene, which produces a protein called sacsin. To this date we are not completely sure about the function of sacsin, but it is thought to help fold other proteins into their functional shape.

Like other cerebellar ataxias, the lack of motor coordination is one of the main symptoms of ARSACS. But other important symptoms are also observed on a regular basis. Spasticity, usually described as “tightness” or muscle stiffness, as well as amyotrophy, or pain and muscle waste, are common among ARSACS patients, albeit with different levels of severity between individuals. To date, there is no known treatment for ARSACS.

As in many other ataxias, when ARSACS patients go for a checkup, the progression of their disease is evaluated by generic performance tests such as SARA (Scale for the Assessment and Ration of Ataxia). These tests help doctors know how advance the ataxia symptoms are in a patient. These “measuring sticks” are useful, but they were developed with other ataxias in mind, and they test for several types of ataxias. Being so broad means some of the important disease characteristics are not taken into account, or that physicians spend too much time recording things that are not relevant for the disease in question. In the case of ARSACS, these general tests do not show the progression of the important symptoms of muscle stiffness and muscle pain.

With these issues in mind, Gagnon and her collaborators set out to develop a better “measuring stick” or index scale for ARSACS motor symptoms. The group included neurologists, an occupational therapist and physical therapist; people who work with ARSACS patients and who have a good idea about what they struggle with the most. The group selected items from scales already being used in other diseases, including the general SARA scale. Their goal was to create a disease index with four key points:

1. Specific for ARSACS,
2. Measures only the abnormal motor function and its progression (does not test any phycological aspects)
3. Does not require specialized equipment (can be applied by a physician anywhere in the world)
4. Can be completed in a short time (they selected eight tests that can be completed during a regular checkup, eliminating tiresome tests and long appointments).

But does it work? The group needed to know that their index was giving them a good measure of how bad the disease was. Did they choose the correct measuring scale, and the right tests? The test of DIS-ARSACS was done in 26 patients aged 18-59, affected by different stages of the disease. Some could still walk, others required help walking, and the remainder were wheelchair users.

ARSACS is usually described as a progressive cerebellar ataxia, which means the symptoms get worse with age. With the new index, the more points they get, the higher the disease severity. If their index was working, they’d see older participants get more points — and they did! Moreover, the scores varied between the group of patients that still walked by themselves vs. the groups that were either walking with some help or were already in a wheelchair. Those in the later groups had higher scores — just as expected. The results show that DSI-ARSACS is a compact, do-it anywhere index to measure disease progression in ARSACS. But it’s just the first step. To really see if the index is valid, they will have to test it in more patients and include patients with different mutations causing ARSACS.

The development of DSI-ARSACS means there is now a reliable and standardized test which is an essential part of conducting clinical trials. It gives researchers a tool to classify the patients for selection and to test if the treatment is working. As you may remember, ARSACS and many other ataxias do not yet have a treatment. But many labs are looking for one right now, and when they have a good candidate, they can also have a good a way to test if their treatment is working.

Key Terms

Biomarker: objective indications of medical state, they are observed from outside the patient and can be measured accurately and reproducibly.

SARA: Acronym for Scale for the Assessment and Ration of Ataxia. An eight-item performance scale use in the measurement of signs of cerebellar ataxia. Read more about the SARA scale in our past Snapshot/

Validity: refers to the degree to which a study accurately reflects or assesses the specific concept that the researcher is attempting to measure.

Index: numerical measurement derived from a series of observations and used as an indicator or measure

Spasticity: tightness or muscle stiffness.

Amyotrophy: muscle pain and muscle waste

Conflict of Interest Statement

Dr. Brenda Toscano Márquez did not contribute to the development or publication of the work by Gagnon et al., but she does work doing basic research using a mouse model of ARSACS. Dr. Ray Truant has no conflict of interest to declare

Citation of Article Reviewed

Cynthia Gagnon, Bernard Brais, Isabelle Lessard, Caroline Lavoie, Isabelle Côté, Jean Mathieu. Development and validation of a disease severity index for ataxia of Charlevoix-Saguenay.Neurology. 2019. 93(16). e1543-e1549. (https://www.ncbi.nlm.nih.gov/pubmed/31534027)

References

1. Bouhlal Y, Amouri R, El Euch-Fayeche G, Hentati F. Autosomal recessive spastic ataxia of Charlevoix-Saguenay: an overview. Parkinson Relat Disord 2011;17: 418–422