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1.
Brain ; 144(10): 3020-3035, 2021 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-33964137

RESUMEN

Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in five large consanguineous nuclear families allowed us to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report these two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the underlying cause of this novel form of leukodystrophy with ataxia and sensorineural deafness that includes fibrotic cardiomyopathy and hepatopathy as associated features in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as the RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology; mutations in primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.


Asunto(s)
Alelos , Ataxia/genética , Sordera/genética , Laminopatías/genética , Mutación/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Secuencia de Aminoácidos , Animales , Ataxia/diagnóstico , Células COS , Niño , Chlorocebus aethiops , Sordera/diagnóstico , Drosophila , Femenino , Células HEK293 , Humanos , Laminopatías/diagnóstico , Masculino , Linaje , Adulto Joven
2.
Int J Mol Sci ; 23(12)2022 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-35743164

RESUMEN

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP3-gated calcium channel that modulates intracellular Ca2+ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of ITPR1-related conditions, the ITPR1 gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.


Asunto(s)
Inositol , Adulto , Atrofia , Cerebelo/anomalías , Discapacidades del Desarrollo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Malformaciones del Sistema Nervioso , Linaje , Ataxias Espinocerebelosas , Degeneraciones Espinocerebelosas
3.
Genet Med ; 23(12): 2352-2359, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34446925

RESUMEN

PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.


Asunto(s)
Leucoencefalopatías , Estudios Transversales , Progresión de la Enfermedad , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Fenotipo
4.
J Hum Genet ; 66(10): 1035-1037, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33785861

RESUMEN

Monoallelic mutations on TMEM63A have been recently reported as cause of a previously unrecognized disorder named "infantile-onset transient hypomyelination". Clinical and neuroradiological presentation is described as highly similar to Pelizaeus-Merzbacher Disease but evolution over time was surprisingly benign with a progressive spontaneous improving course. We report on a new TMEM63A-mutated girl. The clinical picture was similar to the one already described except for the presence of recurrent episodes of unilateral eyelid twitching, and for the evidence of spinal cord involvement on MRI. These are interesting findings helping in distinguishing this condition from classic PMD since early disease stages. However, additional observations are needed to confirm if these are common features of this condition.


Asunto(s)
Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Proteína Proteolipídica de la Mielina/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Médula Espinal/diagnóstico por imagen , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Mutación/genética , Enfermedad de Pelizaeus-Merzbacher/diagnóstico por imagen , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Enfermedad de Pelizaeus-Merzbacher/patología , Médula Espinal/metabolismo , Médula Espinal/patología
5.
Neurol Sci ; 42(11): 4471-4487, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34482485

RESUMEN

Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a neurological disorder characterized by the radiological triad of white matter abnormalities, intracranial calcifications and cystic lesions variable in size resulting from a diffuse cerebral microangiopathy. Typically, progressive focal neurological deficits and seizures are the first clinical manifestation, but the severity of symptoms can vary according to the size and location of the cystic lesions holding compressive effects on the surrounding brain tissue. The most common histopathological finding is diffuse microangiopathy, which might be associated to pathogenic mutations in SNORD118 gene causing Labrune syndrome. Similar neuroradiological appearances have been found in the Coats plus syndrome, a systemic disorder caused by a genetic diffuse microangiopathy that affects not only the brain but also the retina and multiple organs, with a more complex clinical picture that address the diagnosis; biallelic mutations in CTC1 gene, encoding the conserved telomere maintenance component 1 (CTC1), are responsible of this systemic disorder. The aim of this contribution is to review the existing literature focusing on the neuroimaging characteristics by reporting cases in which radiological findings were highly suggestive for LCC.


Asunto(s)
Neoplasias Encefálicas , Enfermedades de los Pequeños Vasos Cerebrales , Quistes , Leucoencefalopatías , Quistes/complicaciones , Quistes/diagnóstico por imagen , Quistes/genética , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Neuroimagen
7.
Minerva Pediatr ; 71(2): 196-200, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29460552

RESUMEN

The aim of this paper was to highlight the importance of a multidisciplinary and multiprofessional management of SIDS for a complete approach to this tragic event. Both biomedical and psychosocial aspects are evaluated, focusing on the impact of SIDS diagnosis on the family. The paper describes the organization of our team, composed of a network of specialists involved in both prevention and management of SIDS. A protocol is proposed to improve SIDS diagnosis and management. In our team, the clinical pediatrician is the coordinator of specialists and the mediator between the family and the other specialists, thanks to his direct relationship with parents.


Asunto(s)
Grupo de Atención al Paciente/organización & administración , Relaciones Profesional-Familia , Muerte Súbita del Lactante/diagnóstico , Humanos , Lactante , Recién Nacido , Padres/psicología , Especialización , Muerte Súbita del Lactante/prevención & control
8.
Neurogenetics ; 19(2): 111-121, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29691679

RESUMEN

Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Adolescente , Edad de Inicio , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Pruebas Genéticas/métodos , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Polimorfismo de Nucleótido Simple
9.
Brain ; 140(10): 2550-2556, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28969374

RESUMEN

Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.


Asunto(s)
Genes Homeobox/genética , Proteínas de Homeodominio/genética , Leucoencefalopatías/genética , Mutación/genética , Adolescente , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Potenciales Evocados Auditivos del Tronco Encefálico , Salud de la Familia , Femenino , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Imagen por Resonancia Magnética , Masculino , Modelos Moleculares
10.
Neurogenetics ; 15(1): 41-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24202401

RESUMEN

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a heterogeneous neurodegenerative leukodystrophy caused by recessive mutations in MLC1 or GLIALCAM (types MLC1 and MLC2A) of by dominant mutations in GLIALCAM (MLC2B). GlialCAM functions as an auxiliary subunit of both MLC1 and ClC-2 chloride channel, increasing and modifying the function of the latter. Dominant mutations in GLIALCAM cause transient features of MLC but lacks clinical deterioration. Most recessive and dominant mutations in GLIALCAM studied so far affect the targeting of GlialCAM and its associated subunits. Here, we have investigated two patients with MLC2. The first patient has MLC2B disease, as shown by the improvement in MRI and clinical parameters. In this case, we identified a novel GLIALCAM mutation (p.Q56P) which affected the localization of GlialCAM and its associated subunits, however activating ClC-2 function as the wild-type protein. The second patient has MLC2A disease, as indicated by the lack of clinical improvement, even though, interestingly, the MRI of this patient shows a partial improvement. In this case, we found a recessive mode of inheritance, as the patient harbors two compound heterozygous mutations in GLIALCAM. One of them introduces a stop codon (p.Q56X), whereas the second mutation is a missense mutation (p.R73W), for which we could not identify any trafficking defect or an altered functional effect on ClC-2 in vitro.


Asunto(s)
Quistes/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Mutación , Proteínas/genética , Adolescente , Encéfalo/patología , Canales de Cloruro CLC-2 , Proteínas de Ciclo Celular , Niño , Canales de Cloruro/genética , Codón de Terminación , ADN Complementario/metabolismo , Exones , Femenino , Regulación de la Expresión Génica , Genes Dominantes , Genes Recesivos , Células HEK293 , Células HeLa , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Técnicas de Placa-Clamp , Fenotipo , Estructura Secundaria de Proteína , Análisis de Secuencia de ADN
11.
Hum Mol Genet ; 21(10): 2166-80, 2012 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-22328087

RESUMEN

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare leukodystrophy characterized by macrocephaly, subcortical fluid cysts and myelin vacuolation, has been linked to mutations in the MLC1 gene. This gene encodes a membrane protein that is highly expressed in astrocytes. Based on MLC pathological features, it was proposed that astrocyte-mediated defects in ion and fluid homeostasis could account for the alterations observed in MLC-affected brains. However, the role of MLC1 and the effects of pathological mutations on astrocyte osmoregulatory functions have still to be demonstrated. Using human astrocytoma cells stably overexpressing wild-type MLC1 or three known MLC-associated pathological mutations, we investigated MLC1 involvement in astrocyte reaction to osmotic changes using biochemical, dynamic video imaging and immunofluorescence techniques. We have found that MLC1 overexpressed in astrocytoma cells is mainly localized in the plasma membrane, is part of the Na,K-ATPase-associated molecular complex that includes the potassium channel Kir4.1, syntrophin and aquaporin-4 and functionally interacts with the calcium permeable channel TRPV4 (transient receptor potential vanilloid-4 cation channel) which mediates swelling-induced cytosolic calcium increase and volume recovery in response to hyposmosis. Pathological MLC mutations cause changes in MLC1 expression and intracellular localization as well as in the astrocyte response to osmotic changes by altering MLC1 molecular interactions with the Na,K-ATPase molecular complex and abolishing the increase in calcium influx induced by hyposmosis and treatment with the TRPV4 agonist 4αPDD. These data demonstrate, for the first time, that MLC1 plays a role in astrocyte osmo-homeostasis and that defects in intracellular calcium dynamics may contribute to MLC pathogenesis.


Asunto(s)
Astrocitos/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Canales Catiónicos TRPV/metabolismo , Calcio/metabolismo , Cationes Bivalentes , Quistes/genética , Quistes/metabolismo , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/metabolismo , Humanos , Mutación , Ósmosis , Transfección
12.
Cerebellum ; 13(1): 79-88, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24013853

RESUMEN

Cerebellar cysts are rare findings in pediatric neuroimaging and rather characteristic for dystroglycanopathies and GPR56-related encephalopathy. We aim to report on seven children with cerebellar cysts showing absence of weakness and ruling out mutations within eight dystroglycanopathy genes and GPR56. Data about neurological and ophthalmological features, outcome, and creatine kinase values were collected from clinical histories and follow-up examinations. All MR images were qualitatively evaluated for infra- and supratentorial abnormalities. A SNP 6.0-Array was performed in three children. The POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56 genes were screened in all patients by Sanger sequencing. Seven children from five families were studied. Ataxia, intellectual disability, and language impairment were found in all patients, ocular motor apraxia in five, and severe myopia in three. None of the patients had weakness, only three a minimally increased creatine kinase value. Qualitative neuroimaging evaluation showed cerebellar cysts and dysplasia in the cerebellar hemispheres and vermis in all children. Additional findings were an enlarged fourth ventricle in all children, vermian hypoplasia and brain stem morphological abnormalities in five. The SNP array showed no pathogenetic imbalances in all children evaluated. In all patients, no mutations were found in POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56. The peculiar combination of the same clinical and neuroimaging findings in our patients highly suggests that this phenotype may represent a novel entity, possibly falling within the spectrum of dystroglycanopathies.


Asunto(s)
Apraxias , Ataxia , Enfermedades Cerebelosas , Quistes/complicaciones , Discapacidad Intelectual , Adolescente , Apraxias/genética , Apraxias/patología , Ataxia/genética , Ataxia/patología , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/patología , Cerebelo/patología , Niño , Preescolar , Quistes/genética , Quistes/patología , Análisis Mutacional de ADN , Familia , Femenino , Estudios de Seguimiento , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Miopía/genética , Miopía/patología , Trastornos de la Motilidad Ocular/genética , Trastornos de la Motilidad Ocular/patología , Estudios Retrospectivos , Síndrome
13.
Mol Cell Neurosci ; 56: 307-21, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23851226

RESUMEN

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare congenital leukodystrophy characterized by macrocephaly, subcortical cysts and demyelination. The majority of patients harbor mutations in the MLC1 gene encoding for a membrane protein with largely unknown function. Mutations in MLC1 hamper its normal trafficking and distribution in cell membranes, leading to enhanced degradation. MLC1 protein is highly expressed in brain astrocytes and in circulating blood cells, particularly monocytes. We used these easily available cells and monocyte-derived macrophages from healthy donors and MLC1-mutated patients to study MLC1 expression and localization, and to investigate how defective MLC1 mutations may affect macrophage functions. RT-PCR, western blot and immunofluorescence analyses show that MLC1 is expressed in both monocytes and macrophages, and its biosynthesis follows protein trafficking between endoplasmic reticulum and trans-Golgi network and the secretory pathway to the cell surface. MLC1 is transported along the endosomal recycling pathway passing through Rab5+ and Rab11A+vesicles before lysosomal degradation. Alterations in MLC1 trafficking and distribution were observed in macrophages from MLC1-mutated patients, which also showed changes in the expression and localization of several proteins involved in plasma membrane permeability, ion and water homeostasis and ion-regulated exocytosis. As a consequence of these alterations, patient-derived macrophages show abnormal cell morphology and intracellular calcium influx and altered response to hypo-osmotic stress. Our results suggest that blood-derived macrophages may give relevant information on MLC1 function and may be considered as valid biomarkers for MLC diagnosis and for investigating therapeutic strategies aimed to restore MLC1 trafficking in patient cells.


Asunto(s)
Quistes/metabolismo , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Monocitos/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Membrana Celular/metabolismo , Niño , Quistes/diagnóstico , Quistes/genética , Retículo Endoplásmico/metabolismo , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Transporte de Proteínas , Vías Secretoras , Red trans-Golgi/metabolismo
14.
Children (Basel) ; 11(5)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38790536

RESUMEN

Background: CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and Results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.

15.
Mol Genet Metab ; 109(4): 366-70, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23768953

RESUMEN

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. METHODS: Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. RESULTS: A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. CONCLUSION: Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Adrenoleucodistrofia/metabolismo , Disulfuro de Glutatión/sangre , Estrés Oxidativo , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Adolescente , Adrenoleucodistrofia/sangre , Adrenoleucodistrofia/patología , Adulto , Niño , Preescolar , Femenino , Radicales Libres/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Compuestos de Sulfhidrilo/sangre
16.
Ann Neurol ; 72(4): 550-8, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23109149

RESUMEN

OBJECTIVE: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry. METHODS: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum. RESULTS: Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum. Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2) -Man(5) . DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C). INTERPRETATION: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Epilepsia/genética , Manosiltransferasas/genética , Distrofias Musculares/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Trastornos de las Proteínas de Coagulación/genética , Trastornos Congénitos de Glicosilación/complicaciones , Análisis Mutacional de ADN , Resistencia a Medicamentos , Distroglicanos/metabolismo , Electromiografía , Retículo Endoplásmico , Epilepsia/etiología , Femenino , Fibroblastos/metabolismo , Glicosilación , Humanos , Lactante , Focalización Isoeléctrica , Hepatopatías/complicaciones , Hepatopatías/genética , Masculino , Manosa/metabolismo , Microcefalia/genética , Microcefalia/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Distrofias Musculares/complicaciones , Mutación/genética , Mutación/fisiología , Mutación Missense/genética , Mutación Missense/fisiología , Embarazo , Trastornos de la Visión/genética , Trastornos de la Visión/patología , Adulto Joven
17.
Clin Neurol Neurosurg ; 225: 107584, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36603335

RESUMEN

Dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular diseases, whose onset varies from fetal to adult life, mostly represented by prenatal-neonatal intracerebral hemorrhage with porencephaly and by periventricular leukomalacia with calcifications, corresponding clinical diagnoses of cerebral palsy mimics. Axenfeld-Rieger syndrome with leukoencephalopathy, HANAC syndrome, young- and late-onset stroke and malformation of cortical development are rarer presentations. Very recently, the existence of recessive COL4A1- and COL4A2-related forms has been documented. We broaden the phenotypic and genotypic spectra of COL4A2-related disease by describing this second family with recessive pathogenic variants and neuroimaging phenotype of leukoencephalopathy with spot-like calcifications.


Asunto(s)
Trastornos Cerebrovasculares , Leucoencefalopatías , Porencefalia , Accidente Cerebrovascular , Embarazo , Femenino , Humanos , Colágeno Tipo IV/genética , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Hemorragia Cerebral/diagnóstico , Accidente Cerebrovascular/genética , Porencefalia/diagnóstico , Porencefalia/genética , Mutación/genética
18.
Neurogenetics ; 13(3): 205-14, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22552818

RESUMEN

Megalencephalic leukoencephalopathy with subcortical cysts is an autosomal recessive disease characterized by early onset macrocephaly; developmental delay; motor disability in the form of progressive spasticity and ataxia; seizures; cognitive decline; and characteristic magnetic resonance imaging findings. Mutations in two genes, MLC1 (22q13.33; 75 % of patients) or HEPACAM (11q24; 20 % of patients), are associated with the disease. We describe an adult MLC patient with moderate clinical symptoms. MLC1 cDNA analysis from lymphoblasts showed a strong transcript reduction and identified a 246-bp pseudoexon containing a premature stop codon between exons 10 and 11, due to a homozygous c.895-226 T>G deep-intronic mutation. This category of mutations is often overlooked, being outside of canonically sequenced genomic regions. The mutation c.895-226 T>G has a leaky effect on splicing leaving part of the full-length transcript. Its role on splicing was confirmed using a minigene assay and an antisense morpholinated oligonucleotide targeted to the aberrant splice site in vitro, which partially abrogated the mutation effect.


Asunto(s)
Quistes/diagnóstico , Quistes/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Intrones , Proteínas de la Membrana/genética , Mutación , Oligonucleótidos Antisentido/genética , Encéfalo/patología , Análisis Mutacional de ADN , Exones , Salud de la Familia , Femenino , Humanos , Linfocitos/citología , Imagen por Resonancia Magnética/métodos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Modelos Genéticos , Linaje , Empalme del ARN , Análisis de Secuencia de ADN
19.
Eur J Hum Genet ; 30(8): 984-988, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35581417

RESUMEN

Krabbe disease (KD) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in GALC. Most patients manifest the severe classic early-infantile form, while a small percentage of cases have later-onset types. We present two siblings with atypical clinical and neuroimaging phenotypes, compared to the classification of KD, who were found to carry biallelic loss-of-function GALC variants, including a recurrent 30 kb deletion and a previously unreported deep intronic variant that was identified by mRNA sequencing. This family represents a unique description in the KD literature and contributes to expanding the clinical and molecular spectra of this rare disorder.


Asunto(s)
Leucodistrofia de Células Globoides , Galactosilceramidasa/genética , Humanos , Intrones , Leucodistrofia de Células Globoides/genética , Mutación , Fenotipo , Hermanos
20.
Eur J Pediatr ; 170(7): 887-90, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21153419

RESUMEN

UNLABELLED: Cobalamin C (Cbl-C) defect is the most common inborn error of cobalamin metabolism which causes a block in the pathway responsible for the synthesis of its two metabolically active forms methyl- and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The clinical presentation of patients with early-onset Cbl-C defect, characterized by a multisystem disease with severe neurological, ocular, hematological, renal, gastrointestinal, cardiac, and pulmonary manifestations, differs considerably from what observed in the "classical" form of methylmalonic aciduria caused by defect of methylmalonyl-CoA mutase. This last condition is in most cases dominated in the neonatal period by a metabolic encephalopathy "intoxication type" with severe hyperammonemia and ketoacidosis. We report a Cbl-C defect patient presenting a neonatal encephalopathy with severe hyperammonemia and ketoacidosis who was successfully treated with peritoneal dialysis. CONCLUSION: To the best of our knowledge, there are no reported cases of Cbl-C defect showing an acute presentation resembling a classical methylmalonic aciduria. This observation enlarges the spectrum of inherited diseases to be considered in the differential diagnosis of neonatal hyperammonemia.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Homocistinuria/diagnóstico , Hiperamonemia/etiología , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Diagnóstico Diferencial , Femenino , Homocistinuria/complicaciones , Humanos , Recién Nacido , Deficiencia de Vitamina B 12/congénito
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