Three Individuals with PURA Syndrome in a Cohort of Patients with Neuromuscular Disease

AbstractPur-α protein (PURA) syndrome manifests in early childhood with core features such as neurodevelopmental and speech delay, feeding difficulties, epilepsy, and hypotonia at birth. We identified three cases with PURA syndrome in a cohort of patients with unexplained muscular weakness, presenting with a predominantly neuromuscular and ataxic phenotype. We further characterize the clinical presentation of PURA syndrome including myopathic facies and muscular weakness as the main clinical symptoms in combination with elevated serum creatine kinase levels. Furthermore, we report two novel variants located in the conservative domains PUR-I and PUR-II. For the first time, we present the muscle biopsies of PURA syndrome patients, showing myopathic changes, fiber size variability, and fast fiber atrophy as the key features. PURA syndrome should be taken into consideration as a differential diagnosis in pediatric patients with unexplained muscle weakness.

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Phylogenomic Evidence of Reinfection and Persistence of SARS-CoV-2: First Report from Colombia

Vaccines ◽

10.3390/vaccines9030282 ◽

2021 ◽

Vol 9 (3) ◽

pp. 282

Author(s):

Juan David Ramírez ◽

Marina Muñoz ◽

Nathalia Ballesteros ◽

Luz H. Patiño ◽

Sergio Castañeda ◽

...

Keyword(s):

Viral Persistence ◽

Transmission Dynamics ◽

Polymorphism Analysis ◽

Rt Pcr ◽

Paired Samples ◽

Infection Dynamics ◽

Oxford Nanopore ◽

Novel Variants ◽

First Time ◽

Oxford Nanopore Technologies

The continuing evolution of SARS-CoV-2 and the emergence of novel variants have raised concerns about possible reinfection events and potential changes in the coronavirus disease 2019 (COVID-19) transmission dynamics. Utilizing Oxford Nanopore technologies, we sequenced paired samples of three patients with positive RT-PCR results in a 1–2-month window period, and subsequent phylogenetics and genetic polymorphism analysis of these genomes was performed. Herein, we report, for the first time, genomic evidence of one case of reinfection in Colombia, exhibiting different SARS-CoV-2 lineage classifications between samples (B.1 and B.1.1.269). Furthermore, we report two cases of possible viral persistence, highlighting the importance of deepening our understanding on the evolutionary intra-host traits of this virus throughout different timeframes of disease progression. These results emphasize the relevance of genomic surveillance as a tool for understanding SARS-CoV-2 infection dynamics, and how this may translate effectively to future control and mitigations efforts, such as the national vaccination program.

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Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

European Journal of Human Genetics ◽

10.1038/s41431-020-00769-7 ◽

2021 ◽

Author(s):

Meena Balasubramanian ◽

Alexander J. M. Dingemans ◽

Shadi Albaba ◽

Ruth Richardson ◽

Thabo M. Yates ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Function ◽

Autism Spectrum ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Related Disorder ◽

Feeding Difficulties ◽

Facial Phenotype ◽

Novel Variants ◽

Common Behaviour

AbstractWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

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Genetic and Antigenic Characterization of Avian Avulavirus Type 6 (AAvV-6) Circulating in Canadian Wild Birds (2005–2017)

Viruses ◽

10.3390/v13040543 ◽

2021 ◽

Vol 13 (4) ◽

pp. 543

Author(s):

Tamiko Hisanaga ◽

Catherine Soos ◽

Nicola Lewis ◽

Oliver Lung ◽

Matthew Suderman ◽

...

Keyword(s):

Clinical Symptoms ◽

Fusion Gene ◽

Full Genome ◽

Genome Sequences ◽

Viral Shedding ◽

Genetic Groups ◽

Antigenic Characterization ◽

Specific Pathogen ◽

First Time

We describe for the first time the genetic and antigenic characterization of 18 avian avulavirus type-6 viruses (AAvV-6) that were isolated from wild waterfowl in the Americas over the span of 12 years. Only one of the AAvV-6 viruses isolated failed to hemagglutinate chicken red blood cells. We were able to obtain full genome sequences of 16 and 2 fusion gene sequences from the remaining 2 isolates. This is more than double the number of full genome sequences available at the NCBI database. These AAvV-6 viruses phylogenetically grouped into the 2 existing AAvV-6 genotype subgroups indicating the existence of an intercontinental epidemiological link with other AAvV-6 viruses isolated from migratory waterfowl from different Eurasian countries. Antigenic maps made using HI assay data for these isolates showed that the two genetic groups were also antigenically distinct. An isolate representing each genotype was inoculated in specific pathogen free (SPF) chickens, however, no clinical symptoms were observed. A duplex fusion gene based real-time assay for the detection and genotyping of AAvV-6 to genotype 1 and 2 was developed. Using the developed assay, the viral shedding pattern in the infected chickens was examined. The chickens infected with both genotypes were able to shed the virus orally for about a week, however, no significant cloacal shedding was detected in chickens of both groups. Chickens in both groups developed detectable levels of anti-hemagglutinin antibodies 7 days after infection.

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LIMB-GIRDLE MUSCULAR DYSTROPHY: ITS LARGER SIGNIFICANCE

PEDIATRICS ◽

10.1542/peds.41.2.382 ◽

1968 ◽

Vol 41 (2) ◽

pp. 382-384

Author(s):

S. C.

Keyword(s):

Peripheral Nerves ◽

Neuromuscular Disorders ◽

Serum Enzymes ◽

Muscle Disease ◽

Muscular Dystrophies ◽

Muscular Weakness ◽

Conduction Velocities ◽

Clinical Awareness ◽

Muscle Biopsies

The current literature reflects the interest of pediatricians, neurologists, and internists in the neuromuscular disorders of childhood.1-5 Clinical awareness and the availability and refinement of ancillary procedures, such as electromyography, measurement of nerve conduction velocities, determination of serum enzymes and muscle biopsies, have made it possible to differentiate many of these conditions and correctly localize the pathology of these lower motor neuron disorders to the anterior horn cells, the peripheral nerves, and/or the muscles.1 Primary muscle disease is the most frequent cause of progressive muscular weakness in children with neuromuscular disorders.2 The primary myopathies are either hereditary or acquired. The muscular dystrophies and the myotonic syndrome are representative of the genetic variety, while the acquired disorders are recognized clinically as polymyositis and dermatomyositis.

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Bovine ephemeral fever epidemics in Kingdom Saudi Arabia: clinical, epidemiological and molecular investigation

The Journal of Infection in Developing Countries ◽

10.3855/jidc.8201 ◽

2017 ◽

Vol 11 (11) ◽

pp. 854-860 ◽

Cited By ~ 1

Author(s):

Ahmed A Zaghawa ◽

Fadhel Housawi ◽

Abdulmohsen Al-Naeem ◽

Ahmed Elsify ◽

Yamen Mohammed Hegazy

Keyword(s):

Saudi Arabia ◽

Water Buffalo ◽

Virus Isolation ◽

Clinical Symptoms ◽

Rt Pcr ◽

Serum Samples ◽

Bovine Ephemeral Fever ◽

Geographical Regions ◽

Epidemiological Pattern ◽

First Time

Introduction: Bovine ephemeral fever virus (BEFV) is an arthropod borne Rhabdovirus affects cattle and water buffalo causes acute febrile disease. Methodology: The clinical picture and epidemiological pattern of BEF were described among cattle in epidemics of 2007, 2009 and 2011 in four geographical regions of Kingdom Saudi Arabia (Eastern, Jizan, Qasim, and Riyadh). Serum samples were tested using VNT. Virus isolation and molecular characterization were carried out for the first time in KSA. Results: The main clinical symptoms were fever, stiffness, lameness, salivation and subcutaneous emphysema. The prevalence and the mortality rate of BEF have decreased from 70% and 4.6% in 2007 to 30% and 0.6% in 2011, respectively in the 4 studied areas. There was no region association with higher prevalence of BEF. The intracluster correlation (ICC) was estimated for the first time in KSA as 0.0034. BEFV had been isolated from 11 out of 20 samples (55%) and isolation was confirmed by VNT. The molecular detection of BEFV by RT-PCR and real- time RT-qPCR were found more sensitive for diagnosis of the disease than virus isolation; 80% and 90% for the former tests and 55% for the latter. Three isolates were sequenced, they showed 84.7% - 100% identities in between and shared 90.4%-96.5% sequence identity with a previously published sequence from Australia (KF679404). The generated sequences belonged to 3rd cluster of BEFV glycoprotein. Conclusions: BEF occurrence has cyclic nature and the efficacy of vaccines prepared from local strains has to be evaluated and considered in diseases control.

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D-thyroxine reduces lipoprotein(a) serum concentration in dialysis patients.

Journal of the American Society of Nephrology ◽

10.1681/asn.v9190 ◽

1998 ◽

Vol 9 (1) ◽

pp. 90-96

Author(s):

C Bommer ◽

E Werle ◽

I Walter-Sack ◽

C Keller ◽

F Gehlen ◽

...

Keyword(s):

Serum Concentration ◽

Ldl Cholesterol ◽

Clinical Symptoms ◽

Hormone Secretion ◽

Elevated Serum ◽

Serum Levels ◽

Controlled Study ◽

Dialysis Patients ◽

Lipoprotein A ◽

Thyroxine Therapy

Uremia raises lipoprotein(a) (Lp(a)) serum concentration and the risk of arteriosclerosis in dialysis patients. The treatment of high Lp(a) levels is not satisfactory today. The decrease of Lp(a) in hypothyroid patients on L-T4 therapy raised the question of whether dextro-thyroxine (D-thyroxine) reduces not only serum cholesterol, but also Lp(a) serum concentration. In a single-blind placebo-controlled study, the influence of D-thyroxine therapy on Lp(a) serum concentration was evaluated in 30 hemodialysis patients with elevated Lp(a) serum levels. Lp(a) was quantified in parallel by two methods, i.e., rocket immunoelectrophoresis and nephelometry, and apo(a) isoforms were determined by a sensitive immunoblotting technique. Regardless of the apo(a) isoforms, 6 mg/d D-thyroxine reduced elevated Lp(a) levels significantly by 27 +/- 13% in 20 dialysis patients (P < 0.001) compared with 10 control subjects (-9.9 +/- 8.4%). In parallel, D-thyroxine therapy significantly lowered total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and LDL cholesterol/HDL cholesterol ratio (P < 0.01); raised T4 and T3 serum levels; and suppressed thyroid-stimulating hormone secretion without causing clinical symptoms of hyperthyroidism in any of the patients. D-Thyroxine reduces elevated serum Lp(a) concentration in dialysis patients. The effect in nondialysis patients can be expected but remains to be proven.

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Placental markers of folate-related metabolism in preeclampsia

Reproduction ◽

10.1530/rep-10-0484 ◽

2011 ◽

Vol 142 (3) ◽

pp. 467-476 ◽

Cited By ~ 24

Author(s):

C Mislanova ◽

O Martsenyuk ◽

B Huppertz ◽

M Obolenskaya

Keyword(s):

Clinical Symptoms ◽

Total Content ◽

Plasma Homocysteine ◽

Positive Relation ◽

Rt Pcr ◽

Methylene Tetrahydrofolate Reductase ◽

Tight Association ◽

The Impact ◽

First Time ◽

Related Compounds

The etiology and degree of clinical symptoms of preeclampsia depend on genotypic and phenotypic maternal and trophoblast factors, and elevated levels of plasma homocysteine (Hcy) are one of the pathogenetic factors of preeclampsia. To assess the impact of the folate-related metabolism, we characterized the indices of this metabolism in 40 samples from uncomplicated term placentas and 28 samples from preeclamptic pregnancies by quantifying the total content of folate, methionine (Met), Hcy and related cysteine, and glutathione (GSH) in compliance with the 677 C/T genotype of methylene tetrahydrofolate reductase (MTHFR). The prevalence ofMTHFRgenotypes was not significantly different between the two groups. The polymorphism ofMTHFRwas not unambiguously connected with the content of total placental Met, Hcy and related cysteine, and GSH either in uncomplicated or in complicated pregnancies. By contrast, the combination of the heterozygousMTHFRgenotype with folate deficiency in the samples from preeclamptic pregnancies was characterized by a statistically significant decrease in the Met content, a trend toward increased Hcy levels and a tight association between metabolically directly and indirectly related compounds, e.g. positive relation between Hcy versus cysteine and folate versus GSH and negative relation between folate versus Hcy and both Hcy and cysteine versus GSH. We demonstrated the expression of cystathionine-β-synthase (CBS) in human placenta at term by RT-PCR and western blot analysis, for the first time, and confirmed its catalytic activity and the accumulation of cysteine and CBS in placental explants cultivated in the presence of elevated Hcy concentrations. We suggest that disturbance in placental folate-related metabolism may be one of the pathogenetic factors in preeclampsia.

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Identification of two novel variants in GAA underlying infantile-onset Pompe disease in two Pakistani families

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0477 ◽

2020 ◽

Vol 33 (4) ◽

pp. 553-556

Author(s):

Aman Ullah ◽

Bibi Zubaida ◽

Huma Arshad Cheema ◽

Muhammad Naeem

Keyword(s):

Pompe Disease ◽

Age Of Onset ◽

Pathogenic Variants ◽

Whole Exome ◽

Sequence Variations ◽

Heterozygous Variant ◽

Novel Variants ◽

Carrier Identification ◽

First Time ◽

Pakistani Families

AbstractBackgroundPompe disease (PD) is an autosomal recessive metabolic myopathy with an average incidence of one in 40,000 live births. It has a variable age of onset and can be diagnosed within the first 3 months. Heart involvement and muscle weakness are its primary manifestations.Case presentationWe describe two families affected by PD with two rare, novel variants. To date, pathogenic variants in acid α-glucosidase (GAA) alone have accounted for all cases of the disease. Both families were screened for pathogenic sequence variations. This study presents the implications of regulatory or modifier sequences in the disease pathogenesis for the first time. A homozygous missense p.Arg854Gln variant in family A and a single heterozygous variant (p.Asn925His) in family B were found to be segregating according to the disease phenotype. The variants were not detected in our in-house database comprising 50 whole-exome sequences of healthy individuals from a local unrelated Pakistani population. In silico analyses predicted that the variants would have deleterious effects on the protein structure.ConclusionsThe variants likely underlie the infantile-onset PD (IOPD) in these Pakistani families. The study expands the mutation spectrum of GAA associated with IOPD and highlights the insufficiency of screening the GAA coding sequence to determine the cause of IOPD. The work should be helpful in carrier identification, improving genetic counselling, and prenatal diagnosis.

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Severe Trombiculiasis in Hunting Dogs Infested With Neotrombicula inopinata (Acari: Trombiculidae)

Journal of Medical Entomology ◽

10.1093/jme/tjz071 ◽

2019 ◽

Vol 56 (5) ◽

pp. 1389-1394 ◽

Cited By ~ 2

Author(s):

M Areso Apesteguía ◽

J B Areso Portell ◽

N Halaihel Kassab ◽

M J Gracia Salinas

Keyword(s):

Clinical Symptoms ◽

Mite Species ◽

Clinical Findings ◽

Risk Area ◽

Hunting Dogs ◽

Natural Park ◽

Large Numbers ◽

La Rioja ◽

First Time ◽

Fast Acting

Abstract This study records the clinical findings in nine hunting dogs showing systemic illness associated with trombiculids and identifies the mite species involved. In fall, coinciding with the seasonality of mites, all dogs were infested with mites and had been in the risk area (Sierra Cebollera Natural Park, La Rioja, Spain) a few hours before the onset of symptoms. The symptoms included vomiting, anorexia, weakness and lethargy, diarrhea, and even stupor. The clinical picture was fast-acting and potentially fatal. The infestations varied from low to severe. Molecular analysis of mites that fed on the dogs confirmed that they were larvae of Neotrombicula inopinata (Oudemans, Acari, Trombiculidae). This is the first time that N. inopinata has been identified as feeding on dogs and implicated in canine systemic illness associated with trombiculids. In contrast to other chiggers, N. inopinata does not seem to cause dermatitis. Likewise, the clinical and epidemiological similarity between the clinical symptoms we describe herein and the occurrence of seasonal canine illness (SCI) led us to suspect that this illness may be caused by infestation with these mites. The condition could be the consequence of severe infestation from large numbers of feeding mites, especially N. inopinata. Whether or not the cases were due to a severe allergic host response to salivary proteins or the result of the transmission of a new or emerging trombiculid-borne pathogen is not known.

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Metabolomics Distinguishes DOCK8 Deficiency from Atopic Dermatitis: Towards a Biomarker Discovery

Metabolites ◽

10.3390/metabo9110274 ◽

2019 ◽

Vol 9 (11) ◽

pp. 274 ◽

Cited By ~ 4

Author(s):

Minnie Jacob ◽

Xinyun Gu ◽

Xian Luo ◽

Hamoud Al-Mousa ◽

Rand Arnaout ◽

...

Keyword(s):

Atopic Dermatitis ◽

Biomarker Discovery ◽

Isotope Labeling ◽

Immunoglobulin E ◽

Clinical Symptoms ◽

Elevated Serum ◽

Severe Atopic Dermatitis ◽

Serum Ige ◽

Tryptophan Degradation ◽

Dock8 Deficiency

Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenylalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary.

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