2024-11-0920220300-900910.1007/s13760-020-01588-92-s2.0-85098946115http://dx.doi.org/10.1007/s13760-020-01588-9https://hdl.handle.net/20.500.14288/8704Here, we aim to provide a comprehensive clinical and biomolecular description of familial amyotrophic lateral sclerosis (fALS) in a 25-year-old female patient with respect to the SOD1(A4T) genotype. The clinical diagnosis of the disease was based on family history, neurological examination, electroneurophysiological studies, and revised El Escorial criteria. The heterozygous presence of the A4T mutation in the proband was confirmed by PCR coupled with Sanger sequencing of exon 1 of the SOD1 gene. The mutation was introduced in silico into the three-dimensional structure of the native protein. After energy minimization and quality assessment, non-covalent interactions around threonine-4 and changes in protein stability were calculated computationally. The patient differed widely in age at onset, initial neurological symptoms and findings, and survival time from her kindred, in which several members are affected. SOD1(A4T)-linked fALS in this case had bulbar involvement at onset, a combination of lower and upper motor neuron signs and showed rapid progression. Unlike alanine-4, threonine-4 failed to engage in hydrophobic interactions with the vicinal non-polar amino acids. The overall fold of the modeled SOD1(A4T) mutant remained intact, but unfolding free energy estimations disclosed a decrease in the protein's stability. We report a phenotypically distinct patient with fALS due to the SOD1(A4T) mutation and further expand the largest pedigree ever published for SOD1(A4T)-linked fALS. Genotype-phenotype correlation in fALS is complex, and it demands detailed clinical investigation and advanced scientific research. Awareness of the broadened phenotypic spectrum might potentially enhance the diagnosis and genetic counseling of fALS.Clinical neuropsychologyNeurosciencesJournal Article2240-2993606470600003Q38544