Association of PDE11A global haplotype with major depression and antidepressant drug response

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers cAMP and cGMP to their corresponding monophosphates. PDEs play an important role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. We have previously shown that the individual haplotype GAACC in the PDE11A gene was associated with major depressive disorder (MDD) based on block-by-block analysis. There are two PDE genes, PDE11A and PDE1A, located in chromosome 2q31–q32. In this study, we have further explored whether the whole region 2q31–q32 contribute to MDD or antidepressant response 278 depressed Mexican-American participants and 321 matched healthy controls. Although there is no significant interaction between the two genes, the remission rate of individual carrying the combination genotype at rs1880916 (AG/AA) and rs1549870 (GG) is significantly increased. We analyzed the global haplotype by examining 16 single-nucleotide polymorphisms (SNPs) in PDE11A and six SNPs in PDE1A. None of the haplotypes consisting of six SNPs in the PDE1A have a significant difference between depressed and control groups. Among haplotypes consisting of 16 SNPs across 440 kb in the PDE11A gene, 18 common haplotypes (with frequency higher than 0.8%) have been found in the studied population. Six haplotypes showed significantly different frequencies between the MDD group and the control group. The phylogenetic network result for the 16 SNPs showed that several historic recombination events have happened in the PDE11A gene. The frequency of one haplotype is significantly lower in the remitter group than in the nonremitter group for the depressed participants treated with either desipramine or fluoxetine. Thus, our data suggest that the PDE11A global haplotype is associated with both MDD and antidepressant drug response

Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article

<p>Abstract</p> <p>Background</p> <p>The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family.</p> <p>Methods</p> <p>Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped.</p> <p>Results</p> <p>Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied.</p> <p>Conclusion</p> <p>While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study.</p

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

Summary SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive

Genetic investigation of two different families with dominant forms of limb-girdle muscular dystrophy

As distrofias musculares tipo cinturas (DMC) incluem um grupo heterogêneo de doenças genéticas, caracterizadas por degeneração progressiva da musculatura esquelética pélvica e escapular, cuja herança pode ser autossômica dominante (DMC1) ou autossômica recessiva (DMC2). As formas dominantes são relativamente raras, compreendendo menos que 10% dos casos. Até o momento foram mapeados 8 locos para DMC1, (DMC1A-H), onde 3 genes já foram identificados (DMC1A-C) e 17 locos para DMC2 (DMC2A-Q), onde 16 genes já foram identificados. No presente estudo, identificamos uma família uruguaia (família 1) com 11 indivíduos afetados por DMC, distribuídos em 3 gerações, com um padrão de herança autossômico dominante. Os objetivos desse trabalho foram: mapear e refinar o loco gênico associado a uma manifestação familiar de DMC1, verificar se há co-localização da região mapeada com outras formas de DMC1 descritas na literatura e, apontar genes candidatos na região mapeada e triar mutações. Foi realizado estudo de ligação, no qual mapeou-se o loco para essa doença na região 4q13-q24 com Lod score de valor máximo 4.78 para o marcador D4S414. A região foi delimitada entre os marcadores D4S392 e D4S1572. A análise da região redefiniu o loco em 4q21.22-21.23, com uma redução de 33 Mb para 4Mb. Esse loco compreende a DMC1G (família 2), descrita anteriormente pelo nosso grupo. A triagem de mutação, realizada em amostras de afetados das duas famílias, nos permitiu encontrar uma alteração Thr141Iso no exon 5 do gene FAM175A apenas nos pacientes da família 2. Essa mesma alteração foi encontrada em 1 dos 500 controles testados, o que não nos permite excluir esse gene como um candidato para DMC1G já vez que essa frequência foi inferior a 1%. O fato dessa alteração não ter sido vista na família 1 também não nos permite excluí-lo, pois foi sequenciada apenas a região exônica e a metodologia utilizada também não nos permite verificar deleções nem duplicações. Estudos mais detalhados precisam ser realizados a fim de elucidar: (1) se a alteração desse gene é a causadora dessas DMCs ou, (2) se excluído esse gene, poderia ser o responsável.Limb girdle muscular dystrophy (LGMD) include a heterogeneous group of genetic diseases characterized by progressive degeneration of skeletal muscles of the pelvic and scapular girdles, whose inheritance may be autosomal dominant (LGMD1) or autosomal recessive (LGMD2). The dominant forms are relatively rare, comprising less than 10% of cases. So far eight loci were mapped for LGMD1 (LGMD1A-H), where three genes have been identified (LGMD1A-C) and 17 loci for LGMD2 (LGMD2A-Q), with 16 identified genes. In this study, we analised a family from Uruguay (family 1) with 12 individuals affected by LGMD, with an autosomal dominant pattern distributed in three generations. The objectives of this study were: to map and refine the gene locus associated with a familial DMC1, check for co-location of the mapped region to other forms of DMC1 described in the literature and, to point candidate genes mapped in the region and to screen mutations. A linkage study was conducted, and we mapped the locus for this disease in the region 4q13-q24 with a maximum Lod score of 4.78 for marker D4S414. The region was defined between markers D4S392 and D4S1572. The analysis of the region has redefined the locus to 4q21.22-in 21:23, a reduction from 33 Mb to 4 Mb. This site includes LGMD1G (family 2), previously described by our group. Mutation screening, performed on samples of affected pacients from both families, allowed us to find a modification Thr141Iso in exon 5 on FAM175A gene only in patients of family 2. This same alteration was found in one of the 500 controls tested but does not allow us to exclude this gene as a candidate for LGMD1G since that frequency was less than 1%. The fact that this change was not seen in a family 1 does not allow us to exclude it either because only the exonic region was sequenced and the methodology used does not allow us to detect deletions or duplications. More detailed studies should be conducted to elucidate: (1) whether the alteration found in this gene is the cause of these DMCs, or (2) if not this gene, which could be the one responsible

Neural correlates of digital measures shown by structural MRI: a post-hoc analysis of a smartphone-based remote assessment feasibility study in multiple sclerosis

BackgroundA study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests.MethodsIn a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55&nbsp;years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis.ResultsWorse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35).ConclusionsMultiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments

Neural correlates of digital measures shown by structural MRI : a post-hoc analysis of a smartphone-based remote assessment feasibility study in multiple sclerosis

A study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests. In a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis. Worse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ − 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ − 0.41), and pons (r = 0.35/ − 0.35). Multiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments. The online version contains supplementary material available at 10.1007/s00415-022-11494-0