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The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."
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Encefalopatias , Moléculas de Adesão Celular , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Animais , Camundongos , Alelos , Encefalopatias/genética , Moléculas de Adesão Celular/genética , Células Endoteliais/metabolismo , Hemorragias Intracranianas/genética , Malformações do Sistema Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Junções Íntimas/genética , HumanosRESUMO
As a result of the preference for consanguineous/endogamous marriages, the Israeli Arab population is composed of isolated communities with relatively frequent autosomal recessive (AR) conditions in each community. Clinical diagnosis of affected individuals has uncovered the pathogenic variants throughout the years. We investigated the diversity of pathogenic AR variants in a single village in northern Israel by exome analysis of 50 random, healthy adults descendants of the founders. Only likely pathogenic and pathogenic variants in known AR genes were selected. In this study 48 AR variants were found, of which 12 had been previously diagnosed in patients from this village, and for 11 with a frequency compatible with the frequency already known. Among the other 36 variants, 12 had been previously diagnosed in affected individuals in other Arab communities in Israel and 24 variants had not been previously characterized in this population. Of the 35 variants associated with conditions of moderate-severe medical consequences, only eight were known previously in this village. These findings emphasize the importance to better delineate the conditions at risk in a defined community, in particular for the development of preventive measures such as screening tests for reproductive couples, and for genetic counseling.
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Genes Recessivos , Genética Populacional , Isolamento Reprodutivo , Adulto , Alelos , Substituição de Aminoácidos , Consanguinidade , Feminino , Predisposição Genética para Doença , Humanos , Padrões de Herança , Israel , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma , Adulto JovemRESUMO
Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
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Disfunção Cognitiva/genética , Complexo II de Transporte de Elétrons/genética , Variação Genética/genética , Heterozigoto , Atrofia Óptica/genética , Adolescente , Sequência de Aminoácidos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Complexo II de Transporte de Elétrons/química , Feminino , Humanos , Atrofia Óptica/complicações , Atrofia Óptica/diagnóstico por imagem , Estrutura Secundária de ProteínaRESUMO
D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.
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Encefalopatias/metabolismo , Epilepsia/metabolismo , Hiperoxalúria Primária/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Encefalopatias/genética , Criança , Epilepsia/diagnóstico , Epilepsia/genética , Ácidos Glicéricos/metabolismo , Humanos , Hiperoxalúria Primária/genética , Lactente , Masculino , Mutação/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Espasmos Infantis/genética , Espasmos Infantis/metabolismoRESUMO
We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.
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Agenesia do Corpo Caloso/genética , Fosfatase Alcalina/sangue , Encéfalo/diagnóstico por imagem , Proteínas de Membrana/genética , Mutação , Espasmos Infantis/genética , Agenesia do Corpo Caloso/sangue , Agenesia do Corpo Caloso/diagnóstico por imagem , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Espasmos Infantis/sangue , Espasmos Infantis/diagnóstico por imagem , UltrassonografiaAssuntos
Proteínas de Transporte/genética , Transtornos da Motilidade Ciliar , Pneumopatias , Otite , Situs Inversus , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/fisiopatologia , Transtornos da Motilidade Ciliar/terapia , Diagnóstico Diferencial , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/etiologia , Humanos , Mutação com Perda de Função , Pneumopatias/diagnóstico , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Otite/diagnóstico , Otite/etiologia , Otite/fisiopatologia , Administração dos Cuidados ao Paciente , Irmãos , Situs Inversus/diagnóstico por imagem , Situs Inversus/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. DESIGN: Retrospective cohort study. METHODS: Clinical, laboratory, and molecular data from patients' records were collected. RESULTS: Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. CONCLUSIONS: In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.
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Síndrome de Excesso Aparente de Minerolocorticoides , Humanos , Israel/epidemiologia , Masculino , Feminino , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Estudos Retrospectivos , Criança , Pré-Escolar , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Adolescente , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Mutação , Hipertensão/epidemiologia , Hipopotassemia , AdultoRESUMO
BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported. METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays. RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease. CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.
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Doença de Leigh , Doenças Neurodegenerativas , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Doença de Leigh/genética , Doença de Leigh/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Tronco Encefálico/patologia , Mutação/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMO
Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.
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Background: Glycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients. Methods: Off-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment. Results: A 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18-24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter. Conclusions: Repurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.
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Cleft lip and/or cleft palate are a common group of birth defects that further classify into syndromic and non-syndromic forms. The syndromic forms are usually accompanied by additional physical or cognitive abnormalities. Isolated cleft palate syndromes are less common; however, they are associated with a variety of congenital malformations and generally have an underlying genetic etiology. A single report in 2019 described a novel syndrome in three individuals, characterized by cleft palate, developmental delay and proliferative retinopathy due to a homozygous non-sense mutation in the LRRC32 gene encoding glycoprotein A repetitions predominant (GARP), a cell surface polypeptide crucial for the processing and maturation of transforming growth factor ß (TGF-ß). We describe a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy. Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene, which resulted in substitution of a highly conserved isoleucine to threonine. Protein modeling suggested this variant may negatively affect GARP function on latent TGF-ß activation. In summary, our report further expands the clinical features of cleft palate, proliferative retinopathy and developmental delay syndrome and emphasizes the association of LRRC32 pathogenic variants with this new syndrome.
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Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in NPC1. Their considerably discrepant neurological disease courses were dependent on the timing of initiation of miglustat treatment. The outcomes support the significant role of early treatment with miglustat in the disease course of early infantile NPC and suggest that therapy should be considered even before the occurrence of neurological involvement. Moreover, this report emphasizes the importance of early diagnosis, in light of the availability of a potential disease-modifying medication.
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OBJECTIVE: Disorders of sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. METHODS: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. RESULTS: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two atients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. CONCLUSIONS: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management - and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.
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BACKGROUND: An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation. METHODS: Audiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies. RESULTS: HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT4) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT4 levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 µg/dL, p = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies. CONCLUSIONS: Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT4 therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.
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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the causative agent of the current COVID-19 pandemic. Lysosomal storage disorders (LSD) comprise of 70 inherited inborn errors of metabolism. Affected individuals suffer from multi-systemic involvement with variable severity and rate of disease progression between different diseases. Some of the LSDs have established treatments, whether parenteral or oral therapies. The full impact of the COVID-19 pandemic together with the lockdown on the wellbeing and medical management of patients with rare diseases, such as LSDs, is widely unknown. Herein, we describe the effects of the COVID-19 pandemic and its associated mandatory home lockdown on patients with LSDs in Israel. RESULTS: We present a prospective multi-center questionnaire study including 48 LSD patients from four medical centers in Israel. The study objective was to assess the impact of the COVID-19 pandemic restrictions on individuals with LSDs in Israel, as reported by their caregivers. Secondary objectives were to assess the morbidity from SARS CoV-2 in LSD patients and the impact of changes in mood and behavior on compliance to treatment and to assess the relationship between changes in mood to changes in cognition and behavior. Thirty one of 38 patients (82%) who received any kind of regular treatment did not miss treatments. Among patients receiving enzyme replacement therapy (ERT) in the in-hospital setting, 5 patients (20%) experienced treatment disruptions. Four patients had tested positive for SARS-Cov-2 virus infection by PCR. Seven out of the 48 patients (14%) described mood changes with cognitive and motor deterioration during the home quarantine. CONCLUSIONS: We observed high rates of treatment adherence and low morbidity through the COVID-19 pandemic in patients with LSDs in Israel. LSDs patients can be a model for patients with complex chronic diseases requiring routine treatments and surveillance during a pandemic or other disruption of daily routine.
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COVID-19 , Pandemias , Controle de Doenças Transmissíveis , Humanos , Israel/epidemiologia , Lisossomos , Estudos Prospectivos , SARS-CoV-2RESUMO
Persistent hypokalemic hypochloremic metabolic alkalosis represents a heterogeneous group of genetic disorders of which the most common is Bartter syndrome (BS). BS is an inherited renal tubulopathy caused by defective salt reabsorption in the thick ascending loop of Henle, which results in persistent hypokalemic hypochloremic metabolic alkalosis. Here we report a 10-year-old girl of a consanguineous family. She presented prenatally with severe polyhydramnios and distended bowel loops. Thereafter, she displayed failure to thrive and had recurrent admissions due to dehydration episodes associated with diarrhea, and characterized by hypokalemia, hypochloremia and metabolic alkalosis. BS was considered her working diagnosis for several years despite negative genetic analysis of the known genes associated with BS. Whole exome sequencing identified a novel homozygous c.1652delT deleterious frameshift mutation in the SLC26A3 gene, which confirmed the diagnosis of congenital chloride diarrhea (CCD), a rare autosomal recessive disease that mimics biochemically BS. A review of twelve additional reported cases of CCD that were initially misdiagnosed as BS, emphasizes CCD in the differential diagnosis of BS, and highlights the clinical discrepancies between these two entities. Taken together, our report further emphasizes the typical clinical features of CCD, and the importance of next generation sequencing in the diagnosis of syndromes with genetic heterogeneity. We suggest including SLC26A3 in the extended BS targeted gene panels.
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Alcalose/diagnóstico , Alcalose/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hipopotassemia/sangue , Hipopotassemia/diagnóstico , Alcalose/sangue , Criança , Diagnóstico Diferencial , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , HumanosRESUMO
De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.
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Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Hipercinese/genética , Hipotonia Muscular/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Sítios de Ligação , Encefalopatias/diagnóstico , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Exoma , Feminino , Humanos , Hipercinese/diagnóstico , Ativação do Canal Iônico , Hipotonia Muscular/diagnóstico , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , SíndromeRESUMO
Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate. Taken together we report a diagnostic metabolic fingerprint for mitochondrial aconitase 2 deficiency.
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Aconitato Hidratase/deficiência , Aconitato Hidratase/genética , Ácido Aconítico/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/sangue , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Humanos , Hidroxibutiratos/sangue , Isocitratos/sangue , Ácidos Cetoglutáricos/sangue , Masculino , Metabolômica/métodos , Fosfoenolpiruvato/sangueRESUMO
BACKGROUND: Delayed antibiotic treatment for acute otitis media (AOM) is recommended for children >6 months with nonsevere illness, no risk factors for complications or history of recurrent AOM. This study evaluates relationship between delayed antibiotic treatment for antecedent AOM and severity of subsequent acute mastoiditis admission. METHODS: A prospective observational study of children aged 0-14 years admitted with acute mastoiditis to 8 hospitals between 2007 and 2012 calculates rates of severe acute mastoiditis admission [defined by ≥1 of the following: complication (mastoid subperiosteal abscess, brain abscess and sagittal vein thrombosis), need for surgical procedure and duration of admission >6 days].Severe acute mastoiditis admissions in children with antecedent AOM treated with immediate antibiotics were compared with those with delayed antibiotic treatment. RESULTS: Antecedent AOM was diagnosed in 216 of 512 acute mastoiditis admissions (42.1%), of whom 159 (73%) immediately received antibiotics, and 57 (27%) had delayed antibiotic treatment. Higher rate of recurrent AOM was noted in the immediate compared with delayed antibiotic treatment group (29% vs. 8.7%, P = 0.0021). Complication rates were 19.5% versus 10.5% (P = 0.12), rates of surgical procedures required, 30% versus 10% (P = 0.0033); admission rates >6 days, 37% versus 29% (P = 0.28) for immediate antibiotic therapy and delayed antibiotic treatment. On logistic regression analysis, immediately treated AOM patients had increased need for surgery for acute mastoiditis with adjustment for history of recurrent AOM (relative risk: 3.2, 95% confidence interval: 1.4-7.0). CONCLUSIONS: Delayed antibiotic treatment for antecedent AOM is not associated with an increase in severity parameters in subsequent acute mastoiditis admission.