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

Language impairments

Attentional and executive dysfunction

Psychiatric issues, such as autism spectrum disorder, depression, anxiety, or psychosis

Sleep issues

Gastrointestinal issues

Frequent, severe seizures that are often resistant to medication
Developmental delays or regression
Motor difficulties