204 research outputs found

    Undiagnosed Phenylketonuria Can Exist Everywhere:Results From an International Survey

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    Many countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS

    Novel Sequence Variants in the NPC1 Gene in Egyptian Patients with Niemann-Pick Type C

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    BACKGROUND: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, progressive neuro-visceraldisease caused by biallelic mutations in either NPC1gene (95% of cases) or NPC2 gene. AIM: This caseseries study aimed at the molecular analysis of certain hot spots of NPC1 genein NPC Egyptian patients. METHODS: The study included 15 unrelated NPC patients and selected parents,as well as20 healthy controls of matched sex and age. Clinical investigations were performed according to well established clinical criteria. Assessment of the chitotriosidase level, as an initial screening tool for NPC, was done in all cases. Polymerase chain reaction amplification of NPC1 exons (17–25) encountering the hotspot residues (855–1098 and1038–1253) was carried out followed by direct sequencingfor mutational analysis. RESULTS: All includedpatients with mainly neurovisceral involvement were characterized. The onset of the disease varied from early-infantile (58.3%) to late-infantile (26.7%) and juvenile-onset (6.7%). Ahigh chitotriosidase level wasobservedin all patients. Molecular analysis of NPC1 (exons 17–25) confirmed 15 mutant alleles out of 30 studied ones. They included two novel homozygous missense variants (p.Ser1169Arg and p.Ser1197Phe) and previously reportedfour mutations (p.Arg958*, p.Gly910Ser, p.Ala927Glyfs*38, and andp.Cys1011*). CONCLUSION: The two studied amino acid residues (855–1098 and 1038–1253) could beconsidered aspotential hotspot regions in NPC1 Egyptian patients

    ¹H-NMR metabolic profiling, antioxidant activity, and docking study of common medicinal plant-derived honey

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    The purpose of this investigation was to determine ¹H-NMR profiling and antioxidant activity of the most common types of honey, namely, citrus honey (HC1) (Morcott tangerine L. and Jaffa orange L.), marjoram honey (HM1) (Origanum majorana L.), and clover honey (HT1) (Trifolium alexandrinum L.), compared to their secondary metabolites (HC2, HM2, HT2, respectively). By using a ¹H-NMR-based metabolomic technique, PCA, and PLS-DA multivariate analysis, we found that HC2, HM2, HC1, and HM1 were clustered together. However, HT1 and HT2 were quite far from these and each other. This indicated that HC1, HM1, HC2, and HM2 have similar chemical compositions, while HT1 and HT2 were unique in their chemical profiles. Antioxidation potentials were determined colorimetrically for scavenging activities against DPPH, ABTS, ORAC, 5-LOX, and metal chelating activity in all honey extract samples and their secondary metabolites. Our results revealed that HC2 and HM2 possessed more antioxidant activities than HT2 in vitro. HC2 demonstrated the highest antioxidant effect in all assays, followed by HM2 (DPPH assay: IC50 2.91, 10.7 μg/mL; ABTS assay: 431.2, 210.24 at 50 ug/mL Trolox equivalent; ORAC assay: 259.5, 234.8 at 50 ug/mL Trolox equivalent; 5-LOX screening assay/IC50: 2.293, 6.136 ug/mL; and metal chelating activity at 50 ug/mL: 73.34526%, 63.75881% inhibition). We suggest that the presence of some secondary metabolites in HC and HM, such as hesperetin, linalool, and caffeic acid, increased the antioxidant activity in citrus and marjoram compared to clover honey

    Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder

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    BACKGROUND: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called 'neurocardiofaciodigital' syndrome. OBJECTIVE AND METHODS: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. RESULTS: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. CONCLUSION: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome

    Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

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    Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

    ARTICLE Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

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    PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications

    Mutations in LAMB1 Cause Cobblestone Brain Malformation without Muscular or Ocular Abnormalities

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    Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation

    Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene

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    Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening (‘Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screenin

    Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation

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    Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect
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