Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 50 million people worldwide in 2020 and this number will triple to 152 million by 2050. Much of the increase will be in developing countries like Colombia. In familial forms, highly penetrant mutations have been identified in three genes, APP, PSEN1, and PSEN2, supporting a role for amyloid-β peptide. In sporadic forms, more than 30 risk genes involved in the lipid metabolism, the immune system, and synaptic functioning mechanisms. We used whole-exome sequencing (WES) to evaluate a family of 97 members, spanning three generations, with a familiar AD, and without mutations in APP, PSEN1, or PSEN2. We sequenced two affected and one unaffected member with the aim of identifying genetic variants that could explain the presence of the disease in the family and the candidate variants were validated in eleven members. We also built a structural model to try to determine the effect on protein function. WES analysis identified two rare variants in SORL1 and MTHFD1L genes segregating in the family with other potential risk variants in APOE, ABCA7, and CHAT, suggesting an oligogenic inheritance. Additionally, the structural 3D models of SORL1 and MTHFD1L variants shows that these variants produce polarity changes that favor hydrophobic interactions, resulting in local structural changes that could affect the protein function and may contribute to the development of the disease in this family.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of genetically transmitted connective tissue disorders that directly affect collagen synthesis, with a broad range of symptoms. Case presentation: This study presents a clinical case of a Colombian woman with myopathic EDS and multiple comorbidities taking 40 years of medical history to make the right diagnosis. This article also presents a review of the current literature on EDS, not only to remind the syndrome but also to help the clinician correctly identify symptoms of this diverse syndrome. Conclusion: A multidisciplinary approach to the diagnosis of the patient, including clinical and molecular analysis, and neuropsychological and psychological assessment, is important to improve the treatment choice and the outcome prediction of the patients.

IntroductionHereditary ataxias and spastic paraplegias are disorders characterized by clinical and genetic variability, considered extremes of the ataxia-spasticity spectrum. One of the genes identified in this spectrum is POLR3A (RNA Polymerase III Subunit A), which encodes the RPC1 subunit of RNA polymerase III, an enzyme essential for tRNA synthesis and myelin homeostasis.ObjectiveTo identify genetic variants associated with spastic ataxia in a patient using whole-exome sequencing, complemented by clinical, neuropsychological, psychological, and biomarker-based assessments.Materials and MethodsClinical diagnosis was established based on medical history and neurological examination. Complementary neuropsychological and psychological assessments were performed using standardized instruments to evaluate cognitive functioning, emotional symptoms, perceived stress, and personality traits. Venous blood samples were collected under standardized fasting conditions to quantify tryptophan, serotonin, catecholamines, and cortisol. Whole-exome sequencing was performed, followed by a bioinformatic analysis consisting of variant filtering and prioritization.ResultsIn the POLR3A gene, the intronic variant c.1909+22G>A was identified, which activates a cryptic splicing site, generating a frameshift and a stop codon; and the variant c.3781G>T (p.Glu1261*) in exon 29, which generates a stop codon, resulting in the production of a truncated protein. Both variants were classified as likely pathogenic. Neurological examination revealed cerebellar ataxia, with preserved global cognition but selective executive impairment. Psychological assessment showed depressive symptoms, elevated stress, and emotional vulnerability, while biochemical parameters remained within reference ranges.ConclusionsThe implementation of exome analysis in this study enabled the identification of two heterozygous variants associated with the patient's phenotype, confirming that this technique is highly useful for molecular diagnosis in rare diseases.