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.
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.
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.
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.
Objectives
Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non‐dystrophic myotonias. These disorders are electrophysiologically characterized by altered ...membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co‐occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co‐segregates myotonia, JME, or abnormal EEG without seizures was observed.
Methods
All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant.
Results
Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp‐wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified.
Significance
These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family.
Plain Language Summary
This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.
Fragile X-associated tremor/ataxia syndrome is a late-onset neurodegenerative disorder that affects about 40% of carriers of CGG-repeat expansions in the premutation range within the fragile X gene ...(FMR1). Main clinical features include intention tremor, cerebellar ataxia, and parkinsonism. Recently, great emphasis on the deposition of soluble aggregates produced by a RAN translation process, as main pathogenic mechanism, has been given. These aggregates contain a small protein with a polyglycine stretch on the aminoterminal end named FMRpolyG and, so far, have been isolated and characterized in drosophila and mouse models, in post mortem brain of fragile X-associated tremor/ataxia syndrome patients, in fibroblasts of fragile primary ovarian insufficiency patients, but never in fibroblasts from a fragile X-associated tremor/ataxia living patients. In adult carriers the syndrome is frequently misdiagnosed due to the lack of specific markers.
We standardized immunocytochemistry, immunoprecipitation and western blot procedures to study and biochemically characterize the FMRpolyG protein in fibroblasts from human skin biopsy.
We demonstrate for the first time, in fibroblasts from a patient affected by Fragile X-associated tremor/ataxia syndrome, the presence ex vivo of inclusions consisting of FMRpolyG- Hsp70 soluble aggregates.
These observations can pave the way to develop a cellular model for studying ex vivo and in vitro the mechanisms involved in the production of FMRpolyG aggregates, their toxicity, and the role of the FMRpolyG-Hsp70 interaction in the pathogenesis of fragile X-associated tremor/ataxia syndrome.
•Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease.•The expansion of GGGGCC in C9orf72 is the major genetic causes of ALS and FTD.•The C9orf72 repeat was also rarely found in ...other disease, including MSA.•In this study was reported an analysis of C9orf72 in 100 MSA italians patients.•We detect the C9orf72 repeat in 2 MSA patients and the intermediate repeat in four.
Exanucleotide expansions in C9orf72 gene have been described as potential risk factor in some patients with Multiple system atrophy (MSA) and other forms of atypical parkinsonism. The goal of our study was to extend the knowledge on the involvement of C9orf72 in MSA studying a cohort of 100 patients from Italy. We identified 2 heterozygous patients in the pathological range (> 30 repeats) and 4 heterozygous patients for expansions in the premutation range (20 -30 repeats). Our findings strengthen the previously hypothesized role for this gene as a risk factor for MSA and raise the possibility of a more complex and still unknown involvement of this gene in the heterogeneity of MSA.
DCTN1 encodes the largest subunit of dynactin complex essential in the retrograde axonal transport and cytoplasmic transport of vesicles; mutations in DCTN1 have been reported predominantly in ...individuals with Perry syndrome and, recently, in patients with progressive supranuclear palsy. Our genetic screening of DCTN1 in 79 patients with progressive supranuclear palsy, 100 patients with multiple system atrophy, and 28 patients with dementia with Lewy bodies from Italy revealed only synonymous and intronic variants, suggesting that DCTN1 mutations do not have a key role in the development of atypical parkinsonism in the Italian population.
Background and purpose
Glucose transporter‐1 (GLUT1) deficiency syndrome (GLUT1‐DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. ...GLUT1‐DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant.
Methods
We present clinical and genetic features of a five‐generation family with GLUT1‐DS.
Results
The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8‐year‐old proband, who also had drug‐responsive absences associated with attention‐deficit/hyperactivity disorder. His 52‐year‐old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core.
Conclusions
Our study illustrates the extremely heterogenous phenotypes in familial GLUT1‐DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1‐DS.
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