Applicability of clinical genetic testing for deep brain stimulation treatment in monogenic Parkinson's disease and monogenic dystonia: a multidisciplinary team perspective.

In this perspective article, we highlight the possible applicability of genetic testing in Parkinson's disease and dystonia patients treated with deep brain stimulation (DBS). DBS, a neuromodulatory technique employing electrical stimulation, has historically targeted motor symptoms in advanced PD and dystonia, yet its precise mechanisms remain elusive. Genetic insights have emerged as potential determinants of DBS efficacy. Known PD genes such as GBA, SNCA, LRRK2, and PRKN are most studied, even though further studies are required to make firm conclusions. Variable outcomes depending on genotype is present in genetic dystonia, as DYT-TOR1A, NBIA/DYTPANK2, DYT-SCGE and X-linked dystonia-parkinsonism have demonstrated promising outcomes following GPi-DBS, while varying outcomes have been documented in DYT-THAP1. We present two clinical vignettes that illustrate the applicability of genetics in clinical practice, with one PD patient with compound GBA mutations and one GNAL dystonia patient. Integrating genetic testing into clinical practice is pivotal, particularly with advancements in next-generation sequencing. However, there is a clear need for further research, especially in rarer monogenic forms. Our perspective is that applying genetics in PD and dystonia is possible today, and despite challenges, it has the potential to refine patient selection and enhance treatment outcomes.

Potential protective role of a NOD2 polymorphism in the susceptibility to multiple sclerosis is not associated with interferon therapy.

Pattern recognition receptors, such as specific nucleotide-binding oligomerization domain protein 2, and their polymorphisms may be involved in the pathogenesis of multiple sclerosis (MS). They may also play a role in the formation of neutralizing antibodies against interferon-ß (INF-ß), and may exhibit lowered efficacy. Identification of these polymorphisms may be useful for early identification of potential non-responders and to allow for modification of treatment regimens earlier. The differences in genotype distribution and allele frequency of the rs3135499 and rs2066842 NOD2 polymorphisms between patients with MS and healthy controls were analysed in the present study. The group of patients were divided into responders and non-responders to INF-ß therapy to evaluate the association of both polymorphisms with response to therapy. No differences in the genotype frequencies between the responder and non-responder groups were observed. However, a statistically significant difference in genotype frequencies of TT homozygotes for rs2066842 between patients with MS and healthy controls was observed (χ2=11.8; P=0.003). A recessive genotype model and allele distribution in rs2066842 suggest that the genotype TT and allele T itself are protective against MS. The odds ratio of 0.12 represents an 8.33x lower risk for MS if an individual has a TT genotype. The significantly lower incidence of the TT genotype of rs2066842 in patients with MS suggests that the TT genotype and T allele may be a protective genetic factor against MS.

Chronic iron overload induces gender-dependent changes in iron homeostasis, lipid peroxidation and clinical course of experimental autoimmune encephalomyelitis.

To analyze iron- and gender-dependent mechanisms possibly involved in pathogenesis of multiple sclerosis (MS) in this study we evaluated the effects of iron overload (IO) on iron status and lipid peroxidation processes (LPO) in tissues of female and male DA rats during chronic relapsing experimental autoimmune encephalomyelitis, a well-established MS animal model. Rats were treated by iron sucrose (75mg/kg bw/day) or with saline solution during two weeks before the sensitization with bovine brain homogenate in complete Freund's adjuvant. Clinical signs of EAE were monitored during 29 days. Serum and tissues of CNS and liver were sampled before immunization and at day 13th post immunization (during acute phase of EAE). The determination of ferritin, iron, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and evaluation of histopathology were performed by ELISA, ICP spectrometry and immunohistochemistry. Results showed that IO in female EAE rats accelerated the onset of disease. In contrast, in male rats it accelerated the progression of disease and increased the mortality rate. During acute phase of EAE female IO rats sequestered more Fe in the liver, spinal cord and in the brain and produced more ferritin than male EAE rats. Male rats, however, reacted on IO by higher production of MDA or 4-HNE in the neural tissues and showed greater signs of plaque formation and gliosis in spinal cord. The data point to sexual dimorphism in mechanisms that regulate peripheral and brain iron homeostasis and imply that men and women during MS might be differentially vulnerable to exogenous iron overload.

Angiotensin-converting enzyme insertion/deletion gene polymorphism in multiple sclerosis: a meta-analysis.

The activity of angiotensin-converting enzyme (ACE) has been increased in the blood and cerebrospinal fluid of multiple sclerosis (MS) patients. In addition, there has been suppression of disease development in experimental autoimmune encephalomyelitis after blockade of ACE. These findings suggest that ACE may play a role in the MS pathogenesis. Since the previous studies investigating the association between the insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene and MS reported contradictory results, we performed a meta-analysis of four studies conducted in European populations of Slavic origin (1062 patients and 1067 controls) using the Comprehensive Meta-analysis 3.0 software. The results demonstrated that the ACE I/D polymorphism had no statistically significant association with an increased MS risk (all p ≥ 0.05) under all genetic comparison models: (1) allelic (D vs. I), (2) recessive (DD vs. ID + II), (3) dominant (DD + ID vs. II), and (4) additive (DD vs. ID vs. II). This meta-analysis indicates that the ACE I/D polymorphism is not associated with susceptibility to MS in Europeans of Slavic origin. Further studies with larger sample sizes from genetically different populations are warranted.

MMP-2 -1575G/A polymorphism modifies the onset of optic neuritis as a first presenting symptom in MS?

Previous studies show altered activities of matrix metalloproteinase (MMP)-2 and MMP-9 in serum and cerebrospinal fluid of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. Optic neuritis (ON) is a common symptom of both disorders. Here we investigated the impacts of MMP-2 -1575G/A and MMP-9 -1562 C/T gene polymorphisms on disease phenotype in 100 MS patients with ON as a first symptom and 376 MS patients with other initial symptomatology. The MMP-2 -1575G/A polymorphism led to a 5-year-earlier age of disease onset in MS patients with ON as a first symptom (p=0.009).

CTLA-4 +49 and TNF-alpha-308 gene polymorphisms in celiac patients with exocrine pancreatic insufficiency.

Celiac disease (CD) is a life-long gluten sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals. Human leukocyte antigen (HLA) genotype contributes to the genetic risk for CD, but "non-HLA" genes also play a role. Clinical presentation could be classical, but majority of patients present with non-classical, atypical signs and symptoms. Endocrine and/or exocrine pancreatic insufficiency (EXPI) is common in celiac patients. The aim of our study was to assess EXPI among our CD patients by measurement of faecal pancreatic elastase (FE1) and to find potential association of CTLA-4 +49 and TNF-alpha-308 gene polymorphism and EXPI. Eighty three patients entered the study. Tissue transglutaminase antibodies (anti-TTG), faecal elastase-1 (FE1) assays and genotyping for the CTLA-4 +49A/G and TNF-alpha308 were performed. Of 83 patients with CD EXPI had 13 (15.6 %). There was no statistically significant difference in frequency of polymorphisms for both genes (CTL-4 +49 i TNF-alpha-308) in the group with and without EXPI. In conclusion, EXPI is common in symptomatic CD patients, but further genetic studies with larger number of patients are needed.

Angiotensin-converting enzyme gene polymorphism in patients with multiple sclerosis from Bosnia and Herzegovina.

BACKGROUND: Increased activity of angiotensin-converting enzyme (ACE) in the blood and cerebrospinal fluid of patients with multiple sclerosis (MS), and the inhibition of ACE in experimental autoimmune encephalomyelitis, suggested that ACE may play a role in the pathogenesis and progression of MS. We recently published the first report on the potential association of MS and ACE I/D polymorphism in Slovenian and Croatian patients with MS, in which it was shown that the DD genotype might contribute to a higher risk of developing MS in men. To confirm these findings in a similar ethnic population, we analyzed ACE I/D gene polymorphism in patients with MS from Bosnia and Herzegovina. SUBJECTS AND METHODS: One hundred and seventy patients with MS and 170 healthy controls were genotyped by the polymerase chain reaction method. RESULTS: There was no significant difference in the distribution of ACE I/D genotypes (p=0.783) or in the allelic frequencies (p=0.538) between patients with MS and control subjects. When patients with MS were stratified by sex, no statistically significant differences in allele or genotype distributions were observed. Finally, there was no indication of an impact of the ACE I/D genotype on disease course or severity. CONCLUSION: The ACE I/D polymorphism is not a risk factor for development of MS, nor does it contribute to disease severity in this Bosnia and Herzegovina population.

MTHFR C677T and A1298C polymorphisms as a risk factor for congenital heart defects in Down syndrome.

BACKGROUND: Congenital heart defects (CHD) are present in most, but not all, cases of Down syndrome (DS). The presence of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms has been reported as a risk factor for CHD in DS. The aims of the present study were to assess (i) the frequency of MTHFR C677T and A1298C polymorphisms in DS individuals in the Croatian population; (ii) the relationship between the two maternal MTHFR polymorphisms and CHD-affected DS children; and (iii) the transmission frequencies of the variant alleles of the two MTHFR polymorphisms in CHD-affected DS. METHODS: The study population included 112 DS subjects and 221 controls. CHD were present in 48% of the DS subjects (54/112). The mothers of 107 DS individuals were available for the study; none was a periconceptional folic acid user. Allele transmission was analyzed in 34 complete parent-offspring triads. RESULTS: The frequencies of the allele, individual, and combined genotypes of MTHFR C677T and A1298C in DS subjects were not statistically different compared to the normal healthy Croatian controls. The maternal MTHFR polymorphisms were not found to be a risk factor for DS-related CHD. The allele transmission of the two MTHFR polymorphisms showed no deviations from random segregation. CONCLUSIONS: Because the fetus is lost in a great proportion of trisomy 21 pregnancies, both maternal and fetal, not only live-born MTHFR C677T and A1298C, as well as maternal nutrition and lifestyle during pregnancy, should be analyzed to asses the impact on CHD in DS.