News > The second family affected with a PRDM8-related disease

The second family affected with a PRDM8-related disease

Hereditary spastic paraplegias (HSPs) comprise a group of heterogeneous inherited-neurological diseases characterized by spasticity and lower limb weakness. On the other hand, HSP presents a high level of clinical and genetic heterogeneity with an obvious overlap with other neurodegenerative or metabolic disorders that makes HSP diagnosis very challenging.

Hereditary spastic paraplegias (HSPs) comprise a group of heterogeneous inherited-neurological diseases characterized by spasticity and lower limb weakness. So far, more than 82 loci and 73 HSP-causing genes have been identified, which account for the causes of HSP in ~50% of cases. Since this disease, especially in its advanced stages, can be associated with mobility impairments in the affected individuals, it is associated with a heavy psychological and financial burden on the family and society. Therefore, identifying the causative genes as well as their mutations carriers can be effective in genetic counseling and consequently, prevent the birth of other patients.
On the other hand, HSP presents a high level of clinical and genetic heterogeneity with an obvious overlap with other neurodegenerative or metabolic disorders that makes HSP diagnosis very challenging. An accurate and early diagnosis of some disorders may help for their probable treatment. In this regard, finding causative genes of several disorders including deafness, intellectual disability, muscular dystrophies, and neurodegenerative disorders including HSP and neuropathies has been one of the main goals of the Genetics research center (GRC) at the University of Social Welfare and Rehabilitation Sciences (USWR). For this purpose, in parallel with the use of traditional methods such as linkage analysis, next-generation sequencing (NGS) based methods, especially whole-exome sequencing (WES), have been used in this center. Such studies have led to the identification of phenotype and genotype details of these diseases in the Iranian population. For example, (1) many novel disease-causing genes, (2) several diseases/syndromes, as well as (3) several ultra-rare diseases have been identified. Many of these ultra-rare disorders are the second reports in their categories globally. For example, in one of the most recent research projects in the GRC and during the genetic analysis of 70 HSP probands, another family affected with a PRDM8-related disease was identified. Mutation in this gene has been reported only once in a Pakistani family affected with an early-onset Lafora disease (LD). Lafora disease is a severe form of progressive myoclonus epilepsy characterized by generalized seizures, myoclonus, intellectual decline, ataxia, spasticity, dysarthria, visual loss, and in advanced stages, psychosis and dementia. To date, mutations in the EPM2A and EPM2B genes have been identified as the common causes of typical LD.
In this study, two affected siblings with an initial diagnosis of HSP were studied. Genetic analysis (linkage analysis, WES, and Sanger sequencing to confirm the candidate variants and co-segregation analysis) were performed for this family. Our findings identified a novel variant in the PRDM8 gene, which was only reported once in regard to early-onset LD, thus skin fibroblasts of both affected individuals of this family were examined for the presence of Lafora bodies. Similar to the skin biopsy of the previously reported Pakistani family, Lafora bodies were not detected in the fibroblasts of our affected individuals (in contrast to the typical forms of LD). The results of this study were published in January 2022 in an article entitled ?The second family affected with a PRDM8-related disease? at the Neurological Sciences journal, with an impact factor of 3.307.
Neurol Sci. 2022 Jan 16. doi: 10.1007/s10072-021-05815-w.

2022/02/14  -  13:08 / شماره خبر : 21836 / تعداد نمایش : 730