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1.
Mol Genet Metab ; 133(4): 386-396, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34226107

RESUMEN

OBJECTIVE: Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). METHODS: We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. RESULTS: Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. INTERPRETATION: The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.


Asunto(s)
Gangliosidosis GM2/diagnóstico por imagen , Gangliosidosis GM2/fisiopatología , Enfermedades de Inicio Tardío/diagnóstico por imagen , Enfermedades de Inicio Tardío/fisiopatología , Imagen por Resonancia Magnética/métodos , Análisis Espectral/métodos , Adulto , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/patología , Enfermedad de Sandhoff/diagnóstico por imagen , Enfermedad de Sandhoff/fisiopatología , Enfermedad de Tay-Sachs/diagnóstico por imagen , Enfermedad de Tay-Sachs/fisiopatología , Tálamo/diagnóstico por imagen , Tálamo/patología , Adulto Joven
3.
J Inherit Metab Dis ; 41(4): 647-656, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29484516

RESUMEN

OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurodegenerative disorder in bile acid synthesis. The natural history of neurological abnormalities in CTX is not well understood. The object of this study was to determine neurological progression in CTX. METHODS: A literature search on PubMed for "cerebrotendinous xanthomatosis" yielded 91 publications that reported cases of CTX patients. Two independent reviewers abstracted information about the presence and age of onset of neurological abnormalities in published CTX cases. For each neurological abnormality, we estimated the probability of its onset at any given age using cumulative incidence function analysis. We also present our own case series, in which five CTX patients were evaluated. RESULTS: The literature search yielded 194 CTX cases (ages ranging from newborn to 67 years old). The most common neurological abnormalities were corticospinal tract abnormalities including weakness, hyperreflexia, spasticity, Babinski sign (59.8%), ataxia (58.8%), cognitive decline (46.4%), and gait difficulty (38.1%); 68 (35.0%) had baseline cognitive problems. Cumulative incidence function analysis revealed that ataxia, gait difficulties, and corticospinal tract abnormalities developed throughout life, while cognitive decline tended to develop later in life. Of the less common neurological abnormalities, seizures, psychiatric changes and speech changes developed throughout life, while parkinsonism and sensory changes tended to develop later in life. Our case series corroborated this temporal pattern of neurological abnormalities. CONCLUSION: We provide estimates for the neurological progression of CTX, categorizing neurological abnormalities according to time and probability of development. Our approach may be applicable to other rare disorders.


Asunto(s)
Ácido Quenodesoxicólico/uso terapéutico , Enfermedades del Sistema Nervioso/fisiopatología , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Resultado del Tratamiento , Xantomatosis Cerebrotendinosa/diagnóstico
4.
Brain ; 140(12): 3139-3152, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29136088

RESUMEN

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood-brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.


Asunto(s)
Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Adrenoleucodistrofia/diagnóstico por imagen , Microcirculación , Sustancia Blanca/irrigación sanguínea , Adolescente , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/terapia , Enfermedades Asintomáticas , Barrera Hematoencefálica/metabolismo , Estudios de Casos y Controles , Circulación Cerebrovascular , Niño , Preescolar , Trasplante de Células Madre Hematopoyéticas , Hemicigoto , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Mutación , Permeabilidad , Sustancia Blanca/diagnóstico por imagen , Adulto Joven
5.
Brain ; 139(Pt 6): 1666-72, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27190017

RESUMEN

Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.


Asunto(s)
Leucoencefalopatías/genética , Mosaicismo , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Adulto , Anciano de 80 o más Años , Quimerismo , Femenino , Predisposición Genética a la Enfermedad/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucoencefalopatías/cirugía , Masculino , Persona de Mediana Edad , Mutación Missense
6.
J Neurosci ; 35(40): 13713-9, 2015 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-26446223

RESUMEN

Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in the SPTLC1 gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growth in vitro exhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially uses l-alanine over its canonical substrate l-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation with l-serine or removal of l-alanine independently restored normal growth patterns in mutant SPTLC1(C133W) DRG. Therefore, we report that substrate availability and selectivity of SPT influence the regulation of neurite growth in DRG neurons. SIGNIFICANCE STATEMENT: Hereditary sensory neuropathy type 1 is an autosomal-dominant disorder that leads to a sensory neuropathy due to mutations in the serine palmitoyltransferase (SPT) enzyme. We investigated how mutant SPT and substrate levels regulate neurite growth. Because SPT is an important enzyme in the synthesis of sphingolipids, our data are of broader significance to other peripheral and metabolic disorders.


Asunto(s)
Ganglios Espinales/citología , Conos de Crecimiento/fisiología , Mutación/genética , Neuronas/fisiología , Dinámicas no Lineales , Serina C-Palmitoiltransferasa/genética , Alanina/farmacología , Análisis de Varianza , Animales , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Ácidos Grasos Monoinsaturados/farmacología , Conos de Crecimiento/efectos de los fármacos , Inmunosupresores/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Serina/farmacología , Especificidad por Sustrato , Factores de Transcripción/metabolismo
7.
Brain ; 138(Pt 11): 3206-20, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26377633

RESUMEN

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Barrera Hematoencefálica/metabolismo , Encéfalo/irrigación sanguínea , Enfermedades Desmielinizantes/metabolismo , Endotelio Vascular/metabolismo , Microvasos/metabolismo , ARN Mensajero/metabolismo , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Adolescente , Adrenoleucodistrofia/metabolismo , Adrenoleucodistrofia/patología , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Células Cultivadas , Niño , Claudina-5/genética , Claudina-5/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Enfermedades Desmielinizantes/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Endotelio Vascular/patología , Ácidos Grasos/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Heterocigoto , Homocigoto , Células Endoteliales de la Vena Umbilical Humana , Humanos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Proteínas de Microfilamentos , Microscopía Confocal , Microvasos/citología , Microvasos/patología , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adulto Joven , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismo
8.
Mol Ther ; 23(5): 824-834, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25592337

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. We used recombinant adenoassociated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene (ABCD1) to mouse central nervous system (CNS). In vitro, efficient delivery of ABCD1 gene was achieved in primary mixed brain glial cells from Abcd1-/- mice as well as X-ALD patient fibroblasts. Importantly, human ABCD1 localized to the peroxisome, and AAV-ABCD1 transduction showed a dose-dependent effect in reducing VLCFA. In vivo, AAV9-ABCD1 was delivered to Abcd1-/- mouse CNS by either stereotactic intracerebroventricular (ICV) or intravenous (IV) injections. Astrocytes, microglia and neurons were the major target cell types following ICV injection, while IV injection also delivered to microvascular endothelial cells and oligodendrocytes. IV injection also yielded high transduction of the adrenal gland. Importantly, IV injection of AAV9-ABCD1 reduced VLCFA in mouse brain and spinal cord. We conclude that AAV9-mediated ABCD1 gene transfer is able to reach target cells in the nervous system and adrenal gland as well as reduce VLCFA in culture and a mouse model of X-ALD.


Asunto(s)
Adrenoleucodistrofia/genética , Dependovirus/genética , Terapia Genética , Vectores Genéticos/genética , Transducción Genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/terapia , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Células Cultivadas , Dependovirus/clasificación , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Genes Reporteros , Vectores Genéticos/administración & dosificación , Glutatión Peroxidasa/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Neuroglía/metabolismo , Transporte de Proteínas , Serogrupo , Glutatión Peroxidasa GPX1
9.
Pediatr Rev ; 42(Suppl 1): S122-S125, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33386381
11.
Muscle Nerve ; 51(4): 489-95, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25042817

RESUMEN

INTRODUCTION: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. METHODS: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. RESULTS: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14-54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = -0.8) and median motor amplitude (r2 = -0.75). CONCLUSIONS: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials.


Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Conducción Nerviosa/fisiología , Piel/inervación , Piel/patología , Adolescente , Adulto , Anciano , Biomarcadores/análisis , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Recolección de Datos , Femenino , Neuropatías Hereditarias Sensoriales y Autónomas/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
12.
Neuropediatrics ; 45(3): 169-74, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24459069

RESUMEN

OBJECTIVE: The objective of this study is to systematically review the literature on worldwide numbers of leukodystrophy patients undergoing hematopoietic stem cell transplantation (HSCT) as well as the safety and efficacy of the procedure in this patient population. MATERIALS AND METHODS: A PubMed and EMBASE search up to June 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. The effect estimates of HSCT upon survival in early-stage disease versus late-stage disease were compared. RESULTS: One hundred and fifty-two studies qualified for inclusion and reported on a total of 689 patients. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Meta-analysis in a subset of larger studies indicates that transplantation in earlier stages of disease fairs better than in the late stages. Beyond survival, little longitudinal data on functional outcome is reported and neurological outcome is sparse. CONCLUSION: Further studies are needed to determine the neurological outcome following HSCT in the leukodystrophies. HSCT in the early stages of cerebral disease is still recommended for select leukodystrophies.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucodistrofia Metacromática/cirugía , Bases de Datos Factuales , Humanos
13.
Lipids Health Dis ; 13: 161, 2014 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-25305670

RESUMEN

BACKGROUND: Sphingolipids are increasingly recognized to play a role in insulin resistance and diabetes. Recently we reported significant elevations of 1-deoxysphingolipids (1-deoxySL) - an atypical class of sphingolipids in patients with metabolic syndrome (MetS) and diabetes type 2 (T2DM). It is unknown whether 1-deoxySL in patients with diabetes type 1 (T1DM) are similarly elevated. FINDINGS: We analyzed the long chain base profile by LC-MS after hydrolyzing the N-acyl and O-linked headgroups in plasma from individuals with T1DM (N = 27), T2DM (N = 30) and healthy controls (N = 23). 1-deoxySLs were significantly higher in the groups with T2DM but not different between T1DM and controls. In contrast to patients with T2DM, 1-deoxSL levels are not elevated in T1DM. CONCLUSIONS: Our study indicates that the 1-deoxySL formation is not per-se caused by hyperglycemia but rather specifically associated with metabolic changes in T2DM, such as elevated triglyceride levels.


Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Esfingosina/análogos & derivados , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Lípidos , Masculino , Persona de Mediana Edad , Esfingolípidos/sangre , Esfingosina/sangre
14.
J Child Neurol ; 39(5-6): 161-170, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38659405

RESUMEN

GM2 gangliosidoses (GM2) are a group of rare lysosomal storage disorders in which accumulation of GM2 gangliosides results in progressive central nervous system damage. The infantile GM2 phenotype is characterized by delays in milestones by 6 months of age, followed by rapid loss of motor, cognitive, and visual function. Advancements in early diagnosis and pharmacotherapies provide promise for improved outcomes. However, the lack of feasible and clinically meaningful clinical outcome assessments for GM2 poses a challenge to characterizing GM2 natural history and selecting clinical trial endpoints. The purpose of this study was to develop a remotely administered infantile GM2 rating scale to measure health-related function in children with infantile GM2. A 2-phase mixed methods design was employed. In phase 1 of the study, 8 families of children with Infantile GM2 completed a natural history survey and a 1:1 semistructured interview to provide caregiver perspectives on the impacts of GM2 on health-related function. In phase 2 of the study, 8 expert clinicians provided feedback via surveys and participated in videoconference-hosted focus groups to refine scale administration and scoring procedures. These methods guided the development of 16 scale items to assess function in 5 health-related function domains: vision, hand and arm use, communication, gross motor, and feeding. This study used caregiver perspectives and expert clinician feedback to develop a remotely administered clinical outcome assessment of clinically meaningful health-related function in children with infantile GM2. Future studies will further evaluate the feasibility, reliability, and validity of the Infantile GM2 Clinical Rating Scale.


Asunto(s)
Gangliosidosis GM2 , Humanos , Masculino , Femenino , Gangliosidosis GM2/diagnóstico , Lactante , Preescolar , Índice de Severidad de la Enfermedad
15.
J Neuromuscul Dis ; 11(4): 735-747, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38788085

RESUMEN

Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.


Asunto(s)
Enfermedades Neurodegenerativas , Trastornos del Neurodesarrollo , Serina C-Palmitoiltransferasa , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/metabolismo , Neuropatías Hereditarias Sensoriales y Autónomas/fisiopatología , Enfermedades Neurodegenerativas/metabolismo , Serina C-Palmitoiltransferasa/metabolismo , Serina C-Palmitoiltransferasa/genética , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismo , Esfingolípidos/metabolismo
16.
Ann Clin Transl Neurol ; 11(1): 207-224, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38009419

RESUMEN

OBJECTIVE: Late-onset GM2 gangliosidosis (LOGG) subtypes late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) are ultra-rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases. METHODS: We examined MEDLINE/non-MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons. RESULTS: Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar (p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS (p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio [95% confidence interval]) included the presence of psychosis/bipolar symptoms (4.95 [1.59-19.52], p = 0.011), no swallowing symptoms (0.16 [0.036-0.64], p = 0.011), and cerebellar atrophy (5.81 [2.10-17.08], p = 0.0009). Lower age of onset (0.96 [0.93-1.00], p = 0.075) and tremor (2.50 [0.94-7.43], p = 0.078) were marginally statistically significant but felt relevant to include in the model. INTERPRETATION: These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD.


Asunto(s)
Gangliosidosis GM2 , Enfermedades Neurodegenerativas , Trastornos Psicóticos , Humanos , Niño , Progresión de la Enfermedad , Atrofia , Gangliosidosis GM2/diagnóstico por imagen
17.
Nat Biotechnol ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39039307

RESUMEN

Genome editing technologies based on DNA-dependent polymerases (DDPs) could offer several benefits compared with other types of editors to install diverse edits. Here, we develop click editing, a genome writing platform that couples the advantageous properties of DDPs with RNA-programmable nickases to permit the installation of a range of edits, including substitutions, insertions and deletions. Click editors (CEs) leverage the 'click'-like bioconjugation ability of HUH endonucleases with single-stranded DNA substrates to covalently tether 'click DNA' (clkDNA) templates encoding user-specifiable edits at targeted genomic loci. Through iterative optimization of the modular components of CEs and their clkDNAs, we demonstrate the ability to install precise genome edits with minimal indels in diverse immortalized human cell types and primary fibroblasts with precise editing efficiencies of up to ~30%. Editing efficiency can be improved by rapidly screening clkDNA oligonucleotides with various modifications, including repair-evading substitutions. Click editing is a precise and versatile genome editing approach for diverse biological applications.

18.
Orphanet J Rare Dis ; 19(1): 79, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38378692

RESUMEN

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.


Asunto(s)
Trastornos del Neurodesarrollo , Humanos , Estudios Transversales , Mutación Missense/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética
19.
Ann Neurol ; 71(4): 520-30, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22522443

RESUMEN

OBJECTIVE: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. METHODS: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. RESULTS: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. INTERPRETATION: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.


Asunto(s)
Oxidorreductasas de Alcohol/deficiencia , Oxidorreductasas de Alcohol/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Edad de Inicio , Secuencia de Bases , Parálisis Cerebral/diagnóstico , Niño , Preescolar , Análisis Mutacional de ADN , Discapacidades del Desarrollo/tratamiento farmacológico , Diagnóstico Diferencial , Dopaminérgicos/uso terapéutico , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Trastornos del Movimiento/tratamiento farmacológico , Mutación , Neurotransmisores/análisis , Neurotransmisores/uso terapéutico
20.
J Clin Endocrinol Metab ; 108(11): e1306-e1315, 2023 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-37220095

RESUMEN

CONTEXT: Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. OBJECTIVE: To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. DESIGN: We conducted a retrospective medical chart review of pediatric patients with ALD. SETTING: All patients were seen in a leukodystrophy clinic in an academic medical center. PATIENTS: We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). MAIN OUTCOME MEASURES: We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. RESULTS: Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. CONCLUSIONS: Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.


Asunto(s)
Insuficiencia Suprarrenal , Adrenoleucodistrofia , Masculino , Recién Nacido , Humanos , Niño , Femenino , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/epidemiología , Estudios Retrospectivos , Tamizaje Neonatal/métodos , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/epidemiología , Diagnóstico Precoz
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