Neurological comorbidity and severity of COVID-19

Journal of Neurology - Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and...     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Investigating the genetic role of aquaporin4 gene in migraine

Aquaporin4 (AQP4) has an important role in water homeostasis of human brain and a dysfunction of AQP4 could induce pathological conditions in neuronal activity. The purpose of our work was to evaluate the association of polymorphisms in the AQP4 gene with the risk and the clinical features of migraine. A total of 293 migraineurs and 249 controls were involved in the study. They were genotyped for four single nucleotide polymorphisms (SNPs) of AQP4 gene. No significant difference in the distribution of AQP4 genotypic and allelic frequencies between cases and controls was found. In addition, haplotype analysis did not show any significant difference. Comparison of the clinical features of the disease according to different AQP4 genotypes showed no significant difference. Our data do not support the hypothesis that the AQP4 gene could represent a genetic susceptibility factor for migraine.     

Mutations in the lamin B1 gene are not present in multiple sclerosis

Background:  Whole gene duplication of the lamin B1 gene ( LMNB1 ), encoding for a protein of the nuclear lamina, causes an adult-onset autosomal dominant leukodystrophy (ADLD). Clinical features of ADLD (onset in adult life, dysautonomic symptoms, followed by pyramidal and cerebellar dysfunctions) partially resemble those of multiple sclerosis (MS), particularly the primary-progressive form. Our aim was to test whether LMNB1 gene mutations were present amongst patients with a diagnosis of MS.
Methods:  One hundred eighty-two MS patients were screened for copy number variations of the LMNB1 gene using a qPCR assay. Point mutations in the LMNB1 gene were searched by denaturing high-performance liquid chromatography and direct sequencing in a subgroup of 16 patients with familial MS.
Results:  No duplication/deletion of the lamin B1 gene was found amongst MS patients, and no point mutation was identified in the familial cases.
Conclusion:  Our work indicates that lamin B1 defects are probably not responsible for signs and symptoms resembling multiple sclerosis.     

Familial Alzheimer's disease. Evidences for clinical and genetic heterogeneity.

We report the genealogical, clinical and molecular genetic findings of a new family with autosomal dominant early-onset Alzheimer's disease (FAD) discovered in Torino (Italy). Up to now, the pedigree comprises 1500 members, distributed in 8 generations. 22 patients affected with Alzheimer's disease have been identified. The clinical course of the disease was fairly uniform in all the patients. An high incidence of myoclonic jerks and epileptic seizures was found. Molecular genetic studies showed the presence of positive but nonsignificant lod scores between chromosome 21 anonymous DNA markers and the disease. The data obtained from the Torino family were computed together with those of additional 47 pedigrees, with both early-onset and late-onset Alzheimer's disease. A predisposing locus for the disease was found on the pericentromeric region of chromosome 21 only in early-onset FAD pedigrees.     

Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimer's disease (FAD) associated with a mutation (G----A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at theta = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.     

Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis

There are conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene. The C677T polymorphism reduces enzymatic capability by 50% and causes hyperhomocysteinaemia. We performed a meta-analysis of all published studies investigating the association between the MTHFR gene and migraine. Pooled odds ratios (OR) were estimated using random (RE) and fixed effects (FE) models. Among the overall 2961 migraineurs there was no significant difference compared with controls. Only in migraine with aura was the TT genotype associated with a higher risk of disease compared with the CC genotype [FE OR 1.30, 95% confidence interval (CI) 1.06, 1.58; RE OR 1.66, 95% CI 1.06, 2.59]. In the same subgroup a significant difference was observed in the comparison between TT and CT + CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43). This study provides evidence for an association of the MTHFR gene only in migraine with aura.     

A family with autosomal dominant leukodystrophy linked to 5q23.2–q23.3 without lamin B1 mutations

Background and purpose: Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult‐onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. Methods: We carried out a genome‐wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real‐time PCR, multiplex ligation‐dependent probe amplification and Southern blot. Results: We mapped the variant ADLD locus to 5q23.2–q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy‐number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. Conclusions: This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.