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.
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
^ abcdefgDamseh N, Simonin A, Jalas C, Picoraro JA, Shaag A, Cho MT, et al. (August 2015). "Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination". Journal of Medical Genetics. 52 (8): 541–547. doi:10.1136/jmedgenet-2015-103104. PMID26041762.
^ abConroy J, Allen NM, Gorman K, O'Halloran E, Shahwan A, Lynch B, et al. (August 2016). "Novel European SLC1A4 variant: infantile spasms and population ancestry analysis". Journal of Human Genetics. 61 (8): 761–764. doi:10.1038/jhg.2016.44. PMID27193218.
^ abSrour M, Hamdan FF, Gan-Or Z, Labuda D, Nassif C, Oskoui M, et al. (July 2015). "A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly". Clinical Genetics. 88 (1): e1 –e4. doi:10.1111/cge.12605. PMID25930971.
^ abSarigecili E, Bulut FD, Anlas O (July 2022). "A rare cause of microcephaly, thin corpus callosum and refractory epilepsy due to a novel SLC1A4 gene mutation". Clinical Neurology and Neurosurgery. 218: 107283. doi:10.1016/j.clineuro.2022.107283. PMID35605507.{{cite journal}}: CS1 maint: article number as page number (link)
^Pironti E, Salpietro V, Cucinotta F, Granata F, Mormina E, Efthymiou S, et al. (December 2018). "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. doi:10.1080/01677063.2018.1476510. PMID29989513.
