SCA5 Fact Sheet
Ataxia:
SCA5 (Spinocerebellar Ataxia Type 5)
RELATED GENES:
SPTBN2
LOCATION:
Crosomesome 1 1 (11q13.2)
MUTATION TYPE:
SPTBN2 -> point mutations, deletions and others
LAST UPDATE:
01/04/2025 by Marcio Galvão
HERITAGE:
Autosomal Dominant
Content generated with the support of Generative AI, reviewed by the author.
1. ABOUT SCA5
Spinocerebellar Ataxia Type 5 (SCA5) is a specific type of ataxia within a group of inherited disorders that affect the central nervous system. In SCA5, genetic defects cause problems in specific nerve fibers that carry messages to and from the brain, resulting in degeneration of the cerebellum (the brain's motor coordination center) [1] .
SCA5 is a progressive disease caused by mutations in the SPTBN2 gene (chromosome 11q13.2), which encodes the beta-III spectrin protein. The mutation was mapped to chromosome 11 in 1994 (Ranum et al.), and in 2006, mutations (in-frame deletions and missense mutations) that compromise protein stability were identified (Ikeda et al.). The beta-III spectrin protein, together with other proteins (alpha-spectrin, F-actin), forms the cytoskeleton that gives shape and mechanical resilience to the plasma membrane of cells, which is necessary to stabilize and organize other proteins that function in important cellular processes. It also stabilizes glutamate transporters and calcium channels in the membranes of Purkinje cells , cerebellar neurons essential for motor function (Perkins et al., 2010). The mutation in the SPTBN2 gene that expresses this protein affects normal functioning and can cause the death of these neurons (dysregulation of intracellular signaling and endoplasmic reticulum stress), which consequently causes the symptoms of SCA5 ataxia. Those interested in more technical information can consult [4], [5], [8] and [9] .
SCA5 is also known as Holmes' ataxia, because Dr. Gordon Holmes was the first to describe the disease in 1907, or Lincoln's ataxia , because SCA5 was diagnosed in descendants (eleventh generation) of the paternal grandparents of U.S. President Abraham Lincoln, although there is no direct evidence that Lincoln himself was affected [8] . Compared to other spinocerebellar ataxias such as SCA1 , SCA2 and SCA3, SCA5 ataxia progresses more slowly and generally does not affect the patient's life expectancy [8].
Figure 1 - Diagram generated by the author with the support of Artificial Intelligence
2. TYPICAL SYMPTOMS
Spinocerebellar Ataxia Type 5 (SCA5) is classically defined as a "pure" cerebellar ataxia, as its clinical manifestations are predominantly restricted to degeneration of the cerebellum, the structure responsible for motor coordination and balance. Typical symptoms of SCA5 are [5]:
-
Gait ataxia (imbalance when walking, difficulty climbing stairs, and loss of balance when standing on one foot, for example, while bathing).
-
Lack of motor coordination in the arms and hands is also common in SCA5, but it is generally not as disabling as gait. Affected individuals may notice deterioration in handwriting, difficulty buttoning shirts, and other activities that require manual dexterity.
-
Oculomotor abnormalities (such as nystagmus).
Other common manifestations:
-
Cerebellar dysarthria : slurred speech, but rarely severe enough to compromise oral communication.
-
Intention tremor (not at rest).
Unlike other SCAs (such as SCA3), SCA5 rarely presents significant involvement of extracerebellar regions, such as the brainstem or autonomic pathways, preserving cognitive functions, swallowing, digestion, urinary control, and muscle strength. Therefore, people with SCA5 typically continue to live independently [8]. For example, although many patients with SCA5 eventually use some walking aid (such as canes or a walker), the disease rarely reaches the point of wheelchair dependence, as can occur in other ataxias. For more information on the symptoms of SCA5, see [4, 5].
The types of symptoms experienced in SCA5 ataxia and their severity can vary from person to person, even within the same family.
3. ONSET
The onset of symptoms of SCA5 generally occurs in the third or fourth decade of life, but there are records of occurrence from 10 to 68 years of age [8] . The source [6] indicates the average age of onset of symptoms as 33 years, with a range between 6 and 68 years.
Expansion of the clinical spectrum
Initially described as an exclusively adult-onset disease, subsequent genetic studies have identified specific mutations in the SPTBN2 gene associated with early onset (childhood or adolescence), which are linked to more severe phenotypes, including:
-
Delayed motor and cognitive development, suggesting extracerebellar involvement (e.g., cerebral cortex or subcortical pathways) (Avery et al., 2020). It is worth noting that cognitive involvement in pediatric cases is an exception, not the rule. SCA5 is predominantly a "pure" cerebellar ataxia.
-
Accelerated progression of symptoms, such as disabling gait ataxia and marked dysarthria (Hoxha et al., 2022).
This expanded phenotype challenges the classical notion of SCA5 as a “pure” cerebellar ataxia, indicating that severe mutations in SPTBN2 may affect neural networks beyond the cerebellum, albeit to a limited extent (Paulson et al., 2023).
By 2023, more than 20 pathogenic variants of the SPTBN2 gene that can cause SCA5 have been reported, encompassing point mutations, deletions, and splice variants [8, 9] .
4. ANTICIPATION
Analyses of patients (observational reports) have shown that daughters had symptoms 10 to 20 years earlier than their mothers, who also had the disease, and these in turn had symptoms earlier than their mothers, the grandmothers of the granddaughters [5] . Despite this, there is no molecular evidence to support the occurrence of true anticipation in SCA5 (Paulson et al., 2023). That is, the "anticipation" in SCA5 in the reported cases is apparent, not genetic.
Clinical anticipation—the phenomenon in which symptoms appear progressively earlier in subsequent generations—is a classic feature of trinucleotide repeat expansion diseases (e.g., SCA1, SCA2, SCA3). However, SCA5 involves non-repetitive mutations in the SPTBN2 gene (in-frame deletions or missense mutations), and in this case, the conventional genetic mechanisms of anticipation (e.g., repeat expansion) would be absent. In this context, it is possible that reports of families with apparent anticipation (e.g., symptoms 10–20 years earlier in granddaughters vs. grandparents) are attributable to other factors (ease of diagnosis, epigenetic or environmental modifiers, or different SPTBN2 variants coexisting in the same family lineage).
In cases where symptoms appear in adulthood, the progression of ataxia is slower [8] .
5. INHERITANCE
SCA5 is an autosomal dominant disease. This means that individuals of both sexes have the same probability of inheriting a copy (allele) of the mutated gene and becoming carriers of the mutation. A child of a person with SCA5 has a 50% chance of inheriting a copy of the altered gene (assuming only one parent is a carrier of the mutation, that is, the biological mother or father).
Note: "Autosomal" means that the gene is located on any chromosome except the X and Y sex chromosomes. Genes, like chromosomes, normally exist in pairs (we have a pair of each gene, one copy of the gene is inherited from the mother, the other from the father). "Dominant" means that just one copy of the responsible gene (an allele) inherited from either the father is enough to pass on a physical characteristic (such as dimpled cheeks) or a genetic disease (such as hereditary ataxia) from one generation (parents) to the next (children).
Figure 2 - Source: MedlinePlus, US National Library of Medicine .
Notice: Although SCA5 is inherited in an autosomal dominant manner, homozygous mutations in the SPTBN2 gene can cause another type of spinocerebellar ataxia with autosomal recessive inheritance, coded as SCAR14, which usually has more severe symptoms and earlier onset , developmental delays, and cognitive problems. A homozygous mutation occurs when a person inherits two copies of the same mutated gene , one from the biological father and one from the mother. In contrast, a heterozygous mutation occurs when a person inherits only one mutated allele (copy of the gene), with the other allele being normal. Please see [5, 8] for more information.
6. PREVALENCE
SCA5 is a rare ataxia, even among dominantly transmitted ataxias. The prevalence is unknown, but it is estimated to be less than 1 case in every 100,000 population [6] . Families in the United States, France, Germany, Japan, Norway, and other countries have been reported with SCA5.
7. ADDITIONAL INFORMATION
Diagnosis - SCA5 can be diagnosed with molecular genetic testing (DNA testing) to detect rearrangements and heterozygous point mutations in the SPTBN2 gene. This is especially recommended if someone in the family already has a confirmed diagnosis (positive family history of SCA5). Before ordering genetic testing, the neurologist typically performs clinical neurological examinations to analyze symptoms, reflexes, ocular abnormalities, and assess family history. It is also common for them to order imaging tests to check for cerebellar atrophy, for example (Figure 3).
Note: Although diagnosis by genetic testing can be difficult, time-consuming and expensive, it is important because it allows for better genetic counseling for family members (risk of transmitting the mutation to future generations in the family), better management of the disease, which will be well determined, and also allows the patient to participate in clinical trials for medications for specific ataxias.
Figure 3 - NAF (National Ataxia Foundation) webinar "Research and Treatment Development for SCA5" with Dr. Adam Avery [9] .
8. THERAPIES AND DRUGS BEING TRIALED FOR THIS ATAXIA
See article " Reimagining drugs for rare brain disorders " by Marissa Locke Rottinghaus, Feb. 16, 2023
Source [9] lists some possible therapeutic approaches for SCA5 (still under study):
-
Genetic editing (of pagogenic variants of the SPTBN2 gene) by CRISPR/Cas9.
-
ASO (Antisense Oligonucleotides) therapies to reduce the expressivity of the beta-III spectrin mutant protein.
-
New drugs to treat the effects (e.g., problems with glutamate neurotransmitter signaling)
9. TREATMENTS
There is currently no cure for Spinocerebellar Ataxia Type 5 (SCA5), but it is possible to manage symptoms to improve quality of life and provide ongoing support to the patient. It is essential that individuals with SCA5 are monitored by a neurologist and a specialized multidisciplinary medical team, with additional healthcare professionals (such as a geneticist, neuro-ophthalmologist, neurofunctional physical therapist, occupational therapist, speech-language pathologist, nutritionist, etc.) being gradually included as needed based on symptom progression.
Below are general recommendations for symptom management in SCA5:
-
Neurofunctional physical therapy, exercise (especially stationary cycling), and other regular physical activities (such as yoga, Pilates, or water aerobics) are recommended—within each person’s capabilities.
-
To reduce the risk of falls due to balance difficulties while walking, walking aids such as canes, walkers, or (more rarely) wheelchairs may be used depending on the stage of the disease.
-
Occupational therapy and certain home or lifestyle adaptations can be helpful (e.g., installing grab bars in hallways and bathrooms, using a shower chair, adding night lights, rearranging furniture to improve mobility, removing rugs that could cause tripping, using cups with lids and straws, or choosing non-slip and easy-to-wear footwear).
-
Rest whenever needed, and ensure high-quality nighttime sleep. If sleep difficulties arise, consult a physician—there are medications that may help (e.g., cannabidiol oil).
-
Maintain a healthy diet and proper hydration.
-
Supplements and vitamins may be recommended (consult a physician to evaluate the need—do not take supplements without medical supervision).
-
Weight management is advised to prevent further mobility challenges.
-
For dysarthria (slurred speech), if present, speech therapy is recommended. Depending on the stage of disease progression, the use of assistive communication devices (available on smartphones, computers, tablets, etc.) may be considered.
-
Avoid stress as much as possible, as it generally worsens ataxia symptoms.
-
If needed, medications for anxiety or depression can be prescribed. A doctor should evaluate the most appropriate treatment options.
Note: Some patients with various types of cerebellar ataxias have reported improvements in symptoms after undergoing non-invasive cerebellar neuromodulation therapies, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) administered by certified physical therapists. However, it is important to note that while these therapies are commercially available in some places, they have not yet been approved by the FDA in the United States or by ANVISA in Brazil for the treatment of ataxias. In other words, they are considered experimental and without guaranteed results.
See information about medications for ataxia symptoms.
See information about treatments and care for patients.
See information about those with a recent diagnosis.
See information about Support Groups for patients and caregivers.
10. REFERENCES
The references below include academic sources and specialized organizations that supported the information in this fact sheet, including peer-reviewed articles, genetic repositories (OMIM), literature summaries (GeneReviews), and informational materials from ataxia foundations. For more information, see the ataxia.info References list .
Ref #1
Source:
NAF (National Ataxia Foundation)
© Copyright National Ataxia Foundation
Language:
English
Date:
Revised NAF– 01/2019
Ref #2
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH) ©.
Language:
English
Date:
Last Updated: November 2023
Ref #3
Source:
NEUROMUSCULAR DISEASE CENTER (Alan Pestronk, MD)
Washington University, St. Louis, MO - USA
Language:
English
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #4
Source:
Katherine A. Dick, Yoshio Ikeda, John W. Day, Laura PW Ranum
ScienceDirect Copyright © 2024 Elsevier BV
Language:
English
Date:
2012
Ref #5
Source:
OMIM® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit History: carol: 02/04/2021
Ref #6
Source:
Expert reviewer(s): Dr Shinsuke FUJIOKA - Dr Yoshio TSUBOI - Dr Zbigniew WSZOLEK
Copyright ® Orphanet - The portal for rare diseases and orphan drugs
Language:
English.
Date:
Last update: February 2020
Ref #7
Source:
Sarah Denha
YouTube - Copyright ® Oakland University
Language:
English.
Date:
Nov 12, 2021
Ref #8
Source:
Presented by: Dr. Theresa Zesiewicz
YouTube - Copyright © National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into Portuguese.
Date:
March 8th, 2024
Ref #9
Source:
Presented by: Dr. Adam Avery
YouTube - Copyright © National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into Portuguese.
Date:
March 19th, 2024