Valerija Dobricic

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupps Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (β=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (β=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (β=+0.36, p<0.05) and level of education (β=-0.29, p<0.05). CONCLUSION Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.

Phenotype of non-c.907_909delGAG mutations in TOR1A: DYT1 dystonia revisited.

BACKGROUND In addition to the most frequent TOR1A/DYT1 mutation (c.907_909delGAG), a growing number of TOR1A sequence variants are found in dystonia patients. For most, functional characterization has demonstrated pathogenicity at different levels, implying that TOR1A genetic testing should not be limited to screening for c.907_909delGAG. METHODS We tested 461 Serbian patients with isolated or combined dystonia for changes in the TOR1A gene and performed a systematic literature review of the clinical characteristics of patients carrying TOR1A mutations other than c.907_909delGAG. RESULTS One likely pathogenic TOR1A mutation (c.385G>A, p.Val129Ile) was detected in an adult-onset cervical dystonia patient. This change is in proximity to the previously reported p.Glu121Lys mutation and predicted to decrease the stability of TOR1A-encoded protein TorsinA. CONCLUSIONS Our patient and three other reported carriers of non-c.907_909delGAG-mutations within the first three exons of TOR1A showed similar phenotypes of adult-onset focal or segmental cervical dystonia. This observation raises the possibility of genotype-phenotype correlations in DYT1 and indicates that the clinical spectrum of this type of dystonia might be broader then previous classic descriptions.

No Association between Brain-Derived Neurotrophic Factor G196A Polymorphism and Clinical Features of Parkinson's Disease

Aims: To investigate association of the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene with clinical features in Serbian patients with Parkinsons disease (PD). Methods: The study comprised 177 consecutive PD patients. A comprehensive set of clinical scales was applied in all patients. The controls (n = 366) were recruited among students. Single nucleotide polymorphisms (SNPs; rs6265) were analyzed using TaqMan assays. Results: PD patients (118 males) were aged 58.9 ± 10.9 years, with a mean age at onset of 49.0 ± 11.2 years. PD patients and controls had a similar distribution of genotypes and allele frequencies. The presence of the Met allele did not influence the clinical characteristics of PD patients (age at onset, family history, gender, disease duration, form of the disease, initial symptoms, cognitive abilities, depression, anxiety, disease severity, severity of motor and prevalence of nonmotor symptoms, and development of motor complications). Conclusion: Overall, the Val66Met polymorphism did not modify the clinical features in PD patients.

Transcranial sonography in patients with myotonic dystrophy type 1

Introduction: In this study we analyzed transcranial sonography (TCS) in patients with myotonic dystrophy type 1 (DM1). Methods: This cross‐sectional study included 66 DM1 patients and 55 matched healthy controls (HCs). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) and third ventricle width (DTV) were assessed by TCS. Results: BR hypoechogenicity was more common in DM1 patients than in HCs (37.7% vs. 7.8%, P < 0.01). Patients with depression or fatigue were more likely to have BR hypoechogenicity (80.0% vs. 29.4%, P < 0.01 and 51.9% vs. 24.2%, P < 0.05, respectively). Both hypoechogenicity and hyperechogenicity of SN were more frequent in DM1 patients than in controls (26.2% vs. 10.9% and 13.1% vs. 1.8%, respectively, P < 0.01). DTV was increased in DM1 patients compared with HCs (6.0 ± 1.4 vs. 4.9 ± 0.9 mm, P < 0.01). Conclusion: TCS can offer new insight into structural changes of several cerebral areas in patients with DM1. Muscle Nerve 50:278–282, 2014

Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations.

OBJECTIVES The aim of this study was to search for possible differences in the findings of transcranial sonography (TCS) between groups of patients with glucocerebrosidase (GBA)-associated Parkinsons disease (PD) (4 patients with Gaucher disease type 1 and parkinsonism [GD+PD+] and 18 PD patients with heterozygous GBA mutations; [GBA+PD+]) and groups of 12 patients with Gaucher disease type 1 and no signs of parkinsonism (GD+PD-), 9 asymptomatic carriers of heterozygous GBA mutations (GBA+PD-), 32 sporadic PD patients (sPD), and 43 healthy controls. RESULTS In all groups of patients, except asymptomatic carriers of heterozygous GBA mutations (mean ± SD: 0.16 ± 0.03 cm(2)), the maximal areas of substantia nigra hyperechogenicity (aSN-max) was higher (GD+PD+: 0.28 ± 0.15 cm(2); GD+PD-: 0.18 ± 0.06 cm(2); GBA+PD+: 0.27 ± 0.06 cm(2); sPD: 0.28 ± 0.10 cm(2)) when compared to controls (0.12 ± 0.08 cm(2)) (p = 0.001). In GBA-associated PD (GD+PD+ and GBA+PD+) and sPD, aSNmax values were very similar. Moderate or marked SN hyperechogenicity was present in 87.5% of sPD patients and in 83% of PD patients with heterozygous GBA mutations, but in only 11.6% of controls, and in 22.2% and 33.3% of patients from GBA+PD- and GD+PD- groups, respectively (p < 0.001). The prevalence of interrupted or missing echogenicity of the brainstem raphe differed between the groups (p = 0.046), while no difference was observed in the diameter of the third ventricle. CONCLUSIONS TCS findings in GBA-associated PD were consistent to those of patients with sporadic PD.

De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient

Mutations in GNAL (DYT25) have recently been established as the first confirmed cause of focal or segmental adult‐onset dystonia. Mutation carriers show craniocervical involvement; however, the GNAL mutational and phenotypic spectrum remain to be further characterized, and guidelines for diagnostic testing need to be established.

Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort

Alzheimers disease (AD) is the most common form of dementia. To date, more than 200 mutations in three genes have been identified as cause of early-onset autosomal dominant inherited AD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in Serbian patients with positive family history of AD or/and early-onset AD. We performed a genetic screening for mutations in the coding regions of Presenilins 1 and 2 (PSEN1 and PSEN2), as well as exons 16 and 17 of the Amyloid Precursor Protein gene (APP) in a total of 47 patients from Serbia with a clinical diagnosis of familial and/or early-onset AD (mean age at onset of 60.3 years; range 32-77). We found one novel mutation in PSEN1, one novel variant in PSEN2, and three previously described variants, one in each of the analyzed genes. Interestingly, we identified one patient harboring two heterozygous mutations: one in APP (p.L723P) and one in PSEN1 (p.R108Q).

Novel GNAL mutations in two German patients with sporadic dystonia

Isolated adult-onset focal dystonia is the most frequent form of dystonia. Recently, mutations in GNAL have been identified in patients with predominant or isolated cervical dystonia. To evaluate the frequency of GNAL mutations as a cause of dystonia in our patients as compared with other populations and to further delineate the associated phenotypic spectrum, we screened a cohort of 136 unrelated patients from Northern Germany with mostly sporadic, predominantly isolated cervical dystonia (see Supplemental Data Table S1 for clinical characteristics) by direct DNA sequencing of all 12 GNAL coding exons (for detailed methods, see Supplemental Data). Patients were recruited from two separate cohorts: 119 patients were treated with botulinum toxin on a regular basis with good benefit, whereas 17 other patients had undergone deep brain stimulation (two patients previously reported in Lohmann et al.; see supplemental data). Additionally, exon 4 of GNAL was sequenced in 180 healthy German control individuals. We identified two novel GNAL mutations: one heterozygous missense variant in GNAL exon 4, c.289A>G, which leads to substitution of a highly conserved methionine residue with valine (p.Met97Val) (Supplemental Data Fig. S1). This variant was found neither in 360 chromosomes of ethnically matched healthy German control individuals, nor in 570 Filipino control chromosomes, nor in publicly available databases (exome variant server, dbSNP, 1000 Genomes project). This variant was detected in a sporadic patient (patient 1, Table 1) with late-onset segmental (cervical and truncal) dystonia. This patient had undergone deep brain stimulation of the globus pallidus internus, which resulted in marked improvement especially of truncal dystonia, with an 81% reduction of the Burke-Fahn-Marsden dystonia rating scale/motor part at 5-year follow-up compared with baseline (see case report under Supplemental Data and video segments 1 and 2). In silico analysis with Mutation Taster, Polyphen-2, SIFT, and MutPred indicated that this variant is predicted to be disease-causing. In addition, we identified a novel heterozygous single-nucleotide insertion/frameshift mutation in exon 2 of GNAL, c.166_167insA (p.Ser56Lysfs*16), in one patient with typical sporadic focal cervical dystonia (patient 2, Table 1). This mutation is predicted to result in a truncated Gaolf protein of only 72 amino acids, missing most functional domains, and was not found in the above-mentioned public databases (EVS: 6503 individuals). Unfortunately, the parents of both patients 1 and 2 were deceased and therefore unavailable for molecular segregation analysis. The novel missense variant, c.289A>G (p.Met97Val), likely represents a pathogenic mutation with regard to dystonia, because (1) it is located in a highly conserved region of the GNAL-encoded Gaolf protein (Supplemental Data Fig. S1); (2) it was found neither in a set of 930 (360 German and 570 Filipino) control chromosomes nor in publicly available databases; and (3) it is predicted to be disease causing by in silico analysis. The associated phenotype of late-onset segmental (cervical and truncal) dystonia is in accordance with the previously reported phenotypic spectrum. However, the possibility that this variant represents a very rare polymorphism cannot be completely ruled out. Of particular interest, this patient derived excellent continuous long-term benefit from bilateral deep brain stimulation of the globus pallidus internus at 5-year follow-up, which may indicate that this form of monogenic dystonia is particularly responsive to deep brain stimulation; however, this hypothesis needs to be tested in larger patient cohorts. To our knowledge, this is the first GNAL mutation-positive dystonia patient reported who underwent deep brain stimulation. In summary, our results further support a role for GNAL mutations as a rare but relevant genetic cause of isolated dystonia with predominant cervical involvement.

HD phenocopies--possible role of Saitohin gene.

Saitohin (STH) is located in the intron of the human gene for microtubule-associated protein tau. Q7R polymorphism has been identified in the STH gene. Some neurodegenerative disorders were found to be associated with the presence of certain STH allele. This study genotyped 37 subjects with diagnosis of Huntingtons disease, but lacking mutations in HD, PRNP, JPH-3, and FTL genes for STH polymorphism. It was determined that Q allele of STH gene was over-represented in a tested group of patients (P > Pt). Over-representation of Q allele in a group of patients might be considered as genetic risk factor for HD like diseases.