RESUMO
AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane. Heterozygous AFG3L2 mutations cause spinocerebellar ataxia type 28 (SCA28) or dominant optic atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe spastic ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia and myoclonic epilepsy. We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the overactivation of the stress-sensitive protease OMA1, which over-processes OPA1, leading to mitochondrial fragmentation. Recently, OMA1 has been identified as the pivotal player communicating mitochondrial stress to the cytosol via a pathway involving the inner mitochondrial membrane protein DELE1 and the cytosolic kinase HRI, thus eliciting the integrated stress response. In general, the integrated stress response reduces global protein synthesis and drives the expression of cytoprotective genes that allow cells to endure proteotoxic stress. However, the relevance of the OMA1-DELE1-HRI axis in vivo, and especially in a human CNS disease context, has been poorly documented thus far. In this work, we demonstrated that mitochondrial proteotoxicity in the absence/mutation of AFG3L2 activates the OMA1-DELE1-HRI pathway eliciting the integrated stress response. We found enhanced OMA1-dependent processing of DELE1 upon depletion of AFG3L2. Also, in both skin fibroblasts from SPAX5 patients (including a novel case) and in the cerebellum of Afg3l2-/- mice we detected increased phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α), increased levels of ATF4 and strong upregulation of its downstream targets (Chop, Chac1, Ppp1r15a and Ffg21). Silencing of DELE1 or HRI in SPAX5 fibroblasts (where OMA1 is overactivated at basal state) reduces eIF2α phosphorylation and affects cell growth. In agreement, pharmacological potentiation of integrated stress response via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts and cell survival and dendritic arborization ex vivo in primary Afg3l2-/- Purkinje neurons. Notably, Sephin-1 treatment in vivo extended the lifespan of Afg3l2-/- mice, improved Purkinje neuron morphology, mitochondrial ultrastructure and respiratory capacity. These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the integrated stress response may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis.
Assuntos
Deficiência Intelectual , Atrofia Óptica , Ataxias Espinocerebelares , Humanos , Animais , Camundongos , Criança , Ataxias Espinocerebelares/genética , Espasticidade Muscular , Peptídeo Hidrolases , ATPases Associadas a Diversas Atividades Celulares/genética , Proteases Dependentes de ATP/genética , Proteínas Mitocondriais , MetaloproteasesRESUMO
In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5'-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200-900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.
Assuntos
Disfunção Cognitiva , Homocistinúria , Degeneração Macular , Deficiência de Vitamina B 12 , Pré-Escolar , Humanos , Lactente , Masculino , Disfunção Cognitiva/tratamento farmacológico , Homocistinúria/tratamento farmacológico , Homocistinúria/genética , Hidroxocobalamina/uso terapêutico , Degeneração Macular/tratamento farmacológico , Mamíferos , Oxirredutases , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/tratamento farmacológicoRESUMO
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid ß-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
Assuntos
Erros Inatos do Metabolismo Lipídico , Miopatias Mitocondriais , Doenças Musculares , 3-Hidroxiacil-CoA Desidrogenases , Adolescente , Cardiomiopatias , Criança , Pré-Escolar , Coenzima A , Diagnóstico Tardio , Ácidos Graxos/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/deficiência , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças do Sistema Nervoso , RabdomióliseRESUMO
BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Malformações do Sistema Nervoso/genética , Polimicrogiria/genética , Tubulina (Proteína)/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Mutação de Sentido Incorreto/genética , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Neuroimagem/métodos , Fenótipo , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/patologia , Tubulina (Proteína)/deficiência , Adulto JovemRESUMO
PurposePREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.ResultsFive subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader-Willi syndrome.ConclusionPREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader-Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Serina Endopeptidases/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Ativação Enzimática , Fácies , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prolil Oligopeptidases , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Adulto JovemRESUMO
Isolated sulfite oxidase deficiency (ISOD) is a life-threatening, autosomal recessive disease characterized by severe neurological impairment. As no long-term effective treatment is available, distinction from other treatable diseases, such as molybdenum cofactor deficiency (MoCD) type A, should be made. We reviewed 47 patients (45 previously reported in the literature). Cases were reviewed for consanguinity, sex, age at onset, death, clinical findings (including spasticity, seizures, psychomotor retardation, feeding difficulties, ectopia lentis, microcephaly), laboratory findings [urinary sulfite, S-sulfocysteine (in plasma and urine), plasma cystine, total homocysteine, uric acid, and oxypurines in urine] and radiological findings (including cerebral/cerebellar atrophy, cystic white matter changes, ventriculomegaly). We also aligned the published SUOX gene mutations to the reference sequence NM_000456.2. Onset occurred mostly during the first 72 h of life (57%) and within the first year of life in all but two patients (96%). All patients presented with neurological abnormalities, such as neonatal axial hypotonia and/or peripheral hypertonia (100%), (pharmacoresistant) seizures (84%), or developmental delay (97%). Feeding problems were also common. As found in our review, measurement of homocysteine in plasma, amino acids in plasma/urine, and sulfite in fresh urine supports the diagnosis of ISOD. Analysis of uric acid (plasma) and oxypurines (urine) is useful to rule out MoCD. In all patients in whom brain magnetic resonance imaging/computed tomography (MRI/CT) was performed, brain abnormalities were found. The purpose of this literature review is to provide a thorough overview of clinical, neuroimaging, biochemical, and genetic findings of patients with ISOD.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/deficiência , Sulfito Oxidase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Mutação , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Sulfito Oxidase/genéticaRESUMO
AIM: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. METHOD: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. RESULTS: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. INTERPRETATION: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. WHAT THIS PAPER ADDS: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities.
Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/patologia , Adolescente , Fatores Etários , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Ventilação/métodosRESUMO
Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.
Assuntos
Acidose Láctica/genética , Encefalopatias/genética , Cardiomiopatia Hipertrófica/genética , Proteínas de Ligação ao GTP/genética , Processamento de Proteína Pós-Traducional , Acidose Láctica/fisiopatologia , Sequência de Aminoácidos , Encéfalo/patologia , Encefalopatias/fisiopatologia , Cardiomiopatia Hipertrófica/fisiopatologia , Linhagem Celular , Criança , Pré-Escolar , Consanguinidade , Feminino , Fibroblastos , Proteínas de Ligação ao GTP/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Biossíntese de Proteínas , Interferência de RNA , RNA de Transferência/genética , RNA de Transferência/metabolismo , Alinhamento de SequênciaRESUMO
Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a ß1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
Assuntos
Defeitos Congênitos da Glicosilação/genética , Manosiltransferases/genética , Mutação , Polissacarídeos/metabolismo , Biomarcadores/metabolismo , Defeitos Congênitos da Glicosilação/metabolismo , Feminino , Genes Letais , Glicosilação , Humanos , Masculino , Análise de Sequência de DNA , Análise de SobrevidaRESUMO
Niemann-Pick type C is a lysosomal storage disease associated with mutations in NPC1 or NPC2, resulting in an accumulation of cholesterol in the endosomal-lysosomal system. Niemann-Pick type C has a clinical spectrum that ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease combined with remarkably, in some cases, hematological defects such as thrombocytopenia, anemia and petechial rash. A role of NPC1 in hematopoiesis was never shown. Here, we describe platelet function abnormalities in three unrelated patients with a proven genetic and biochemical NPC1 defect. Their platelets have reduced aggregations, P-selectin expression and ATP secretions that are compatible with the observed abnormal alpha and reduced dense granules as studied by electron microscopy and CD63 staining after platelet spreading. Their blood counts were normal. NPC1 expression was shown in platelets and megakaryocytes (MKs). In vitro differentiated MKs from NPC1 patients exhibit hyperproliferation of immature MKs with different CD63(+) granules and abnormal cellular accumulation of cholesterol as shown by filipin stainings. The role of NPC1 in megakaryopoiesis was further studied using zebrafish with GFP-labeled thrombocytes or DsRed-labeled erythrocytes. NPC1 depletion in zebrafish resulted in increased cell death in the brain and abnormal cellular accumulation of filipin. NPC1-depleted embryos presented with thrombocytopenia and mild anemia as studied by flow cytometry and real-time QPCR for specific blood cell markers. In conclusion, this is the first report, showing a role of NPC1 in platelet function and formation but further studies are needed to define how cholesterol storage interferes with these processes.
Assuntos
Plaquetas/fisiologia , Proteínas de Transporte/fisiologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana/fisiologia , Doença de Niemann-Pick Tipo C/sangue , Proteínas de Peixe-Zebra/fisiologia , Animais , Proteínas de Transporte/genética , Morte Celular , Diferenciação Celular , Criança , Feminino , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/genética , Trombocitopenia/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genéticaRESUMO
BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022. METHODS: Data were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis. RESULTS: We identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype. CONCLUSIONS: This is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.
Assuntos
Síndromes Miastênicas Congênitas , Humanos , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Síndromes Miastênicas Congênitas/diagnóstico , Bélgica/epidemiologia , Masculino , Feminino , Adulto , Criança , Estudos Retrospectivos , Adolescente , Adulto Jovem , Pré-Escolar , Lactente , Pessoa de Meia-Idade , PrevalênciaRESUMO
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by skeletal dysplasia, exocrine pancreatic insufficiency and bone marrow failure. Various other conditions, such as hepatopathy and failure to thrive have been associated with SDS. A retrospective study was conducted to describe mutations, clinical features, and the immunological profile of 11 Belgian patients with genetically confirmed diagnosis of SDS. This study confirms the existing understanding of the classical features of SDS although the typical triad was present in only six out of nine fully studied patients. The following important observations are made in this cohort. Four out of eleven patients were misdiagnosed as having Asphyxiating Thoracic Dystrophy (Jeune syndrome) because of severe thoracic dystrophy. Another two patients presented with unexplained episodes of symptomatic hypoglycaemia. The immunological phenotype was heterogeneous although laboratory abnormalities were noticed in eight out of ten patients assessed. Three patients experienced a life threatening viral infection (respiratory syncytial virus, cytomegalovirus (CMV) and rotavirus). In one patient, CMV infection caused an episode of haemophagocytic lymphohistiocytosis. One patient has bronchiectasis at the age of 3 years due to recurrent respiratory tract infections. These findings strengthen the suspicion of an abnormal immune system in SDS. Liver anomalies, usually described as benign and transitory in SDS patients, were severe in two patients of the cohort. One patient developed hepatopulmonary syndrome. The findings in this national cohort of SDS patients could contribute to the prevention of misdiagnosis in the future and enable more rapid recognition of certain severe complications.
Assuntos
Doenças da Medula Óssea/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Erros de Diagnóstico , Síndrome de Ellis-Van Creveld/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Lipomatose/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Adulto , Bélgica , Doenças da Medula Óssea/complicações , Infecções por Citomegalovirus/complicações , Diagnóstico Diferencial , Insuficiência Pancreática Exócrina/complicações , Feminino , Humanos , Lipomatose/complicações , Masculino , Estudos Retrospectivos , Síndrome de Shwachman-DiamondRESUMO
Hypotonia-cystinuria syndrome (HCS) is an autosomal recessive disorder caused by combined deletions of SLC3A1 and PREPL. Clinical features include cystinuria, neonatal hypotonia with spontaneous improvement, poor feeding in neonates, hyperphagia in childhood, growth hormone deficiency, and variable cognitive problems. Only 14 families with 6 different deletions have been reported. Patients are often initially misdiagnosed, while correct diagnosis enables therapeutic interventions. We report two novel deletions, further characterizing the clinical and molecular genetics spectrum of HCS.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Anormalidades Craniofaciais/genética , Cistinúria/genética , Deficiência Intelectual/genética , Doenças Mitocondriais/genética , Hipotonia Muscular/genética , Serina Endopeptidases/genética , Sistemas de Transporte de Aminoácidos Básicos/deficiência , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Sequência de Bases , Criança , Deleção Cromossômica , Cromossomos Humanos Par 21/genética , Anormalidades Craniofaciais/patologia , Cistinúria/patologia , Feminino , Heterogeneidade Genética , Homozigoto , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Doenças Mitocondriais/patologia , Dados de Sequência Molecular , Hipotonia Muscular/patologia , Prolil Oligopeptidases , Deleção de Sequência , Serina Endopeptidases/deficiência , Índice de Gravidade de DoençaRESUMO
Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia.
Assuntos
Transtornos Cromossômicos/genética , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Mutação/genética , Receptores Citoplasmáticos e Nucleares/genética , Degenerações Espinocerebelares/genética , Células Cultivadas , Criança , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/dietoterapia , Humanos , Masculino , Mosaicismo , Peroxinas , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/dietoterapia , Adulto JovemRESUMO
Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPLL isoform localizes to mitochondria, whereas PREPLS remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPLL is involved in mitochondrial homeostasis.
RESUMO
NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred de novo. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.
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BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients.
Assuntos
Distonia , Erros Inatos do Metabolismo , Fenilcetonúrias , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Humanos , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/genéticaRESUMO
An amendment to this paper has been published and can be accessed via the original article.
RESUMO
Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X-linked disorders. Parenteral hydroxocobalamin (P-OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long-term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1-3; cblA: patient 4; cblX: patient 5) following daily P-OHCbl dose intensification (DI). In patient 4, P-OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P-OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P-OHCbl doses. After age 36 months, patients 1-3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P-OHCbl-DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P-OHCbl-DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P-OHCbl doses were administrated to improve tolerability.