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1.
Ann Neurol ; 93(2): 330-335, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36333996

RESUMEN

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities. ANN NEUROL 2023;93:330-335.


Asunto(s)
Distonía , Trastornos Distónicos , Proteínas de Complejo Poro Nuclear , Humanos , Cuerpo Estriado , Distonía/genética , Trastornos Distónicos/genética , Neostriado , Proteínas de Complejo Poro Nuclear/genética
2.
Mov Disord ; 39(5): 897-905, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38436103

RESUMEN

BACKGROUND: Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. OBJECTIVE: The aim is to identify the missing genetic causes of PKD. METHODS: Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. RESULTS: We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10-8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10-6) missense variants in KCNJ10. CONCLUSIONS: We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Distonía , Mutación Missense , Canales de Potasio de Rectificación Interna , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Distonía/genética , Secuenciación del Exoma , Mutación Missense/genética , Linaje , Canales de Potasio de Rectificación Interna/genética
3.
Mov Disord ; 38(10): 1950-1956, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37470282

RESUMEN

BACKGROUND: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established. OBJECTIVES: To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients. METHODS: FGF14 expansions screening combined with longitudinal deep-phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis. RESULTS: Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia. CONCLUSIONS: FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Ataxia Cerebelosa , Ataxias Espinocerebelosas , Degeneraciones Espinocerebelosas , Humanos , Ataxia/complicaciones , Ataxia Cerebelosa/epidemiología , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/complicaciones , Estudios Prospectivos , Ataxias Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/epidemiología , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/complicaciones
4.
Mov Disord ; 37(7): 1547-1554, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35722775

RESUMEN

BACKGROUND: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. OBJECTIVE: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. METHODS: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. RESULTS: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. CONCLUSION: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Distonía , Trastornos Distónicos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Trastornos del Movimiento , Trastornos Parkinsonianos , Distonía/genética , Trastornos Distónicos/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Trastornos del Movimiento/genética , Trastornos Parkinsonianos/genética , Fenotipo
5.
Clin Genet ; 98(3): 251-260, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32557569

RESUMEN

Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under-investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty-five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early-onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria.


Asunto(s)
ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Enfermedades del Sistema Nervioso/genética , Factores de Transcripción/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Edad de Inicio , Preescolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Síndrome de Cockayne/fisiopatología , Reparación del ADN/genética , Diagnóstico Precoz , Femenino , Feto , Asesoramiento Genético/tendencias , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/fisiopatología , Pronóstico , Xerodermia Pigmentosa/diagnóstico , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/fisiopatología
6.
Am J Med Genet A ; 182(5): 1236-1242, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32052936

RESUMEN

Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis. Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development.


Asunto(s)
Síndrome de Cockayne/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Enfermedades Neurodegenerativas/genética , Proteínas Nucleares/genética , Diagnóstico Prenatal , Factores de Transcripción/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Catarata/diagnóstico , Catarata/patología , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/epidemiología , Síndrome de Cockayne/patología , Femenino , Feto/patología , Humanos , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/patología , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/epidemiología , Enfermedades Neurodegenerativas/patología , Embarazo
7.
J Med Genet ; 55(5): 329-343, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29572252

RESUMEN

BACKGROUND: Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS. METHODS AND RESULTS: We assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA. CONCLUSION: By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.


Asunto(s)
Síndrome de Cockayne/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Trastornos por Fotosensibilidad/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Síndrome de Cockayne/fisiopatología , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Intrones/genética , Masculino , Mutación Missense/genética , Trastornos por Fotosensibilidad/fisiopatología , Embarazo , Rayos Ultravioleta , Adulto Joven
8.
Acta Neuropathol ; 134(6): 889-904, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28685322

RESUMEN

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.


Asunto(s)
Heterocigoto , Mutación , Miopatías Estructurales Congénitas/diagnóstico , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Miopatías Estructurales Congénitas/fisiopatología , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Índice de Severidad de la Enfermedad
9.
Gene ; 893: 147902, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-37839763

RESUMEN

Next-generation sequencing has improved the diagnosis of inborn errors of metabolism, allowing rapid confirmation of cases detected by clinical/biochemical studies or newborn screening. The challenge, however, remains for establishing the pathogenicity of the identified variants, especially for novel missense changes or small in-frame deletions. In this work we report a propionic acidemia patient exhibiting a severe neonatal form with coma and hyperammonaemia. Genetic analysis identified the previously described pathogenic PCCB variant p.R512C in the maternal allele and two novel PCCB variants in cis in the paternal allele, p.G246del and p.S322F. Expression analysis in a eukaryotic system confirmed the deleterious effect of the novel missense variant and of the one amino acid deletion, as they both exhibited reduced protein levels and reduced or null PCC activity compared to the wild-type construct. Accordingly, the double mutant resulted in no residual activity. This study increases the knowledge of the genotype-phenotype correlations in the rare disease propionic acidemia and highlights the necessity of functional analysis of novel variants to understand their contribution to disease severity and to accurately classify their pathogenic status. In conclusion, two novel PCCB pathogenic variants have been identified, expanding the current mutational spectrum of propionic acidemia.


Asunto(s)
Liasas de Carbono-Carbono , Acidemia Propiónica , Humanos , Recién Nacido , Liasas de Carbono-Carbono/genética , Mutación Missense , Acidemia Propiónica/genética , Eliminación de Secuencia
10.
J Neurol ; 271(4): 2078-2085, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38263489

RESUMEN

BACKGROUND: Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. OBJECTIVES: To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. METHODS: FGF14 expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia. RESULTS: After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an FGF14 (GAA)≥250 expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients. CONCLUSIONS: FGF14 (GAA)≥250 expansion may account for MSA look-alike cases and should be screened among slow progressors.


Asunto(s)
Atrofia de Múltiples Sistemas , Ataxias Espinocerebelosas , Degeneraciones Espinocerebelosas , Humanos , Atrofia de Múltiples Sistemas/diagnóstico , Estudios Prospectivos , Ataxias Espinocerebelosas/diagnóstico , Cerebelo , Degeneraciones Espinocerebelosas/diagnóstico
11.
Forensic Sci Int Genet ; 71: 103028, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38518711

RESUMEN

INTRODUCTION: Sudden Unexplained Death in Childhood (SUDC) needs to be fully assessed considering its impact on the family, parents and siblings. Inborn Errors of Metabolism (IEM) such as Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) should be taken into consideration when SUDC occurres. Our aim is to present a family with two successive SUDC and to discuss the post-mortem genetics investigations revealing an IEM implication. CASES REPORT: A complete autopsy with genetic testing was performed when the proband, a 4-year-old girl, died. A few years previously, her older brother had died at the same age and off the same condition. Years later, his exhumation was necessary in order to perform a post-mortem diagnosis.The two siblings were revealed to have had the same pathogenic genotype of the ACADM gene, heterozygous substitutions in ACADM (NM_000016.5): c.985 A>G p.(Lys329Glu) and c.347 G>A p.(Cys116Tyr). In addition, they also both carried a VUS in TECRL, a gene implicated in Catecholaminergic Polymorphic Tachycardia Ventricular (CPVT) and SUDC. CONCLUSION: We illustrate the importance of exome analyses for investigating unexplained sudden death, especially in children, with the possible impact for genetic counselling in the family. The finding of the implication of ACADM gene in this case, raises likely responsibility of the public health system in countries such as France, who delayed implementation of new born screening for these conditions. Exome analyses in this case detected unexpected complexity in interpretation linked to the identification of a second candidate gene for SUDC.


Asunto(s)
Acil-CoA Deshidrogenasa , Muerte Súbita , Humanos , Femenino , Preescolar , Muerte Súbita/etiología , Masculino , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo Lipídico/genética , Linaje , Genotipo , Pruebas Genéticas , Hermanos , Recurrencia
12.
N Engl J Med ; 360(12): 1211-6, 2009 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-19297573

RESUMEN

Cytogenetic studies of the parents of a girl with the DiGeorge (or velocardiofacial) syndrome, who carried a deletion at 22q11.2, revealed an unexpected rearrangement of both 22q11.2 regions in the unaffected father. He carried a 22q11.2 deletion on one copy of chromosome 22 and a reciprocal 22q11.2 duplication on the other copy of chromosome 22. Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the DiGeorge syndrome. This finding has implications for genetic counseling and represents a case of genetic compensation in a human genomic disorder.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/genética , Compensación de Dosificación (Genética) , Duplicación de Gen , Padre , Femenino , Reordenamiento Génico , Humanos , Recién Nacido , Masculino , Repeticiones de Microsatélite , Linaje , Fenotipo
13.
Front Genet ; 13: 762047, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35251122

RESUMEN

Cockayne syndrome is a rare condition that encompasses a very wide spectrum of clinical severity. Mutations upstream of a transposon called PiggyBac Transposable Element Derived 3 in intron 5 of the CSB/ERCC6 gene could bring about less severe forms than mutations located downstream of that transposon insertion. Our aim was to study genotype-phenotype correlation by determining whether the position of each mutation of the CSB/ERCC6 gene has an impact on the phenotype. A hundred and forty-seven Cockayne patients, who had two pathogenic mutations in the CSB/ERCC6 gene and for whom clinical data was available, were retrospectively selected and included in the study. Data analysis was performed under the Bayesian paradigm. Analysis of the proportion of the different subtypes of Cockayne syndrome according to the position of the mutations was done using an ordinal logistic regression model. Using a vague prior, the risk of developing a more severe subtype when exposed to 2 mutations downstream compared to 2 mutations upstream was 2.0 [0.9-4.5]. Estimations varied through the sensitivity analysis. We could reasonably conclude that a relationship between the number of downstream mutations and the Cockayne syndrome clinical expression exists but it is still difficult to give a precise estimate of this relationship. The real effect could be more complex that the one described in the initial model and other genetic factors might be taken into consideration together with the mutation site to better explain clinical variability.

14.
Orphanet J Rare Dis ; 17(1): 121, 2022 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-35248096

RESUMEN

BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC6/CSB or ERCC8/CSA that participate in the transcription-coupled nucleotide excision repair (TC-NER) of UV-induced DNA damage. CS patients display a large heterogeneity of clinical symptoms and severities, the reason of which is not fully understood, and that cannot be anticipated in the diagnostic phase. In addition, little data is available for affected siblings, and this disease is largely undiagnosed in North Africa. METHODS: We report here the clinical description as well as genetic and functional characterization of eight Tunisian CS patients, including siblings. These patients, who belonged to six unrelated families, underwent complete clinical examination and biochemical analyses. Sanger sequencing was performed for the recurrent mutation in five families, and targeted gene sequencing was done for one patient of the sixth family. We also performed Recovery RNA Synthesis (RRS) to confirm the functional impairment of DNA repair in patient-derived fibroblasts. RESULTS: Six out of eight patients carried a homozygous indel mutation (c.598_600delinsAA) in exon 7 of ERCC8, and displayed a variable clinical spectrum including between siblings sharing the same mutation. The other two patients were siblings who carried a homozygous splice-site variant in ERCC8 (c.843+1G>C). This last pair presented more severe clinical manifestations, which are rarely associated with CSA mutations, leading to gastrostomy and hepatic damage. Impaired TC-NER was confirmed by RRS in six tested patients. CONCLUSIONS: This study provides the first deep characterization of case series of CS patients carrying CSA mutations in North Africa. These mutations have been described only in this region and in the Middle-East. We also provide the largest characterization of multiple unrelated patients, as well as siblings, carrying the same mutation, providing a framework for dissecting elusive genotype-phenotype correlations in CS.


Asunto(s)
Síndrome de Cockayne , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Reparación del ADN/genética , Enzimas Reparadoras del ADN/química , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Homocigoto , Humanos , Mutación/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Hermanos , Factores de Transcripción/genética
16.
Neurol India ; 69(2): 362-366, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33904453

RESUMEN

BACKGROUND: Cockayne syndrome is an autosomal recessive disorder caused by biallelic mutations in ERCC6 or ERCC8 genes. AIMS: To study the clinical and mutation spectrum of Cockayne syndrome. SETTING AND DESIGN: Medical Genetics Outpatient Department of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. This was a prospective study from 2007 to 2015. MATERIALS AND METHODS: Clinical details were recorded, and sequencing of ERCC6 and ERCC8 were performed. RESULTS AND CONCLUSIONS: Of the six families, one family had a homozygous mutation in ERCC8 and the other five families had homozygous mutations in ERCC6. Novel variants in ERCC6 were identified in four families. Phenotypic features may vary from severe to mild, and a strong clinical suspicion is needed for diagnosis during infancy or early childhood. Hence, molecular diagnosis is needed for confirmation of diagnosis in a child with a suspicion of Cockayne syndrome. Prenatal diagnosis can be provided only if molecular diagnosis is established in the proband.


Asunto(s)
Síndrome de Cockayne , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Factores de Transcripción , Niño , Preescolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Femenino , Humanos , India , Mutación , Embarazo , Estudios Prospectivos , Factores de Transcripción/genética
17.
Genes (Basel) ; 12(12)2021 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-34946871

RESUMEN

Cockayne syndrome (CS) is a rare disease caused by mutations in ERCC6/CSB or ERCC8/CSA. We report here the clinical, genetic, and functional analyses of three unrelated patients mutated in ERCC6/CSB with a severe phenotype. After clinical examination, two patients were investigated via next generation sequencing, targeting seventeen Nucleotide Excision Repair (NER) genes. All three patients harbored a novel, c.3156dup, homozygous mutation located in exon 18 of ERCC6/CSB that affects the C-terminal region of the protein. Sanger sequencing confirmed the mutation and the parental segregation in the three families, and Western blots showed a lack of the full-length protein. NER functional impairment was shown by reduced recovery of RNA synthesis with proficient unscheduled DNA synthesis after UV-C radiations in patient-derived fibroblasts. Despite sharing the same mutation, the clinical spectrum was heterogeneous among the three patients, and only two patients displayed clinical photosensitivity. This novel ERCC6 variant in Tunisian patients suggests a founder effect and has implications for setting-up prenatal diagnosis/genetic counselling in North Africa, where this disease is largely undiagnosed. This study reveals one of the rare cases of CS clinical heterogeneity despite the same mutation. Moreover, the occurrence of an identical homozygous mutation, which either results in clinical photosensitivity or does not, strongly suggests that this classic CS symptom relies on multiple factors.


Asunto(s)
Síndrome de Cockayne/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Western Blotting , Células Cultivadas , Niño , Preescolar , Síndrome de Cockayne/diagnóstico por imagen , Síndrome de Cockayne/fisiopatología , Consanguinidad , Reparación del ADN/genética , Femenino , Fibroblastos/efectos de la radiación , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Linaje , Rayos Ultravioleta
18.
Eur J Med Genet ; 64(1): 104105, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33227433

RESUMEN

Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum: CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS2 patients, used the GAMLSS package to construct specific CS growth charts compared to healthy children from WHO and CDC databases. Growth data were obtained from 88 CS patients with a total of 1626 individual growth data points. 49 patients were classified as CS1 and 39 as CS2 with confirmed mutations in CSB/ERCC6, CSA/ERCC8 or ERCC1 genes. Individuals with CS1 initially have normal growth parameters; microcephaly occurs from 2 months whereas onset of weight and height restrictions appear later, between 5 and 22 months. In CS2, growth parameters are already below standard references at birth or drop below the 5th percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in CS1 and at birth in CS2. Height and head circumference are more severely affected in CS2 compared to CS1 whereas weight curves are similar in CS1 and CS2 patients. These new growth charts will serve as a practical tool to improve the nutritional management of children with CS.


Asunto(s)
Estatura , Síndrome de Cockayne/diagnóstico , Gráficos de Crecimiento , Niño , Preescolar , Síndrome de Cockayne/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Femenino , Humanos , Lactante , Masculino , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Factores de Transcripción/genética
19.
J Neurol ; 268(5): 1927-1937, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33417001

RESUMEN

BACKGROUND: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia. OBJECTIVE: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48. METHODS: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy). RESULTS: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48). CONCLUSION: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.


Asunto(s)
Ataxia Cerebelosa , Ataxia , Proteínas de Choque Térmico , Humanos , Mutación/genética , Estudios Retrospectivos , Ubiquitina-Proteína Ligasas/genética
20.
Hum Mol Genet ; 17(22): 3521-31, 2008 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-18725397

RESUMEN

Deficiency in the nuclear-encoded mitochondrial protein frataxin causes Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associating spinocerebellar ataxia and cardiomyopathy. Although the exact function of frataxin is still a matter of debate, it is widely accepted that frataxin is a mitochondrial iron chaperone involved in iron-sulfur cluster and heme biosynthesis. Frataxin is synthesized as a precursor polypeptide, directed to the mitochondrial matrix where it is proteolytically cleaved by the mitochondrial processing peptidase to the mature form via a processing intermediate. The mature form was initially reported to be encoded by amino acids 56-210 (m(56)-FXN). However, two independent reports have challenged these studies describing two different forms encoded by amino acids 78-210 (m(78)-FXN) and 81-210 (m(81)-FXN). Here, we provide evidence that mature human frataxin corresponds to m(81)-FXN, and can rescue the lethal phenotype of fibroblasts completely deleted for frataxin. Furthermore, our data demonstrate that the migration profile of frataxin depends on the experimental conditions, a behavior which most likely contributed to the confusion concerning the endogenous mature frataxin. Interestingly, we show that m(56)-FXN and m(78)-FXN can be generated when the normal maturation process of frataxin is impaired, although the physiological relevance is not clear. Furthermore, we determine that the d-FXN form, previously reported to be a degradation product, corresponds to m(78)-FXN. Finally, we demonstrate that all frataxin isoforms are generated and localized within the mitochondria. The clear identification of the N-terminus of mature FXN is an important step for designing therapeutic approaches for FRDA based on frataxin replacement.


Asunto(s)
Proteínas de Unión a Hierro/metabolismo , Mitocondrias/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Electroforesis en Gel de Poliacrilamida , Fibroblastos , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Humanos , Proteínas de Unión a Hierro/química , Proteínas de Unión a Hierro/genética , Ratones , Mitocondrias/genética , Proteínas Mitocondriales/metabolismo , Mutagénesis Sitio-Dirigida , Mapeo Peptídico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Frataxina
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