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1.
Am J Hum Genet ; 104(3): 542-552, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827498

RESUMO

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.


Assuntos
Motivos de Aminoácidos/genética , Variação Genética , Proteínas do Tecido Nervoso/genética , Transtornos Neurocognitivos/etiologia , Sequências Repetitivas de Ácido Nucleico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos Neurocognitivos/classificação , Transtornos Neurocognitivos/patologia , Fenótipo , Prognóstico , Síndrome
2.
J Inherit Metab Dis ; 43(6): 1333-1348, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32681751

RESUMO

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.


Assuntos
Defeitos Congênitos da Glicosilação/genética , N-Acetilglucosaminiltransferases/deficiência , N-Acetilglucosaminiltransferases/genética , Espasmos Infantis/genética , Biomarcadores , Pré-Escolar , Defeitos Congênitos da Glicosilação/diagnóstico , Dieta Cetogênica , Feminino , Glicosilação , Humanos , Lactente , Masculino , Mutação , N-Acetilglucosaminiltransferases/química , Espasmos Infantis/diagnóstico , Transferrina/metabolismo
4.
Mol Genet Metab Rep ; 38: 101060, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38469103

RESUMO

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.

5.
J Inherit Metab Dis ; 33(4): 315-29, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20490930

RESUMO

The purpose of this review is to describe neurological phenotypes associated with lysosomal storage diseases (LSDs), focusing on features arising from primary neuronal involvement. Clinical presentation, progression and genetic data, are discussed in detail in Part 2, the electronic material. Main features are summarized in Part 1. Insights gained from several observational studies are discussed. Prospective studies of the natural history of most neuronopathic LSDs have been hampered by the rarity of these conditions and the short survival of affected patients. Increasingly, longitudinal observations relating to neurological manifestations are being reported. Better clinical studies are necessary, including repeated measurements of disease progression to facilitate the development of sensitive scoring systems and appropriate counseling of affected individuals and their families. Ideally, clinical studies should involve a large cohort. As treatment becomes available, knowledge of disease expression and factors that influence the phenotype may enable critical assessment of therapeutic outcomes. It is hoped that increased familiarity with the clinical expression of individual LSDs will allow early diagnosis, so families at risk are given options to consider during future pregnancies. Early diagnosis also permits the introduction of timely intervention, to favoring improved outcome in cases that are potentially treatable.


Assuntos
Aconselhamento Genético , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia
6.
Brain Dev ; 32(3): 180-90, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19269120

RESUMO

UNLABELLED: X-linked adenoleukodystrophy is a genetic disease that affects the degradation of very long-chain fatty acids. In male patients, common pictures are the cerebral form (CALD), myeloneuropathy (AMN), and Addison-only. OBJECTIVE: To describe the clinical course of affected male patients from South Brazil between 1993 and 2007. METHODS: Affected male patients and their maternal lineages were studied from a clinical, neurological and biochemical standpoint. RESULTS: Eighty-three male patients from 30 families were biochemically evaluated: 51 were affected. 27/51 (54%) presented the cerebral form; 11/51 had AMN (22%); 5 had Addison-only (10%), and 8 (16%) were asymptomatic. Between 2002 and 2006, the minimal incidence was 1:35,000 males in our State (South Brazil). Forty-three affected individuals were followed for 5.4+/-3.7 years. Of 10 boys detected at early stages, three developed CALD. These three boys and another five CALD at baseline were referred to hematopoietic stem cell transplantation. Seven transplants were carried out, 5 with good clinical evolution after 2.2 years post-transplant. The non-transplanted case was later defined as a stable cerebral form. DISCUSSION: Among the present families, the observed cases were comparable to the 50% expected by Mendelian segregation. Based on the natural history, the number of cases that developed CALD was similar to the expected. Transplants were successful in 70% of cases. The occurrence of a stable cerebral form pointed to an urgent need for better markers of active cerebral disease.


Assuntos
Adrenoleucodistrofia/genética , Adrenoleucodistrofia/cirurgia , Cromossomos Humanos X , Adrenoleucodistrofia/epidemiologia , Adrenoleucodistrofia/metabolismo , Brasil/epidemiologia , Cromatografia Gasosa/métodos , Coenzima A Ligases/metabolismo , Progressão da Doença , Saúde da Família , Ácidos Graxos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
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