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1.
ACS Appl Mater Interfaces ; 11(43): 39633-39647, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31532618

RESUMO

Effective and timely delivery of therapeutic agents from the systemic circulation to the central nervous system (CNS) is often precluded by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). A new pathway of folate uptake mediated by folate receptor alpha (FRα, molecular weight of 28.29 kg mol-1) occurring in various epithelial cells of the CNS (e.g., choroid plexus) was described. Aiming to investigate this mechanism for the delivery of nanomedicines to the CNS, in this work, we initially produced nanoparticles (NPs) made of a highly hydrophobic poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) block copolymer functionalized with an amine moiety in the edge of the PEG block by a simple nanoprecipitation method. Hydrophilic PEG blocks migrated to the NP surface during formation, exposing primary amine groups that were used to conjugate the targeting ligand, FRα. The size of the NPs was in the 58-98 nm range and standard deviation (S.D., a measure of the size population peak width) of 26-41 nm, as measured by dynamic light scattering (DLS). The FRα conjugation yield ranged between 50% and 75% (determined indirectly by the bicinchoninic acid protein assay). Pristine and FRα-modified NPs showed good compatibility with primary human choroid plexus epithelial cells (HCPEpiCs). The uptake of FRα-conjugated NPs by HCPEpiCs was qualitatively evaluated in vitro using inverted optical fluorescence and confocal microscopy. FRα-modified NPs were internalized by HCPEpiCs to a greater extent than the unmodified counterparts. Then, their permeability was characterized in standard and inverted HCPEpiC monolayers. In both cases, NPs surface modified with the FRα and complexed to folic acid (FA) showed significantly higher apparent permeability coefficient (Papp) values than the pristine ones. Finally, the biodistribution of unmodified and FRα-FA-modified NPs following intravenous (i.v.) administration was compared in ICR mice. Results indicated that conjugation of the FRα-FA complex to the NP surface promotes higher accumulation in the brain, highlighting the promise of FRα-FA-modified NPs to serve as a platform for the targeting of active molecules to the CNS from the systemic circulation.

2.
Genet Med ; 21(9): 2043-2058, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30842647

RESUMO

PURPOSE: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly. METHODS: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset). RESULTS: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1). CONCLUSION: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.

3.
Elife ; 82019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30775969

RESUMO

Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Mitochondrial biogenesis and function defects in these cells are rescued by the silencing of KLF2 or ETV1. Increased ETV1 expression is regulated by KLF2, while the increase of KLF2 protein levels in NPC and ASM stems from impaired signaling downstream sphingosine-1-phosphate receptor 1 (S1PR1), which normally represses KLF2. In patient cells, S1PR1 is barely detectable at the plasma membrane and thus unable to repress KLF2. This manuscript provides a mechanistic pathway for the prevalent mitochondrial defects in lysosomal storage diseases. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

4.
Ann Neurol ; 83(5): 970-979, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29665094

RESUMO

OBJECTIVE: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. METHODS: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children. RESULTS: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study. INTERPRETATION: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.

5.
J Pediatr Genet ; 7(1): 14-18, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29441216

RESUMO

Compromised lysosomal functioning has been identified as a major risk factor for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Furthermore, the association between a defined cathepsin D ( CTSD ) polymorphism and a higher risk of sporadic Alzheimer's disease has been established for particular populations. Here, we analyzed 189 children with rare neurodegenerative disease for carrying the T-allele by polymerase chain reaction-restriction fragment length polymorphism. We found no statistical differences in genotype and allele frequencies between the neurodegenerative group and European descent participants of genetic studies using the Cochran-Armitage's trend test. In contrast to adult-onset neurodegenerative diseases, analysis of clinical datasets of children carrying the T-allele did not demonstrate differences to the general disease group.

6.
JAMA Netw Open ; 1(3): e180769, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-30646031

RESUMO

Importance: Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized. Objectives: To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes. Design, Setting, and Participants: This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score. Main Outcomes and Measures: Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified. Results: Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6). Conclusions and Relevance: All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.


Assuntos
Adrenoleucodistrofia/cirurgia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Humanos , Masculino , Transtornos Neurocognitivos/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Transplante Homólogo
7.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
8.
Am J Psychiatry ; 174(1): 42-50, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27523499

RESUMO

OBJECTIVE: Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized. METHOD: The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry. RESULTS: CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality. CONCLUSIONS: Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.


Assuntos
Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/tratamento farmacológico , Ácido Fólico/líquido cefalorraquidiano , Ácido Fólico/uso terapêutico , Tentativa de Suicídio/psicologia , Adolescente , Transtorno Depressivo Resistente a Tratamento/psicologia , Quimioterapia Combinada , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/psicologia , Humanos , Adulto Jovem
9.
J Alzheimers Dis ; 51(3): 683-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890752

RESUMO

A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.


Assuntos
Encéfalo/diagnóstico por imagem , Cerebrosídeo Sulfatase/genética , Demência/genética , Leucodistrofia Metacromática/genética , Mutação de Sentido Incorreto , Idade de Início , Análise Mutacional de DNA , Demência/diagnóstico por imagem , Diagnóstico Diferencial , Éxons , Humanos , Leucodistrofia Metacromática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
10.
Wien Med Wochenschr ; 165(9-10): 210-3, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26059544

RESUMO

BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) is characterized by a combination of retinopathy, dementia, and epilepsy. As a group, they encompass ten distinct biological and clinical entities and are the most common type of childhood neurodegenerative disease. PATIENTS AND METHODS: Case reports. RESULTS: We demonstrate the clinical course of two neonates (brother and sister) with infantile neuronal ceroid lipofuscinoses (NCL) (CLN 10 disease) presenting with intractable seizures and respiratory insufficiency immediately after birth. Characteristic clinical, radiological and pathological findings of this form of NCL are presented. CONCLUSIONS: We conclude that the diagnosis of CLN10 should be kept in mind as a differential diagnosis in newborns presenting with respiratory insufficiency and severe epilepsy that is largely refractory to anti-epileptic drugs (AED) treatment. Because of the severity of CLN10 disease and futility of treatment, important ethical issues arise when caring for children with this clinical entity.


Assuntos
Catepsina D/deficiência , Lipofuscinoses Ceroides Neuronais/genética , Adulto , Encéfalo/anormalidades , Encéfalo/patologia , Catepsina D/genética , Aberrações Cromossômicas , Consanguinidade , Diagnóstico Diferencial , Ética Médica , Eutanásia Passiva/ética , Feminino , Genes Recessivos/genética , Triagem de Portadores Genéticos , Humanos , Recém-Nascido , Masculino , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/terapia , Cuidados Paliativos/ética
11.
Pediatr Blood Cancer ; 62(6): 1091-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25504888

RESUMO

Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition.


Assuntos
Deficiência de Ácido Fólico/complicações , Síndromes de Imunodeficiência/etiologia , Síndromes de Malabsorção/complicações , Pancitopenia/etiologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino
12.
Orphanet J Rare Dis ; 9: 141, 2014 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-25233840

RESUMO

BACKGROUND: We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in receptor-mediated endocytosis. The clinical presentation includes intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis. Biochemical findings include transient cobalamin deficiency, severe hypertriglyceridemia upon ketogenic diet, microalbuminuria and partial cathepsin D deficiency. METHODS AND RESULTS: Whole exome sequencing followed by Sanger sequencing confirmed a rare (frequency:0.003987) homozygous missense mutation, g.15,116,371 G > A (c.1273G > A), in ZFYVE20 resulting in an amino acid change from Glycine to Arginine at position 425 of the Rbsn protein (p.Gly425Arg), as the only mutation segregating with disease in the family. Studies in fibroblasts revealed expression and localization of Rbsn-5G425R in wild-type manner, but a 50% decrease in transferrin accumulation, which is corrected by wild-type allele transfection. Furthermore, the patient's fibroblasts displayed an impaired proliferation rate, cytoskeletal and lysosomal abnormalities. CONCLUSION: These results are consistent with a functional defect in the early endocytic pathway resulting from mutation in Rbsn-5, which secondarily disrupts multiple cellular functions dependent on endocytosis, leading to a severe multi-organ disorder.


Assuntos
Endocitose/genética , Mutação Puntual/genética , Convulsões/diagnóstico , Convulsões/genética , Proteínas de Transporte Vesicular/genética , Criança , Feminino , Humanos , Transporte Proteico/genética , Convulsões/metabolismo
13.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 5): 1321-35, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24816101

RESUMO

Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 Å resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder.


Assuntos
Hidrolases/química , Hidrolases/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Hidrolases/genética , Modelos Moleculares , Mucopolissacaridose III/fisiopatologia , Fosfatos/metabolismo , Conformação Proteica , Homologia Estrutural de Proteína , Relação Estrutura-Atividade , Sulfatos/metabolismo
14.
Neurology ; 82(11): 945-55, 2014 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-24523486

RESUMO

OBJECTIVE: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. METHODS: We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. RESULTS: Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. CONCLUSION: AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.


Assuntos
Distúrbios Distônicos/genética , Hemiplegia/genética , Mutação/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Metanálise como Assunto , Adulto Jovem
15.
Orphanet J Rare Dis ; 9: 18, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24499656

RESUMO

BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare, genetic neurodegenerative disease. It leads to progressive demyelination resulting in regression of development and early death. With regard to experimental therapies, knowledge of the natural course of the disease is highly important. We aimed to analyse onset and character of first symptoms in MLD and to provide detailed natural course data concerning language and cognition. METHODS: Patients with MLD were recruited nationwide within the scope of the German research network LEUKONET. 59 patients' questionnaires (23 late-infantile, 36 juvenile) were analysed. RESULTS: Time from first symptoms (at a median age of 1.5 years in late-infantile and 6 years in juvenile MLD) to diagnosis took one year in late-infantile and two years in juvenile patients on average. Gait disturbances and abnormal movement patterns were first signs in all patients with late-infantile and in most with juvenile MLD. Onset in the latter was additionally characterized by problems in concentration, behaviour and fine motor function (p=0.0011, p<0.0001, and p=0.0012). Half of late-infantile patients did not learn to speak in complete sentences after an initially normal language acquisition. They showed a rapid language decline with first language difficulties at a median age of 2.5 years and complete loss of expressive language within several months (median age 32, range 22-47 months). This was followed by total loss of communication at a median age of around four years. In juvenile patients, language decline was more protracted, and problems in concentration and behaviour were followed by decline in skills for reading, writing and calculating around four years after disease onset. CONCLUSIONS: Our data reflect the natural course of decline in language and cognition in late-infantile and juvenile MLD in a large cohort over a long observation period. This is especially relevant to juvenile patients where the disease course is protracted and prospective studies are hardly feasible. Knowledge of first symptoms may lead to earlier diagnosis and subsequently to a better outcome following therapeutic intervention. Our data may serve as a reference for individual treatment decisions and for evaluation of clinical outcome after treatment intervention.


Assuntos
Linguagem , Leucodistrofia Metacromática/fisiopatologia , Pré-Escolar , Cognição/fisiologia , Feminino , Humanos , Lactente , Masculino
16.
Nat Commun ; 4: 2123, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23828504

RESUMO

Loss of folate receptor-α function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-α-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-α-positive exosomes. Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-α-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.


Assuntos
Plexo Corióideo/citologia , Plexo Corióideo/metabolismo , Exossomos/metabolismo , Ácido Fólico/metabolismo , Transcitose , Adolescente , Adulto , Animais , Polaridade Celular/efeitos dos fármacos , Criança , Plexo Corióideo/ultraestrutura , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/metabolismo , Cães , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Receptor 1 de Folato/metabolismo , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Modelos Biológicos , Monensin/farmacologia , Transporte Proteico/efeitos dos fármacos , Transportador de Folato Acoplado a Próton/metabolismo , Ratos , Tetra-Hidrofolatos/metabolismo , Transcitose/efeitos dos fármacos , Transferrina/farmacologia , Adulto Jovem
17.
Orphanet J Rare Dis ; 8: 6, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23305374

RESUMO

BACKGROUND: Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited. STUDY DESIGN/METHODS: Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients' and their families' quality of life was assessed. RESULTS: The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents' point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. CONCLUSION: Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.


Assuntos
Acidemia Propiônica/patologia , Adolescente , Criança , Pré-Escolar , Cognição , Feminino , Humanos , Lactente , Deficiência Intelectual , Masculino , Acidemia Propiônica/psicologia , Acidemia Propiônica/terapia , Desempenho Psicomotor , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
18.
Ann Clin Lab Sci ; 42(3): 231-42, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22964611

RESUMO

Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Bax activator Bid, and translocation of Bax to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.


Assuntos
Apoptose , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Catepsina D/metabolismo , Lisossomos/metabolismo , Fenilalanina/metabolismo , Processamento de Proteína Pós-Traducional , Triptofano/metabolismo , Proteínas 14-3-3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Humanos , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Lisossomos/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Permeabilidade/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estaurosporina/farmacologia , Especificidade por Substrato/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
19.
Nucleic Acids Res ; 40(17): 8733-42, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22735700

RESUMO

Mutations in the gene of human RNase T2 are associated with white matter disease of the human brain. Although brain abnormalities (bilateral temporal lobe cysts and multifocal white matter lesions) and clinical symptoms (psychomotor impairments, spasticity and epilepsy) are well characterized, the pathomechanism of RNase T2 deficiency remains unclear. RNase T2 is the only member of the Rh/T2/S family of acidic hydrolases in humans. In recent years, new functions such as tumor suppressing properties of RNase T2 have been reported that are independent of its catalytic activity. We determined the X-ray structure of human RNase T2 at 1.6 Å resolution. The α+ß core fold shows high similarity to those of known T2 RNase structures from plants, while, in contrast, the external loop regions show distinct structural differences. The catalytic features of RNase T2 in presence of bivalent cations were analyzed and the structural consequences of known clinical mutations were investigated. Our data provide further insight into the function of human RNase T2 and may prove useful in understanding its mode of action independent of its enzymatic activity.


Assuntos
Endorribonucleases/química , Sequência de Aminoácidos , Sítios de Ligação , Cobre/farmacologia , Cristalografia por Raios X , Endorribonucleases/genética , Endorribonucleases/metabolismo , Glicosilação , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Dobramento de Proteína , Homologia Estrutural de Proteína , Zinco/química , Zinco/farmacologia
20.
Mol Genet Metab ; 104(3): 369-72, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21737328

RESUMO

BACKGROUND: Cerebral folate deficiency (CFD) is increasingly recognized in various neurological conditions, raising the question of whether it might represent a clear-cut clinical syndrome. METHODS: Retrospective analysis of patients with low cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) values was performed. RESULTS: 58 pediatric patients with low (-2nd to -3rd standard deviation) and 45 patients with very low 5MTHF values (<3rd standard deviation) were identified, including 22 patients with defined underlying neurological conditions. The leading symptoms were mental retardation (n=84), motor retardation (n=75), epilepsy (n=53), ataxia (n=44) and pyramidal tract signs (n=37). There was no relationship between 5MTHF levels and the severity of clinical disease, the duration of clinical disease, distinct neurological symptoms and antiepileptic drug treatment, respectively. Genetical analysis for mutations in the folate receptor 1 gene proved normal in all 16 children studied. CONCLUSIONS: For the majority of patients CFD is not a clear-cut neurometabolic syndrome but the common result of different genetic, metabolic or unknown processes. Nevertheless, CFD may represent a treatable disease-modifying factor which should therefore be addressed in prospective studies.


Assuntos
Anormalidades Múltiplas/patologia , Deficiência de Ácido Fólico/patologia , Deficiência Intelectual/patologia , Adolescente , Ataxia/complicações , Ataxia/patologia , Criança , Pré-Escolar , Epilepsia/complicações , Epilepsia/patologia , Feminino , Deficiência de Ácido Fólico/complicações , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Masculino , Tratos Piramidais/patologia , Estudos Retrospectivos , Síndrome , Tetra-Hidrofolatos/líquido cefalorraquidiano , Adulto Jovem
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