Learn About SPTAN1
Learn: What is SPTAN1?
SPTAN1 is a gene that encodes the α-II spectrin protein, which is a cytoskeletal protein that helps stabilize cell membranes. It helps maintain the integrity of myelinated axons, helps with axonal development, synaptogenesis, and helps to regulate receptor binding and actin crosslinking. A mutation of the SPTAN1 gene can cause a variety of neurodevelopmental issues, depending on the variant (version of the mutation) and the individual. Some kiddos may have developmental delays, infantile spasms or seizure disorders (epilepsy), spastic paraplegia, motor neuropathy, vision and feeding issues, low body tone, microcephaly, cerebral palsy, and other phenotypes.
History
The SPTAN1 gene, which encodes for alpha-II spectrin, was first identified and cloned by McMahon et al. in 1987, where they termed it "alpha-fodrin" from a human lung fibroblast cDNA library; this discovery allowed researchers to compare the structure of alpha-spectrin (SPTA1) with alpha-fodrin, revealing significant structural similarities between the two proteins (Online Mendelian Inheritance in Man, 2023). The SPTAN1 gene contains 57 exons (Online Mendelian Inheritance in Man, 2023).
Early studies focused on the structure and function of spectrin in red blood cells, where it was initially discovered (Terrone et al., 2020). Over time, research uncovered a strong association between mutations in SPTAN1 and a range of neurological disorders, particularly severe forms of early-onset epileptic encephalopathy (EIEE) characterized by developmental delay, intellectual disability, and brain atrophy (Syrbe et al., 2017).
Mutations in SPTAN1 are now recognized as a significant cause of EIEE, with specific phenotypic features like hypsarrhythmia, spastic quadriplegia, and distinctive brain imaging abnormalities depending on the mutation location (Terrone et al., 2020).
While severe EIEE is the most recognized SPTAN1-associated condition, research has also identified milder phenotypes including cases with isolated epilepsy or milder developmental delay, demonstrating a spectrum of clinical presentations depending on the specific genetic variant (Terrone et al., 2020).
References and Additional Reading
Online Mendelian Inheritance in Man. (2023, October 16). Spectrin, alpha, nonerythrocytic 1; SPTAN1. https://omim.org/entry/182810#:~:text=McMahon%20et%20al.,9%2Dkb%20transcript%20was%20identified.
Terrone, G., Pinelli, M., Bernardo, P., Parrini, E., Imperati, F., Brunetti-Pierri, N., & Del Giudice, E. (2020). Intrafamilial variability in SPTAN1-related disorder: From benign convulsions with mild gastroenteritis to developmental encephalopathy (28th vol.). European Journal of Paediatric Neurology. https://www.sciencedirect.com/science/article/abs/pii/S1090379820301537
Syrbe et al. (2017). Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy (140th vol.). Brain a journal of neurology. https://academic.oup.com/brain/article/140/9/2322/4096697
Variants
A "variant" refers to any difference in DNA sequence compared to a reference. A variant may be harmless or have unknown effects. A "mutation" refers to a change in DNA sequence that is considered to be potentially harmful or disease-causing.
Individuals diagnosed with an SPTAN1 mutation will see a variant identified, and these wide range of variants can present with mild phenotypes (observable characteristics) or more severe, like the c.6908_6916dup variant. You may see that an SPTAN1 mutation is often De Novo, meaning seen for the “first time” and not inherited by either parent, but there are dominantly inherited cases as well.
The following published study describes 22 patients from 14 families with five novel SPTAN1 variants.
De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia
Phenotypes
Epileptic encephalopathy (EE) is a condition where seizures and abnormal brain activity cause brain dysfunction, leading to cognitive and behavioral impairments. It's a severe form of epilepsy that usually begins in infancy.
Symptoms
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Language impairments
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Attentional and executive dysfunction
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Psychiatric issues, such as autism spectrum disorder, depression, anxiety, or psychosis
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Sleep issues
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Gastrointestinal issues
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Frequent, severe seizures that are often resistant to medication
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Developmental delays or regression
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Motor difficulties
Read more: Epilepsy and Encephalopathy
Learn: Research
SPTAN1 Caregiver Survey – Key Takeaways for Families by Michelle Wilson, PhD & Francis Wong, MD, MBA, MPH
Full article here; may be behind a paywall. Please see summary below.
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What is SPTAN1?
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A gene that helps support and protect nerve cells.
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Variants can lead to a wide range of developmental and medical challenges.
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Who was included in the survey?
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25 individuals (ages <1 to 41; 14 boys, 11 girls).
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91% of variants were de novo (not inherited).
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Most common challenges (seen in at least half of participants):
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Speech difficulties or absent speech (92%)
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Cognitive delays (76%)
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Abnormal brain imaging (72%)
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Epilepsy (60%)
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Movement, vision, GI, and sensory issues
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Microcephaly
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Other health concerns caregivers reported:
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Pain tolerance differences, hearing issues, bladder problems, muscle/joint pain, skin fragility, blood abnormalities, autoimmune conditions (16%), and organ/skeletal differences (44%).
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Unique observations:
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64% described as happy, easy-going
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52% experienced skill regression over time
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Some inherited cases suggest possible protective effects in females
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What this means:
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SPTAN1 impacts more than just the brain—it can affect multiple body systems, and symptoms may evolve over time.
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Bottom line for families:
There are shared patterns (speech, mobility, epilepsy), but every case is different. Alongside challenges, many caregivers highlight positive, joyful traits in their children.
Published SPTAN1 studies and articles
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Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia, January of 2023
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SPTAN1 Gene, January of 2025
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Pathogenetic Potential of the Mutations of SPTAN 1, February of 2019
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SPTAN1, 2024
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Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy, September of 2017
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Intrafamilial variability in SPTAN1-related disorder: From benign convulsions with mild gastroenteritis to developmental encephalopathy, September of 2020
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 5; DEE5, October of 2023
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De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia, February of 2022
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De novo SPTAN1 mutation in axonal sensorimotor neuropathy and developmental disorder, December of 2020
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SPTAN1 Analysis for Early Infantile Epileptic Encephalopathy, April of 2017
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A unique myopathic phenotype of novel SPTAN1 mutation without encephalopathy in siblings (P2.4-042), April of 2019
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O19: Antisense oligonucleotide targeting a linked-SNP provides allele-specific and effective knockdown to a dominant negative SPTAN1 pathogenic variant, 2024
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Phenotypic and molecular characterization of a recurrent SPTAN1 mutation causing SPG91
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Loss of Function SPTAN1 Variants Result in Ataxia and Intellectual Disability
Learn: Organizations
Our mission is to apply the efficiency, versatility and specificity of antisense technology to charitably provide experimental antisense oligonucleotide (ASO) medicines to treat patients with nano-rare diseases.
TGen, the Translational Genomics Research Institute, part of City of Hope, is an Arizona-based, nonprofit medical research institute dedicated to conducting groundbreaking research with life-changing results. We work to unravel the genetic components of common and complex diseases, including cancer, neurological disorders, infectious disease, and rare childhood disorders. By identifying treatment options in this manner, we believe medicine becomes more rational, more precise and, well, more personal.
National Organization for Rare Diseases NORD
NORD advances practical, meaningful, and enduring change so people with rare diseases can live their fullest and best lives. Every day, we elevate care, advance research, and drive policy in a purposeful and holistic manner to lift up the rare disease community.
The Jackson Laboratory: Rare Disease Translational Center
Our team serves those with rare disease by accelerating the pre-clinical phase. Our vision is to provide patients with an efficient path from diagnosis to therapy, allowing them to live longer, healthier lives.
The EveryLife Foundation for Rare Diseases
A nonprofit, nonpartisan organization dedicated to empowering the rare disease patient community to advocate for impactful, science-driven legislation and policy that advances the equitable development of and access to lifesaving diagnoses, treatments and cures.
An advocacy organization dedicated to connecting the rare disease community. It empowers patients, builds communities while seeking to eliminate the challenges experienced by people with rare diseases.
National Center for Advancing Translational Sciences (NCATS)
This organization provides a collection of resources, Rare Diseases Resources, on topics of interest to the rare disease community. Included is information on rare disease social networks, online medical reference websites and rare disease events. NCATS is part of the National Institutes of Health (NIH).
Europe-based Resources
SKIP Therapeutics develops RNA-based therapies for rare genetic disorders and common diseases.
Nucleic Acid Therapy Accelerator (NATA) initiative
UK-based. They evaluate new technologies to improve the delivery and safety of nucleic acid therapies, work collaboratively with partners to co-develop value and intellectual property rights, advancing therapeutic targets from validation and lead identification to pre-clinical data generation. They aim to develop novel therapeutics, from broadly applicable disease modifying pathways to personalised medicines tailored to individual patients.
A pilot program for individualized medicines in the UK
A group of internationally acclaimed doctors, researchers, patients and companies from across the globe who are committed to expanding the field of individualized medicine.