What is SLC6A1-NDD?

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare genetic disorder caused by pathogenic variants in the SLC6A1 gene. [1,2]

SLC6A1-NDD affects brain development and function and is associated with a broad clinical spectrum that may include developmental delay, intellectual disability, epilepsy, language impairment, hypotonia, movement disorders, behavioural difficulties, autism spectrum disorder and sleep disturbances. [1,2,6]

The severity and combination of symptoms can vary considerably between individuals. [1,2]

SLC6A1 and GAT-1

The SLC6A1 gene, located on chromosome 3p25.3, encodes the sodium- and chloride-dependent GABA transporter 1 (GAT-1). [1]

GAT-1 plays a major role in the reuptake of gamma-aminobutyric acid (GABA) from the extracellular space after neuronal signalling. [2,3]

GABA is the main inhibitory neurotransmitter in the central nervous system and plays a fundamental role in maintaining the balance between neuronal excitation and inhibition. [2]

GAT-1 is expressed in both neurons and astrocytes. By controlling extracellular GABA concentrations, it plays an important role in the regulation of GABAergic neurotransmission. [2,3]

Il gene SLC6A1, sinapsi, la proteina GAT-1

GABA reuptake mechanism

Image source: SLC6A1 Portal, Lal Research Group.

Function of GAT1 GABA transporter

Image source: Shah et al., Frontiers in Molecular Neuroscience, 2024

Disease Mechanism

Disease-causing SLC6A1 variants generally result in reduced GAT-1 function and impaired GABA uptake. [3–5]

Different variants can affect GAT-1 through different molecular mechanisms. Some impair protein folding and trafficking to the cell membrane, while others reach the membrane but show reduced transporter activity. [3–5]

The resulting reduction in GABA transport alters normal GABAergic neurotransmission and contributes to the neurological and neurodevelopmental manifestations of SLC6A1-NDD. [2–6]

Functional studies support loss of function and haploinsufficiency as major disease mechanisms. [4,5]

Studies have also found an association between lower residual GAT-1 activity and more severe clinical phenotypes. However, genotype–phenotype relationships remain complex and individual clinical outcomes cannot currently be reliably predicted from the genetic variant alone. [1,4,6]

Clinical Spectrum

SLC6A1-NDD is characterised by a broad and variable phenotype. [1,2,6]

Common manifestations include:

developmental delay and/or intellectual disability
speech and language impairment
epilepsy, frequently including absence, atypical absence, myoclonic-atonic and atonic seizures
hypotonia
movement disorders, including tremor, stereotypies and ataxia
autism spectrum disorder and other behavioural or psychiatric manifestations
sleep disturbances
developmental regression in some individuals [1,2,6]

Not every individual presents with all of these features, and severity can vary considerably. [1,2]

Epidemiology and Genetics

SLC6A1-NDD is a rare disorder, with an estimated incidence of approximately 2.65 per 100,000 births — around 1 in 38,000. [1,2,7]

The disorder is caused by a heterozygous pathogenic variant in SLC6A1 and follows an autosomal dominant inheritance pattern. [1]

Most reported cases result from a de novo pathogenic variant, although inherited pathogenic variants have also been described. [1,2]

As genetic testing becomes more widely available, individuals with SLC6A1-NDD are increasingly being identified across different ages and clinical presentations. [1,2]

References

1. Goodspeed K, Demarest S, Johannesen K, Kang J, Lal D, Angione K.
SLC6A1-Related Neurodevelopmental Disorder.
GeneReviews®. University of Washington, Seattle. Initial publication: 9 February 2023.

2. Goodspeed K, Pérez-Palma E, Iqbal S, et al.

Current knowledge of SLC6A1-related neurodevelopmental disorders.

Brain Communications. 2020;2(2).
doi: 10.1093/braincomms/fcaa170

3. Mermer F, Poliquin S, Rigsby K, et al.

Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons.

Brain. 2021;144(8):2499–2512.
doi: 10.1093/brain/awab207

4. Stefanski A, Pérez-Palma E, Brünger T, et al.

SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Brain. 2023;146(12):5198–5208.
doi: 10.1093/brain/awad292

5. Buitrago Silva D, Trinidad M, Ljungdahl A, et al.

Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.

American Journal of Human Genetics. 2024;111(6):1222–1238.
doi: 10.1016/j.ajhg.2024.04.021