Abstract Parkinson’s Disease (PD) is the most common form of degenerative parkinsonism with a prevalence of 1% of those older than 65 years. PD is characterized by the combination of slowness of ...movement (bradykinesia), muscular rigidity, resting tremor and postural instability. Recently, using a genome-wide linkage analysis and exome sequencing, a group identified a candidate gene ( CHCHD2 ) in a large Japanese family with autosomal dominant Parkinson’s disease. The aim of this study was to evaluate the presence of CHCHD2 mutations in a cohort of 165 familial patients with clinically diagnosed PD and 200 control subjects from South Italy. No mutations in CHCHD2 were found in our 165 PD patients. This result, suggesting that CHCHD2 mutations might not be common cause of PD in South Italy.
Doublecortin, encoded by the
gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the
gene are the major causes of the "lissencephaly (LIS) ...spectrum", which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother-daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic-phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.
Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which ...represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.
Recently, the
LRP10
gene has been associated with Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). The aim of the present study was to evaluate ...the presence of mutations of the
LRP10
gene in patients with PD or DLB from Southern Italy. Sequencing analysis revealed only 2 missense and 3 synonymous variants in patients and control subjects and a rare variant p.L622F in a PD case. These results suggest that LRP10 mutations are not a frequent cause of PD and DLB in Southern Italy.
Objective
Structural abnormalities in thalami and basal ganglia, in particular the globus pallidus (GP), are a neuroimaging hallmark of hereditary aceruloplasminemia (HA), yet few functional imaging ...data exit in HA carriers. This study investigated the iron-related structural and functional abnormalities in an Italian HA family.
Methods
Multimodal imaging was used including structural 3 T MRI, functional imaging (SPECT imaging with
123
I-ioflupane (DAT-SPECT), cardiac
123
I metaiodobenzylguanidine (
123
I-MIBG) scintigraphy, and
18
F-fluorodeoxyglucose (
18
F-FDG)-PET imaging). In the proband, MRI and scintigraphic evaluations were performed at baseline, 2 and 4 years (structural imaging), and 2 years of follow-up period (functional imaging).
Results
We investigated two cousins carrying a novel splicing homozygous mutation in intron 6 (IVS6 + 1 G > A) of CP gene. Interestingly, MRI features in both subjects were characterized by marked iron accumulation in the thalami and basal ganglia nuclei, while GP was not affected. MRI performed in the proband at 2 and 4 years of follow-up confirmed progressive neurodegeneration of the thalami and basal ganglia without the involvement of GP. Functional imaging showed reduced putaminal DAT uptake in both cousins, whereas cardiac MIBG and FDG uptakes performed in the proband were normal. Longitudinal scintigraphic investigations did not show significant changes over the time.
Conclusions
For HA carriers, our findings demonstrate that GP was spared by iron accumulation over the time. The nigrostriatal presynaptic dopaminergic system was damaged while the cardiac sympathetic system remained longitudinally preserved, thus expanding the imaging features of this rare inherited disorder.
Early onset has been implicated in clinical severity of sporadic Parkinson's Disease (PD) in many populations. PD onset is an important prognostic factor since the continuing neurodegeneration of PD ...is associated with cognitive deficit. The aim of this study is to analyze the age at onset (AAO) and cognitive deficit of PD in regards of the APOE gene. We investigated the AAO in a sample of 393 sporadic Parkinson's cases from Southern Italy. The admixture analysis highlighted the presence of two onset subgroups in our PD sample. Our analysis of early onset Parkinson's disease confirms the effect on more severe memory deficit in subjects with anticipated onset mediated by the APOE e4 (beta = −0.47; p = 0.02). Our study implicates the effect of e4 allele in susceptibility to cognitive symptoms in late onset PD. Even though our results are preliminary the APOE e4 allele may represent a moderating factor for cognitive deficit and anticipation in late onset PD patients.
•The best fitting model of age at onset of Parkinson's Disease is composed by two normal distributions with equal variance.•Early and late onset Parkinson’s Disease distributions have means at 48.5±7.1 and 63.5±7.1 respectively.•The FMM incorporating the APOE genetic effect in late onset Parkinson confirms the correlation between age at onset and memory deficit.
Febrile seizures (FS) affect 5–12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in ≈7% ...of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23–24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na v 1.1 channel α-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy. channelopathy FEB3 locus convulsions epilepsy neuronal excitability
Phospholipase A2-associated neurodegeneration (PLAN), a syndrome of Neurodegeneration with Brain Iron Accumulation (NBIA), is an autosomal recessive disorder caused by mutations in PLA2G6 gene. This ...gene encodes a calcium-independent group VI phospholipase A2 (iPLA-VI) critical in cell membrane homeostasis.
PLAN syndrome encompasses a group of phenotypes with a different age of onset: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy of childhood-onset (atypical NAD) and adult-onset PLA2G6-related dystonia-parkinsonism (PARK14).
INAD is a severe progressive psychomotor disorder characterized by the presence of axonal spheroids throughout the central and peripheral nervous system. Here we report clinical, genetic and histopathological findings of an INAD consanguineous-family from Senegal. Sanger sequencing analysis revealed a new homozygous PLA2G6-mutation in the proband (c.1483C>T) and the co-segregation of the mutation in this family.
Electron microscopy on skin biopsy showed degenerated axons confirming the phenotype.
This study contributes to enrich the landscape of PLA2G6-associated INAD mutations and enforce the genotype-phenotype correlation.
•We describe a 5-years old patient with typical INAD coming from a Senegal's consanguineous family.•Genetic analysis revealed a new PLA2G6-mutation and the co-segregation of the mutation in this family.•The iPLA2 β is not present in patient's cells as suggested by the nonsense-mediated mRNA decay at the RNA level.•This study enriches the landscape of PLA2G6-associated INAD mutations confirming the genotype-phenotype correlation.
DJ‐1 gene mutations have been found to cause early‐onset Parkinson's disease. We report a family from southern Italy with three brothers affected by early‐onset parkinsonism, dementia, and ...amyotrophic lateral sclerosis. Molecular analysis of the DJ‐1 gene in two living patients showed a novel homozygous mutation in exon 7 (E163K) and a new homozygous mutation (g.168_185dup) in the promoter region of the gene. Both mutations cosegregated with the disease and were detected in a heterozygous state in the patients' mother and their healthy siblings. Our findings expand the spectrum of clinical presentations associated with mutations in DJ‐1 gene. Ann Neurol 2005;58:803–807
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