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1.
Mol Genet Metab ; 140(3): 107674, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37542768

RESUMEN

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.


Asunto(s)
Trastornos Congénitos de Glicosilación , Fosfotransferasas (Fosfomutasas) , Accidente Cerebrovascular , Trombosis , Humanos , Niño , Proteína C , Estudios Retrospectivos , Factor XI , Trastornos Congénitos de Glicosilación/patología , Antitrombinas , Hemostasis , Hemorragia
2.
Eur J Pediatr ; 182(9): 3929-3937, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37353601

RESUMEN

Infection is an important cause of death during infancy worldwide and is a frequent etiology of sudden unexpected death in infancy (SUDI). Procalcitonin (PCT) is a useful marker to diagnose infection in patients, and several studies report the stability of PCT after death. The added value of a biological marker, such as the PCT level in the blood, remains controversial in investigating SUDI. The aim of this study was to determine if PCT can help clinicians determine whether infection caused SUDI. We conducted a retrospective, multicenter study with the French SUDI registry (Observatoire National des Morts Inattendues du Nourrisson; OMIN). We collected data from this registry on children who died between May 2015 and June 2021. The levels of PCT in the blood of 540 SUDI patients were measured. We compared PCT and other biological tests performed in terms of infection status, autopsy results, and cause of death using clinical and biological data compiled by pediatricians at the SUDI referral center. PCT levels were significantly higher in the children who died from infection than in those who did not (0.12 µg/L vs. 0.08 µg/L, p < 0.001). A PCT blood level exceeding 0.2 µg/L was more frequently observed when infection was present than in the absence of infection (44.3% vs. 15.4%, p < 0.001). The same data were obtained with a 0.5 µg/L cut-off (36.1% with infection vs. 9.2% without, p < 0.001).  Conclusions: PCT is a sensitive biomarker for detecting infections postmortem; thus, additional samples may be necessary during autopsy. What is known: • PCT is a stable marker postmortem and increases earlier than CRP, i.e., 2-4 h after the beginning of an infection vs. 6 h. • PCT can be measured up to 140 h after death. What is new: • PCT is a sensitive marker for detecting infection in SUDI patients postmortem. • This test can reveal an infection from non-standardized samples obtained during autopsy if such an infection was not determined before death.


Asunto(s)
Polipéptido alfa Relacionado con Calcitonina , Muerte Súbita del Lactante , Humanos , Lactante , Autopsia , Biomarcadores , Estudios Retrospectivos , Muerte Súbita del Lactante/diagnóstico , Muerte Súbita del Lactante/etiología
3.
Clin Infect Dis ; 74(2): 246-253, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33906228

RESUMEN

BACKGROUND: Studies describing the clinical features and short-term prognosis of patients admitted to the intensive care unit (ICU) for menstrual toxic shock syndrome (m-TSS) are lacking. METHODS: This was a multicenter retrospective cohort study of patients with a clinical diagnosis of m-TSS admitted between 1 January 2005 and 31 December 2020 in 43 French pediatric (n = 7) or adult (n = 36) ICUs. The aim of the study was to describe the clinical features and short-term prognosis, as well as to assess the 2011 Centers for Disease and Control (CDC) diagnostic criteria, in critically ill patients with m-TSS. RESULTS: In total, 102 patients with m-TSS (median age, 18 years; interquartile range, 16-24 years) were admitted to 1 of the participating ICUs. All blood cultures (n = 102) were sterile. Methicillin-sensitive Staphylococcus aureus grew from 92 of 96 vaginal samples. Screening for superantigenic toxin gene sequences was performed for 76 of the 92 vaginal samples positive for S. aureus (83%), and toxic shock syndrome toxin 1 was isolated from 66 strains (87%). At ICU admission, no patient met the 2011 CDC criteria for confirmed m-TSS, and only 53 (52%) fulfilled the criteria for probable m-TSS. Eighty-one patients (79%) were treated with antitoxin antibiotic therapy, and 8 (8%) received intravenous immunoglobulins. Eighty-six (84%) patients required vasopressors, and 21 (21%) tracheal intubation. No patient required limb amputation or died in the ICU. CONCLUSIONS: In this large multicenter series of patients included in ICUs for m-TSS, none died or required limb amputation. The CDC criteria should not be used for the clinical diagnosis of m-TSS at ICU admission.


Asunto(s)
Choque Séptico , Infecciones Estafilocócicas , Adolescente , Adulto , Antibacterianos , Niño , Femenino , Humanos , Estudios Retrospectivos , Choque Séptico/diagnóstico , Choque Séptico/epidemiología , Choque Séptico/terapia , Staphylococcus aureus , Superantígenos
4.
Hum Genet ; 141(7): 1269-1278, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34495415

RESUMEN

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0-12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1-47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4-7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0).


Asunto(s)
Enfermedades del Sistema Nervioso , Osteogénesis Imperfecta , Niño , Exoma , Pruebas Genéticas/métodos , Humanos , Masculino , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Osteogénesis Imperfecta/genética , Derivación y Consulta
5.
Hum Mutat ; 42(2): 142-149, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33300232

RESUMEN

Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.


Asunto(s)
Proteínas de Unión al Calcio , Trastornos Congénitos de Glicosilación , Glicoproteínas de Membrana , Receptores Citoplasmáticos y Nucleares , Receptores de Péptidos , Proteínas de Unión al Calcio/genética , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/patología , Tejido Conectivo/patología , Glicosilación , Humanos , Masculino , Glicoproteínas de Membrana/genética , Fenotipo , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Péptidos/genética
6.
Hum Mutat ; 42(12): 1576-1583, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34570399

RESUMEN

Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.


Asunto(s)
Aminoacil-ARNt Sintetasas , Cardiomiopatías , Sordera , Aminoacil-ARNt Sintetasas/genética , Aminoacilación , Cardiomiopatías/genética , Niño , Sordera/genética , Humanos , Pérdida de Heterocigocidad
7.
Genet Med ; 23(11): 2202-2207, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34194004

RESUMEN

PURPOSE: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. METHODS: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. RESULTS: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (PLARS and PFARSB), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2-2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. CONCLUSION: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.


Asunto(s)
Aminoacil-ARNt Sintetasas , Aminoácidos , Aminoacil-ARNt Sintetasas/genética , Aminoacilación , Humanos , ARN de Transferencia/metabolismo
8.
J Inherit Metab Dis ; 44(2): 415-425, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32929747

RESUMEN

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.


Asunto(s)
Arritmias Cardíacas/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/deficiencia , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Trastornos del Neurodesarrollo/genética , Rabdomiólisis/genética , Adolescente , Niño , Preescolar , Exoma , Femenino , Francia , Humanos , Hipotiroidismo/genética , Lactante , Masculino , Mitocondrias/genética , Mutación , Linaje , Fenotipo , Estudios Retrospectivos , Adulto Joven
9.
JAMA ; 325(9): 855-864, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33523115

RESUMEN

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.


Asunto(s)
COVID-19/terapia , Glucocorticoides/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Metilprednisolona/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Adolescente , COVID-19/complicaciones , Niño , Preescolar , Terapia Combinada , Femenino , Fiebre/etiología , Francia , Glucocorticoides/efectos adversos , Humanos , Unidades de Cuidado Intensivo Pediátrico , Tiempo de Internación , Masculino , Metilprednisolona/efectos adversos , Puntaje de Propensión , Recurrencia , Estudios Retrospectivos , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19
10.
Genet Med ; 22(3): 610-621, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31761904

RESUMEN

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Proteínas de Neoplasias/genética , Alelos , Encéfalo/patología , Niño , Preescolar , Femenino , Enfermedades Genéticas Congénitas/patología , Humanos , Lactante , Hígado/patología , Trasplante de Hígado/efectos adversos , Masculino , Músculo Esquelético/patología , Mutación Missense/genética , Fenotipo
11.
J Hum Genet ; 65(2): 91-98, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31645654

RESUMEN

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.


Asunto(s)
ADN Polimerasa gamma/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Enfermedades Mitocondriales/genética , Paraparesia Espástica/genética , Paraplejía Espástica Hereditaria/genética , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico , Mutación , Paraparesia Espástica/diagnóstico , Análisis de Secuencia de ADN , Paraplejía Espástica Hereditaria/diagnóstico , Gemelos Monocigóticos
12.
Calcif Tissue Int ; 107(2): 191-194, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32430692

RESUMEN

Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.


Asunto(s)
Densidad Ósea , Colestanotriol 26-Monooxigenasa/deficiencia , Raquitismo Hipofosfatémico Familiar/complicaciones , Adolescente , Adulto , Consanguinidad , Familia 2 del Citocromo P450 , Humanos , Vitamina D/sangre
13.
Pediatr Transplant ; 24(6): e13773, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32701220

RESUMEN

INTRODUCTION: Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood. METHODS: Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. RESULTS: Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P < .001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P = .009). HRT was used in 82% of girls and 24% of boys (P < .001). In univariate analysis, TBI conditioning (P = .05), female sex (P < .001), acute GVHD (P = .05), extensive chronic GVHD (P = .021), steroid treatment >6 months (P = .016), and malignant diseases (P = .016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P = .003) and extensive chronic GVHD (P = .005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P = .001) and age >10 years (P = .033). Factors independently associated with delayed puberty were extensive chronic GVHD (P = .041) and age >10 years (P = .031). CONCLUSION: This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty.


Asunto(s)
Busulfano/efectos adversos , Pubertad Tardía/etiología , Pubertad/efectos de los fármacos , Pubertad/efectos de la radiación , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Irradiación Corporal Total/efectos adversos , Adolescente , Niño , Preescolar , Ciclofosfamida , Femenino , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Masculino , Análisis Multivariante , Estudios Retrospectivos , Factores de Riesgo , Acondicionamiento Pretrasplante , Resultado del Tratamiento
14.
Genet Med ; 21(9): 2025-2035, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30723320

RESUMEN

PURPOSE: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.


Asunto(s)
Alopecia/genética , Colesterol/metabolismo , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Transferasas Intramoleculares/genética , Edad de Inicio , Alopecia/complicaciones , Alopecia/patología , Niño , Preescolar , Colesterol/genética , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/patología , Epilepsia/complicaciones , Epilepsia/genética , Epilepsia/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Lanosterol/genética , Lanosterol/metabolismo , Masculino , Mutación , Linaje , Fenotipo , Escualeno/análogos & derivados , Escualeno/metabolismo , Secuenciación del Exoma
15.
Mol Genet Metab ; 127(3): 184-190, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31235217

RESUMEN

AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5 years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2 mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500 µmol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500 µmol/L.


Asunto(s)
Alcaptonuria/diagnóstico por imagen , Alcaptonuria/tratamiento farmacológico , Ciclohexanonas/administración & dosificación , Nitrobenzoatos/administración & dosificación , Adulto , Preescolar , Dieta , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Tirosina/sangre , Adulto Joven
16.
Calcif Tissue Int ; 104(4): 355-363, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30554334

RESUMEN

Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.


Asunto(s)
Parálisis Cerebral/tratamiento farmacológico , Osteoporosis/tratamiento farmacológico , Síndrome de Rett/tratamiento farmacológico , Ácido Zoledrónico/uso terapéutico , Adolescente , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Huesos/efectos de los fármacos , Huesos/fisiopatología , Niño , Fracturas Óseas/tratamiento farmacológico , Humanos , Imidazoles/uso terapéutico , Factores de Tiempo , Ácido Zoledrónico/administración & dosificación
17.
Neuropediatrics ; 47(3): 179-81, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26947510

RESUMEN

Peroxisome biogenesis disorders (PBD) are a heterogeneous group of disorders due to PEX genes mutations, with a broad clinical spectrum comprising severe neonatal disease to mild presentation. Recently, Berendse et al reported an improvement of peroxisomal functions with l-arginine supplementation in fibroblasts with specific mutations of PEX1, PEX6, and PEX12. We report the first treatment by l-arginine in a patient homozygous for the specific PEX12 mutation shown to be l-arginine responsive in fibroblasts. We described the effect of l-arginine on biochemical (decrease of some plasma peroxisomal parameters) and neurophysiological (improvement of deafness) parameters. Some subjective clinical effects have also been observed (no more sialorrhea, behavior improvement). More studies are needed to assess the efficacy of l-arginine in some PBD patients with specific mutations.


Asunto(s)
Arginina/uso terapéutico , Proteínas de la Membrana/genética , Trastorno Peroxisomal/tratamiento farmacológico , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Niño , Preescolar , Sordera/etiología , Discapacidades del Desarrollo/etiología , Ácidos Grasos/sangre , Femenino , Humanos , Lactante , Proteínas de la Membrana/deficiencia , Hipotonía Muscular/etiología , Trastorno Peroxisomal/sangre , Trastorno Peroxisomal/complicaciones , Trastorno Peroxisomal/genética , Ácido Fitánico/sangre , Ácidos Pipecólicos/sangre , Sialorrea/etiología
18.
Front Pediatr ; 12: 1431008, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39040669

RESUMEN

Purpose: Renal replacement therapy (RRT) is used in hyperammonemia to reduce the concentration of ammonia in the blood. In the case of plasma hyperosmolarity, RRT can also rapidly decrease plasma osmolarity, which may increase cerebral edema in these patients and favor the occurrence of brain herniation. Methods: We conducted a retrospective clinical study in a tertiary care university-affiliated hospital. All patients admitted in a Pediatric Intensive Care Unit (PICU), less than 18 years old with ammonemia >150 µmol/L and who underwent RRT between January 2015 and June 2023 were included. We collected data on plasma osmolarity levels, osmolar gap and blood ammonia levels before and during RRT. Results: Eleven patients were included (10 with acute liver failure and 1 with a urea cycle disorders). Their mean age was 36.2 months. Before RRT, the median highest measured osmolarity was 320 (305-324) mOsm/L, whereas the median calculated osmolarity was 303 (293-314) mOsm/L, corresponding to an osmolar gap of 14 mOsm/L. Ammonia blood level over 400 µmol/L are significantly associated with higher plasma osmolarity (P-Value <0.001). In one case, a patient had a brain herniation episode after a quick osmolar drop. This episode was reversed by the administration of hyperosmolar agents and the temporary suspension of RRT. Conclusion: This study highlights the hyperosmolarity and high osmolar gap that occur in children with hyperammonemia. A careful monitoring and control of plasma osmolarity evolution may alert clinician on the risk of occurrence of neurological complication such as brain herniation.

19.
EBioMedicine ; 99: 104911, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38168585

RESUMEN

BACKGROUND: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways. METHODS: We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts. FINDINGS: CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated. INTERPRETATION: The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations. FUNDING: French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.


Asunto(s)
Multiómica , Vitamina B 12 , Humanos , Vitamina B 12/metabolismo , Proteómica , Oxidorreductasas/metabolismo , Fibroblastos/metabolismo , ARN de Transferencia/metabolismo
20.
Gastroenterology Res ; 16(4): 244-248, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37691748

RESUMEN

We describe a case of coma-related hyperammonemia in a woman presenting with severe edematous malnutrition (Kwashiorkor-like), without underlying hepatic disease. Our main hypothesis is that the patient developed a functional urea cycle disorder, due to the inability to synthesize N-acetylglutamate which is the activator of the first enzymes (carbamoyl phosphate synthetase) of urea cycle, in a context of severe deficiency of essential amino acids and of acetyl-CoA. Severe hyperammonemia is a medical emergency exposing to the risk of cerebral edema. Urgent treatment should interrupt protein intake, stimulate protein anabolism, and remove ammonia from the blood using renal replacement therapy and ammonia scavengers. Hyperammonemia should be searched in case of unexplained coma, even among patients without hepatic disorder, in particular among young patients. Hyperammonemia should also be searched among patients with severe protein-calorie malnutrition.

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