RESUMO
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.
Assuntos
Defeitos Congênitos da Glicosilação , Fosfotransferases (Fosfomutases) , Acidente Vascular Cerebral , Trombose , Humanos , Criança , Proteína C , Estudos Retrospectivos , Fator XI , Defeitos Congênitos da Glicosilação/patologia , Antitrombinas , Hemostasia , HemorragiaRESUMO
MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.
Assuntos
Homocistinúria , Estudos de Coortes , Homocisteína , Homocistinúria/diagnóstico , Homocistinúria/tratamento farmacológico , Humanos , Recém-Nascido , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/diagnóstico , Transtornos Psicóticos , Estudos RetrospectivosRESUMO
Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.
Assuntos
Fígado Gorduroso , Deficiência de Frutose-1,6-Difosfatase , Hipoglicemia , Animais , Seguimentos , Frutose , Deficiência de Frutose-1,6-Difosfatase/complicações , Deficiência de Frutose-1,6-Difosfatase/diagnóstico , Frutose-Bifosfatase/metabolismo , Hepatomegalia , Humanos , Hipoglicemia/complicações , Fígado/metabolismo , Camundongos , TransaminasesRESUMO
Hyperimmunoglobulinemia D is the less severe form of mevalonate kinase deficiency (MKD) caused by recessive inherited mutation in the mevalonate kinase gene. Hyperimmunoglobulinemia D is characterized by febrile attacks, often associated with transient digestive manifestations, such as abdominal pain, diarrhea, and vomiting. Here we report for the first time 2 patients with MKD revealed by severe neonatal colitis. Both patients had chronic bloody diarrhea and failure to thrive; 1 patient since the age of 1 month and the other since the age of 12 days. Total parenteral nutrition was required. A marked elevation of acute phase reactants was present, and no evidence of infection was found. In patient 1, ileocolonoscopy revealed ulcerative colitis at the age of 5 months. Patient 2 suffered from enterocolitis and shock, associated with multiple bowel adhesions at age 5 weeks; the rectosigmoidoscopy showed aphtoid lesions of the sigmoid colon. Pathologic findings of colonic biopsies revealed a dense polymorph inflammatory infiltrate associated with deep ulcerations. Febrile attacks occurred 2 months after the onset of digestive symptoms in patient 1, and at onset of disease in patient 2. Genomic sequencing of the mevalonate kinase gene revealed compound heterozygous mutations in both patients. Anti-interleukin-1 agent produced long-term remission of all digestive features and laboratory parameters. This report emphasizes that MKD may be the cause of severe early-onset inflammatory colitis, and must be considered by physicians, even in the absence of fever, after ruling out infections. Anti-interleukin-1 therapy may result in a dramatic improvement of MKD-related inflammatory bowel disease.
Assuntos
Colite Ulcerativa/diagnóstico , Colite Ulcerativa/etiologia , Enterocolite/diagnóstico , Enterocolite/etiologia , Deficiência de Mevalonato Quinase/diagnóstico , Proteínas de Fase Aguda/análise , Colite Ulcerativa/genética , Colonoscopia , Análise Mutacional de DNA , Diarreia Infantil/etiologia , Enterocolite/genética , Insuficiência de Crescimento/etiologia , Feminino , Seguimentos , Triagem de Portadores Genéticos , Humanos , Lactente , Recém-Nascido , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Masculino , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/genética , Nutrição Parenteral Total , Fosfotransferases (Aceptor do Grupo Álcool)/genéticaRESUMO
More than 200 antigenically distinct viruses have been documented as causes of sporadic or epidemic respiratory infections in infants and children. The lung itself is rarely sampled directly, and sputum representing lower-airway secretions can rarely be obtained from children. In addition culture of secretions from upper respiratory tract is not useful since the normal flora includes the bacteria commonly responsible for pneumonia. Clinical and radiology data only suggest the diagnosis. The development of techniques to detect antigens of the causative agent in nasopharyngeal secretions, nucleic acid by means of the polymerise-chain reaction assays has significantly improved the identification of the responsible pathogen and the choice of appropriate treatment. Since more 30 years rhinovirus, coronavirus, enterovirus, parainfluenza virus and respiratory syncytial virus were added to influenza, adenovirus and measles virus as causes of respiratory tract infections. This list of pathogens was extended last years with the discovery of human metapneumovirus, bocavirus, polyomavirus. In restricted patient groups, such as the immunocompromised, members of the family of herpesvirus have also been associated with respiratory disease.