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BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis resulting in the accumulation of protoporphyrin, characterized by liver failure in a minority of cases. Although liver transplant (LT) is the therapeutic strategy for advanced hepatic disease, it does not correct the primary defect, which leads to recurrence in liver graft. Thus, hematopoietic stem cell transplantation (HSCT) is an approach for treating EPP. METHODS: We aim to describe the first sequential LT and HSCT for EPP performed in Latin America, besides reviewing the present-day literature. RESULTS: The patient, a 13-year-old female with a history of photosensitivity, presented with symptoms of cholestatic and hepatopulmonary syndrome and was diagnosed with EPP. Liver biopsy demonstrated cirrhosis. She was submitted to a successful LT and showed improvement of respiratory symptoms. However, she had disease recurrence on the liver graft. She underwent a myeloablative HSCT using a matched unrelated donor, conditioning with BuCy (busulfan and cyclophosphamide), and GvHD (graft vs. host disease) prophylaxis with ATG (thymoglobulin), tacrolimus and methotrexate. Neutrophil engraftment occurred on D+18. She has presented mixed chimerism, but normalization of PP levels, being 300 days after HSCT, in good state of health and normal liver function. CONCLUSIONS: Consecutive LT and HSCT for EPP is a procedure that has been described in 10 cases in the literature and, even though these patients are a highly diversified population, studies have shown favorable results. This concept of treatment should be considered in patients with established liver disease.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Hepatopatías , Trasplante de Hígado , Protoporfiria Eritropoyética , Femenino , Humanos , Adolescente , Trasplante de Médula Ósea , Protoporfiria Eritropoyética/terapia , Protoporfiria Eritropoyética/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Hígado/métodos , Acondicionamiento PretrasplanteRESUMEN
Mucopolysaccharidosis type IIIB is a rare autosomal recessive disorder characterized by deficiency of the enzyme N-acetyl-alpha-d-glucosaminidase (NAGLU), caused by biallelic pathogenic variants in the NAGLU gene, which leads to storage of heparan sulfate and a series of clinical consequences which hallmark is neurodegeneration. In this study clinical, epidemiological, and biochemical data were obtained from MPS IIIB patients diagnosed from 2004-2019 by the MPS Brazil Network ("Rede MPS Brasil"), which was created with the goal to provide an easily accessible and comprehensive investigation of all MPS types. One hundred and ten MPS IIIB patients were diagnosed during this period. Mean age at diagnosis was 10.9 years. Patients were from all over Brazil, with a few from abroad, with a possible cluster of MPS IIIB identified in Ecuador. All patients had increased urinary levels of glycosaminoglycans and low NAGLU activity in blood. Main clinical symptoms reported at diagnosis were coarse facies and neurocognitive regression. The most common variant was p.Leu496Pro (30% of alleles). MPS IIIB seems to be relatively frequent in Brazil, but patients are diagnosed later than in other countries, and reasons for that probably include the limited awareness about the disease by health professionals and the difficulties to access diagnostic tests, factors that the MPS Brazil Network is trying to mitigate.
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Mucopolisacaridosis III , Alelos , Brasil/epidemiología , Niño , Heparitina Sulfato , Humanos , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/epidemiología , Mucopolisacaridosis III/genéticaRESUMEN
Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.
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Mucopolisacaridosis II , Brasil , Genotipo , Humanos , Masculino , Mucopolisacaridosis II/genética , Mutación , FenotipoRESUMEN
Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.
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Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/etiología , Disección Aórtica/etiología , Terapia de Reemplazo Enzimático/métodos , Mucopolisacaridosis/complicaciones , Adolescente , Disección Aórtica/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico , Ecocardiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mucopolisacaridosis/tratamiento farmacológico , Factores de TiempoRESUMEN
INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.
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Ataxia/patología , Trastornos Congénitos de Glicosilación/patología , Epilepsia/patología , Glucosiltransferasas/genética , Deformidades Congénitas de las Extremidades/patología , Proteínas de la Membrana/genética , Trastornos Mentales/patología , Debilidad Muscular/patología , Adolescente , Adulto , Ataxia/genética , Niño , Preescolar , Trastornos Congénitos de Glicosilación/genética , Epilepsia/genética , Femenino , Estudios de Asociación Genética/métodos , Glicosilación , Humanos , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/genética , Masculino , Trastornos Mentales/genética , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Debilidad Muscular/genética , Fenotipo , Estudios Retrospectivos , Convulsiones/genética , Convulsiones/patología , Adulto JovenRESUMEN
Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). The products of GAG degradation accumulate within lysosomes and in the extracellular space, thereby interfering with the degradation of other macromolecules. This process leads to chronic degeneration of cells, which in turn affects multiple organs and systems. There are seven distinct types of MPS (I, II, III, IV, VI, VII, and IX), which are divided into subtypes according to the deficient enzyme and the severity of the clinical picture. Although clinical manifestations vary considerably among the different types of MPS, the central nervous system (CNS) is characteristically affected, and magnetic resonance (MR) imaging is the method of choice to evaluate brain and spinal cord abnormalities. Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, cervical spinal canal stenosis with or without spinal cord compression and myelopathy, and bone abnormalities in the skull and spine (dysostosis multiplex) are typical imaging findings described in the literature and reviewed in this article. The differential diagnosis of MPS is limited because the constellation of imaging findings is highly suggestive. Thus, radiologists should be aware of its typical neuroimaging findings so they can recognize cases not yet diagnosed, exclude other metabolic diseases, monitor CNS findings over time, and assess treatment response. (©)RSNA, 2016.
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Imagen por Resonancia Magnética/métodos , Mucopolisacaridosis/diagnóstico por imagen , Neuroimagen/métodos , Humanos , Mucopolisacaridosis/fisiopatologíaRESUMEN
Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.
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Microcefalia , Trastornos del Neurodesarrollo , Humanos , Microcefalia/genética , Brasil , Masculino , Femenino , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Niño , Preescolar , Adolescente , Secuenciación del Exoma , Síndrome , Adulto Joven , Estudios de Cohortes , Adulto , LactanteRESUMEN
Background: Glycosylphosphatidylinositol-anchored protein deficiencies (GPI-ADs) are commonly associated with drug-resistant epilepsy (DRE). Cannabidiol (CBD) is approved for the adjunctive treatment of seizures in Dravet/Lennox-Gastaut Syndromes and Tuberous Sclerosis Complex. We report on the efficacy and safety of CBD for the treatment of DRE in patients with genetically proven GPI-AD. Patients and Methods: Patients received add-on treatment with purified GW-pharma CBD (Epidyolex®). Efficacy endpoints were the percentage of patients with ≥50% (responders) or >25<50% (partial responders) reduction in monthly seizures from baseline and at 12 (M12) months of follow-up. Safety was evaluated through adverse events (AEs) monitoring. Results: Six patients (5 males) were enrolled. The median age at seizures onset was 5 months and the syndromic diagnosis was early infantile developmental and epileptic encephalopathy in 4 patients and focal non-lesional epilepsy or GEFS+ in one patient each. Five out of six (83%) patients were responders at M12, while one was a partial responder. No severe AEs were reported. Mean prescribed CBD dose was 17.85 mg/kg/day and median treatment duration is currently 27 months. Conclusions: In summary, off-label treatment with CBD was effective and safe in patients with DRE due to GPI-ADs.
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BACKGROUND: Leigh Syndrome (LS) is a rare genetic neurometabolic disorder, that leads to the degeneration of the central nervous system and subsequently, early death. LS can be caused by over 80 mutations in mitochondrial or nuclear DNA. Patient registries are important for many reasons, such as studying the natural history of the disease, improving the quality of care, and understanding the healthcare burden. For rare diseases, patient registries are significantly important as patient numbers are small, and funding is limited. Cure Mito Foundation started a global patient registry for LS in September 2021 to identify and learn about the LS patient population, facilitate clinical trial recruitment, and unite international patients and researchers. Priorities were to allow researchers and industry partners to access data at no cost through a clear and transparent process, active patient engagement, and sharing of results back to the community. RESULTS: Patient registry platform, survey design, data analysis process, and patient recruitment strategies are described. Reported results include demographics, diagnostic information, symptom history, loss of milestones, disease management, healthcare utilization, quality of life, and caregiver burden for 116 participants. Results show a high disease burden, but a relatively short time to diagnosis. Despite the challenges faced by families impacted by Leigh syndrome, participants, in general, are described as having a good quality of life and caregivers are overall resilient, while also reporting a significant amount of stress. CONCLUSION: This registry provides a straightforward, no-cost mechanism for data sharing and contacting patients for clinical trials or research participation, which is important given the recruitment challenges for clinical trials for rare diseases. This is the first publication to present results from a global patient registry for Leigh Syndrome, with details on a variety of patient-specific and caregiver outcomes reported for the first time. Additionally, this registry is the first for any mitochondrial disease with nearly 70% of participants residing outside of the United States. Future efforts include continued publication of results and further collaboration with patients, industry partners, and researchers.
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Enfermedad de Leigh , Humanos , Enfermedad de Leigh/genética , Calidad de Vida , Enfermedades Raras , Sistema Nervioso Central , Costo de EnfermedadRESUMEN
RYR1-related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.
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Dantroleno , Rabdomiólisis , Humanos , Niño , Preescolar , Dantroleno/uso terapéutico , Mialgia/tratamiento farmacológico , Mialgia/etiología , Canal Liberador de Calcio Receptor de Rianodina/genética , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/complicaciones , MúsculosRESUMEN
Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD. The phenotype of GSD IV ranges from neonatal death to mild adult-onset disease with variable hepatic, muscular, neurologic, dermatologic, and cardiac involvement. There is a paucity of literature and clinical and dietary management in GSD IV, and liver transplantation (LT) is described to correct the primary hepatic enzyme defect. Objectives: We herein describe five cases of patients with GSD IV with different ages of onset and outcomes as well as a novel GBE1 variant. Methods: This is a descriptive case series of patients receiving care for GSD IV at Reference Centers for Rare Diseases in Brazil and in the United States of America. Patients were selected based on confirmatory GBE1 genotypes performed after strong clinical suspicion. Results: Pt #1 is a Latin male with the chief complaints of hepatosplenomegaly, failure to thrive, and elevated liver enzymes starting at the age of 5 months. Before LT at the age of two, empirical treatment with corn starch (CS) and high protein therapy was performed with subjective improvement in his overall disposition and liver size. Pt #2 is a 30-month-old Afro-American descent patient with the chief complaints of failure to gain adequate weight, hypotonia, and hepatosplenomegaly at the age of 15 months. Treatment with CS was initiated without overall improvement of the symptoms. Pt #3.1 is a female Latin patient, sister to pt #3.2, with onset of symptoms at the age of 3 months with bloody diarrhea, abdominal distention, and splenomegaly. There was no attempt of treatment with CS. Pt #4 is an 8-year-old male patient of European descent who had his initial evaluation at 12 months, which was remarkable for hepatosplenomegaly, elevated ALT and AST levels, and a moderate dilatation of the left ventricle with normal systolic function that improved after LT. Pt #1, #3.2 and #4 presented with high levels of chitotriosidase. Pt #2 was found to have the novel variant c.826G > C p.(Ala276Pro). Conclusions: GSD IV is a rare disease with different ages of presentation and different cardiac phenotypes, which is associated with high levels of chitotriosidase. Attempts of dietary intervention with CS did not show a clear improvement in our case series.
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Hunter disease or mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which is involved in the catabolism of the glycosaminoglycans (GAGs) heparan and dermatan sulphate. Our aim was to analyze three patients with severe Hunter syndrome that showed a total deletion of the iduronate-2-sulphatase (IDS) gene, after exon by exon PCR. DNA was used as a template for PCR synthesis of IDS, FRAXA, FRAXE, and DXS1113 specific amplicons. The DNA analysis for all three patients demonstrated a complete deletion of IDS, FRAXA, and FRAXE contiguous genes. We further performed SNP-array to delineate the deletion breakpoints and to characterize the deletion extension in the different patients. The results indicated a â¼9.4 Mb deletion in Patient 1, a â¼3.9 Mb deletion of the Xq27.3-Xq28 and a â¼3.1 Mb duplication of the X q28 region in Patient 2 and a â¼41.8 Kb deletion in Patient 3. SNP-array was shown to be important to map for deletion breakpoints. A comprehensive molecular analysis in patients with Hunter syndrome, especially in the ones presenting the severe form, is important to the understanding of the genetic determinants of the phenotype and for the genetic counseling to be provided to the families.
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Mucopolisacaridosis II/genética , Eliminación de Secuencia , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Humanos , Iduronato Sulfatasa/genética , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Classic homocystinuria (HCU), or cystathionine beta-synthase (CBS) deficiency, is a rare inborn error of methionine metabolism. Main clinical features may include skeletal and vascular manifestations, developmental delay, intellectual disability and eye disorders. MATERIAL AND METHODS: This is an observational and retrospective study aiming at describing eye abnormalities presented by a cohort of late-diagnosed HCU patients. Data regarding ophthalmological evaluation included visual acuity, refraction, biomicroscopy, Perkins tonometry, fundus examination, retinography, biometry, ocular ultrasound, optical coherence tomography, anterior segment photography and topography. RESULTS: Ten patients with HCU (20 eyes) were included. The most frequent findings were ectopia lentis(n = 20) and myopia (n = 9). Biometry, ultrasound, OCT and topography findings were available for four patients. One patient had keratoconus; one had abnormal retinal pigmentation; and two had lens surgery scars with irregular astigmatism. CONCLUSIONS: Eye abnormalities are very frequent in late-diagnosed HCU patients. The presence of ectopia lentis should always raise the diagnostic hypothesis of HCU.
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Astigmatismo/patología , Desplazamiento del Cristalino/patología , Homocistinuria/complicaciones , Miopía/patología , Adolescente , Adulto , Astigmatismo/etiología , Desplazamiento del Cristalino/etiología , Femenino , Humanos , Masculino , Miopía/etiología , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Background: Cardiovascular involvement is among the main features of MPS disorders and it is also a significant cause of morbidity and mortality. The range of manifestations includes cardiac valve disease, conduction abnormalities, left ventricular hypertrophy, and coronary artery disease. Here, we assessed the cardiovascular manifestations in a cohort of children and adults with MPS I, II, IV, and VI, as well as the impact of enzyme replacement therapy (ERT) on those manifestations. Methods: We performed a chart review of 53 children and 23 adults with different types of MPS that had performed echocardiograms from January 2000 until October 2018. Standardized Z scores were obtained for heart chamber sizes according to the body surface area. When available, echocardiographic measurements that were performed before ERT and at least 18 months after that date were used for the assessment of pre- and post-treatment parameters. Results: Left side valvular disease was a frequent finding, with mitral and aortic thickening being reported in most patients in all four MPS types. Left atrium dilatation was present in 26% of the patients; 25% had increased relative wall thickness; 28% had pulmonary hypertension. The cardiovascular involvement was, in general, more prevalent and more severe in adults than in children, including conduction disorders (40 vs. 16%), mitral stenosis (26 vs. 6%), aortic stenosis (13 vs. 4%), and systolic dysfunction (observed in only one adult patient). ERT promoted a significant reduction of the left ventricular hypertrophy parameters, but failed to improve valve abnormalities, pulmonary hypertension, and left atrial dilatation. Conclusions: Adult patients with MPS may develop severe cardiovascular involvement, not commonly observed in children, and clinicians should be aware of the need for careful monitoring and timely management of those potentially life-threatening complications. Our results also confirm the impact of long-term ERT on left ventricular hypertrophy and its limitations in reversing other prevalent cardiovascular manifestations.
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Tendón Calcáneo/efectos de los fármacos , Ácido Quenodesoxicólico/uso terapéutico , Paraplejía/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Tendón Calcáneo/patología , Adulto , Colestanotriol 26-Monooxigenasa/genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Paraplejía/diagnóstico , Paraplejía/genética , Fenotipo , Resultado del Tratamiento , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/genéticaRESUMEN
Recent studies have shown that patients with phenylketonuria (PKU), even with the early diagnosis and continuous treatment, may have symptoms of attention-deficit hyperactivity disorder (ADHD) and that the prevalence of ADHD in this population would be higher than in the general population. This study aims to determine the prevalence of ADHD in a sample of PKU patients from Southern Brazil. Patients were prospectively assessed by clinical interviews, neurological examination, and application of the MTA-SNAP-IV scales for patients aged 5-17 years and the Adult Self-Report Scale for patients over 17 years. Thirty-one patients (mean age = 17.4; early diagnosis = 27) were followed. Patients with ADHD and younger than 17 years had a median Phe in the last 6 months of life higher than those without the diagnosis of ADHD (ADHD patients = 617.1 µmol/L, no-ADHD patients 393.2 µmol/L, and p = 0.03). There was a predominantly hyperactive/impulsivity clinical presentation of ADHD (n = 4/5 patients), which differs from that reported elsewhere in the literature. Future studies are essential to better define the clinical presentation of ADHD in these patients and further elucidate its pathophysiology.
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Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Fenilcetonurias/complicaciones , Adolescente , Factores de Edad , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Encéfalo/metabolismo , Brasil , Niño , Preescolar , Femenino , Humanos , Masculino , Fenilcetonurias/diagnóstico por imagen , Psicometría/métodosRESUMEN
The rs2229611 SNP (G6PC:c.*23T>C) in the 3'UTR region of the G6PC gene affects the stability of the glucose-6-phosphatase mRNA and occurs in a higher frequency in patients with glycogenosis Ia (GSD Ia) in some populations. Herein, a group of Brazilian patients (n = 116) was analyzed by NGS and the frequency of rs2229611:T>C was determined. The linkage disequilibrium (LD) between pathogenic variants and the rs2229611:T>C SNP was evaluated. The results showed that the rs2229611:T>C is associated to GSD Ia and is in LD with the most frequent pathogenic variants in Brazilian patients with GSD Ia.
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BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1ß, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. RESULTS: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. CONCLUSION: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.
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Enfermedad de la Orina de Jarabe de Arce , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Brasil , Estudios Transversales , Humanos , Enfermedad de la Orina de Jarabe de Arce/genética , FenotipoRESUMEN
Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism whose dietary treatment involves uncooked cornstarch administration and restriction of simple carbohydrate intake. The prevalence of feeding difficulties (FDs) and orofacial myofunctional disorders (OMDs) in these patients is unknown. OBJECTIVE: To ascertain the prevalence of FDs and OMDs in GSD. METHODS: This was a cross-sectional, prospective study of 36 patients (19 males; median age, 12.0 years; range, 8.0-18.7 years) with confirmed diagnoses of GSD (type Ia = 22; Ib = 8; III = 2; IXa = 3; IXc = 1). All patients were being treated by medical geneticists and dietitians. Evaluation included a questionnaire for evaluation of feeding behavior, the orofacial myofunctional evaluation (AMIOFE), olfactory and taste performance (Sniffin' Sticks and Taste Strips tests), and facial anthropometry. RESULTS: Nine (25%) patients had decreased olfactory perception, and four (11%) had decreased taste perception for all flavours. Eight patients (22.2%) had decreased perception for sour taste. Twenty-six patients (72.2%) had FD, and 18 (50%) had OMD. OMD was significantly associated with FD, tube feeding, selective intake, preference for fluid and semisolid foods, and mealtime stress (p < 0.05). Thirteen patients (36.1%) exhibited mouth or oronasal breathing, which was significantly associated with selective intake (p = 0.011) and not eating together with the rest of the family (p = 0.041). Lower swallowing and chewing scores were associated with FD and with specific issues related to eating behavior (p < 0.05). CONCLUSION: There is a high prevalence of FDs and OMDs in patients with GSD. Eating behavior, decreased taste and smell perception, and orofacial myofunctional issues are associated with GSD.