Medicine:SPATCCM
Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (often referred to by its acronym SPATCCM) is a rare autosomal recessive disease caused by mutations in the SLC1A4 gene encoding the ASCT1 protein. The ASCT1 protein is primarily found in astrocytes in the brain where its main role is to import L-serine, a non-essential amino acid.
Symptoms and signs
Clinically, patients present with microcephaly and significant developmental delay. While some patients may be able to walk, others may not due to spasticity of limbs and hypotonic muscle tone, with progressive degeneration over time. Patients may also present with seizures, ranging from single febrile seizure to intractable epilepsy. Following brain MRI, patients may present with thin corpus callosum, decreased myelination, and/or brain atrophy.[1] These symptoms mimic that of other L-serine deficiencies[2]
Cause
There have so far been several identified mutations in the SLC1A4 gene that are linked to SPATCCM, including several frameshift (L314Hfs*42,[1] N324Tfs*29[3]), nonsense (Y191*,[4] W453*[5]), duplication (L86_M88dup[6]), and missense mutations (E256K,[1][7] R457W,[1] G374R,[8] G381R,[9] S181F[3]). These mutations interrupt the transport of serine from astrocytes to neurones, and across the blood brain barrier[10]
L-serine is important in brain development as it is a vital component in protein synthesis, as well as being the precursor to several essential compounds, including phosphatidylserine, sphingomyelin, glycine, and D-serine.[2]
Diagnosis
Diagnosis of SPATCCM generally relies on whole exome sequencing and the identification of a mutation in the SLC1A4 gene, while also lacking any other potential pathogenic mutations.[1]
Treatment
SPATCCM is an incurable genetic disease, however patients are often treated with anti-epileptics including vigabatrin, topiramate or clobazam, to reduce associated seizures.[4][8] Supplementation of L-serine has also been proposed as a treatment.[1][7] and has shown effective in a knock-in mouse model of the disease if administered prenatal and early postnatal.[10]
Epidemiology
Although most of the reported cases of SPATCCM are in people of Ashkenazi Jewish ancestry, it has also been reported in Irish, Hispanic, South Asian, Italian, Czech, Palestinian, and Pakistani ethnicities.[3][5]
SPATCCM has a carrier frequency of 0.7% in the Ashkenazi Jewish population.[1]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination". Journal of Medical Genetics 52 (8): 541–547. August 2015. doi:10.1136/jmedgenet-2015-103104. PMID 26041762.
- ↑ 2.0 2.1 "Serine biosynthesis and transport defects". Molecular Genetics and Metabolism 118 (3): 153–159. July 2016. doi:10.1016/j.ymgme.2016.04.010. PMID 27161889.
- ↑ 3.0 3.1 3.2 "Novel compound heterozygous variants (c.971delA/c.542C > T) in SLC1A4 causes spastic tetraplegia, thin corpus callosum, and progressive microcephaly: a case report and mutational analysis". Frontiers in Pediatrics 11. 2023-07-12. doi:10.3389/fped.2023.1183574. PMID 37502193.
- ↑ 4.0 4.1 "A Novel SLC1A4 Mutation (p.Y191*) Causes Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM) With Seizure Disorder". Child Neurology Open 6. 2019-01-01. doi:10.1177/2329048X19880647. PMID 31763347.
- ↑ 5.0 5.1 "Novel European SLC1A4 variant: infantile spasms and population ancestry analysis". Journal of Human Genetics 61 (8): 761–764. August 2016. doi:10.1038/jhg.2016.44. PMID 27193218.
- ↑ "Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome". Annals of Clinical and Translational Neurology 10 (6): 1046–1053. June 2023. doi:10.1002/acn3.51786. PMID 37194416.
- ↑ 7.0 7.1 "A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly". Clinical Genetics 88 (1): e1–e4. July 2015. doi:10.1111/cge.12605. PMID 25930971.
- ↑ 8.0 8.1 "A rare cause of microcephaly, thin corpus callosum and refractory epilepsy due to a novel SLC1A4 gene mutation". Clinical Neurology and Neurosurgery 218. July 2022. doi:10.1016/j.clineuro.2022.107283. PMID 35605507.
- ↑ "A novel SLC1A4 homozygous mutation causing congenital microcephaly, epileptic encephalopathy and spastic tetraparesis: a video-EEG and tractography - case study". Journal of Neurogenetics 32 (4): 316–321. December 2018. doi:10.1080/01677063.2018.1476510. PMID 29989513.
- ↑ 10.0 10.1 "A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations". Brain 147 (11): 3874–3889. April 2024. doi:10.1093/brain/awae134. PMID 38662784.
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