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1.
Am J Hum Genet ; 109(2): 345-360, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35045343

RESUMO

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.


Assuntos
Cistos do Sistema Nervoso Central/genética , Defeitos Congênitos da Glicosilação/genética , Hamartoma/genética , Deficiência Intelectual/genética , Oligossacarídeos/metabolismo , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Polimicrogiria/genética , alfa-Manosidase/genética , Adolescente , Alelos , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Linhagem Celular Tumoral , Cistos do Sistema Nervoso Central/metabolismo , Cistos do Sistema Nervoso Central/patologia , Vermis Cerebelar/metabolismo , Vermis Cerebelar/patologia , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Feminino , Feto , Glicosilação , Hamartoma/metabolismo , Hamartoma/patologia , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Manose/metabolismo , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Polimicrogiria/metabolismo , Polimicrogiria/patologia , Língua/metabolismo , Língua/patologia , alfa-Manosidase/deficiência
2.
Brain ; 147(6): 1967-1974, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38478578

RESUMO

Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G > A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.


Assuntos
Doença de Leigh , Atrofia Óptica Hereditária de Leber , Humanos , Doença de Leigh/genética , Atrofia Óptica Hereditária de Leber/genética , Masculino , Feminino , Adulto , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Criança , Adolescente , NADH Desidrogenase/genética , Mutação , Adulto Jovem , Sequenciamento do Exoma , Pré-Escolar
3.
Mol Genet Metab ; 142(2): 108486, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733639

RESUMO

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Doença de Depósito de Glicogênio Tipo I , Neutropenia , Neutrófilos , Humanos , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/complicações , Neutropenia/tratamento farmacológico , Masculino , Feminino , Lactente , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Estudos Retrospectivos , Neutrófilos/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do Tratamento , Fator Estimulador de Colônias de Granulócitos/uso terapêutico
4.
Am J Med Genet A ; 194(6): e63551, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321651

RESUMO

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care.


Assuntos
Capilares , Epilepsia , Proteínas Proto-Oncogênicas c-akt , Telangiectasia , Malformações Vasculares , Feminino , Humanos , Recém-Nascido , Masculino , Capilares/anormalidades , Capilares/patologia , Epilepsia/genética , Epilepsia/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Mosaicismo , Mutação/genética , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Telangiectasia/genética , Telangiectasia/patologia , Telangiectasia/diagnóstico , Malformações Vasculares/genética , Malformações Vasculares/patologia , Malformações Vasculares/diagnóstico , Malformações Vasculares/complicações , Adolescente
5.
Genet Med ; 25(7): 100859, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37092538

RESUMO

PURPOSE: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9. METHODS: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics. RESULTS: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have developmental delay/intellectual disability, with 5 of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities. Molecular modeling predicted that the variants are damaging and would lead to reduced protein stability or impaired recognition of interaction partners. Functional analyses in previous studies showed a pathogenic effect of p.(Pro131Leu) and p.(Arg227His). CONCLUSION: We propose CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy.


Assuntos
Epilepsia , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Epilepsia/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Convulsões/genética
6.
Eur J Pediatr ; 182(5): 1941-1948, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36602623

RESUMO

Children undergoing general anesthesia and surgery in the early years of life are exposed to the possible neurotoxicity of anesthetic agents. Prospective studies have shown deficits in behavior, executive function, social communication, and motor function in children undergoing anesthesia and surgery. Different biomarkers of neuronal injury have been evaluated neuronal injury in the pediatric population, among which neurofilaments represent a significant advantage as they are proteins exclusively expressed in neuronal tissue. Our aim was to evaluate the utility of serum neurofilament light (NfL) as a prognostic biomarker of neuronal injury in the pediatric population. A literature search was performed on PubMed, Embase, and Cochrane Databases in November 2022 for studies concerning serum NfL in the pediatric population in addition to a neurological assessment. Inclusion criteria were as follows: (1) prospective or retrospective studies, (2) studies including pediatric population until the age of 18 years, (3) serum NfL sampling, and (4) evaluation of neurological outcome. Data collection regarding study design, pediatric age, serum NfL levels, and results for neurological assessment were extracted from each study. Four manuscripts met the inclusion criteria and evaluated the prognostic utility of serum NfL in neonatal encephalopathy in correlation with the neurodevelopmental outcome that was assessed by the Bayley Scales of Infant Development until the age of 2 years. Children with neonatal encephalopathy showed significantly higher serum NfL vs. healthy controls and high serum NfL levels predicted an adverse neurological outcome. The decrease of serum NfL to a nadir point between 10 and 15 years old reflects the brain growth in healthy controls. No studies were available in the perioperative period.  Conclusions: Serum NfL is a valuable biomarker in evaluating neuronal injury in the pediatric population. Further studies with perioperative serial sampling of serum NfL combined with standardized neurodevelopmental tests should be conducted to evaluate the neurotoxicity of anesthetic agents and monitor the effectiveness of specific neuroprotective strategies in pediatric patients undergoing anesthesia and surgery. What is Known: • Preclinical animal data have shown neurotoxicity of the anesthetic agents in the developing brain. • Data regarding anesthetic neurotoxicity in humans show limitations and no objective tools are available. What is New: • This systematic review showed that serum NfL is a valuable biomarker of neuronal injury in the pediatric population. • Perioperative use of serum NfL may be considered in future trials evaluating anesthetic neurotoxicity in the pediatric population and in monitoring neuroprotective strategies.


Assuntos
Encefalopatias , Filamentos Intermediários , Adolescente , Animais , Criança , Pré-Escolar , Humanos , Recém-Nascido , Biomarcadores , Estudos Prospectivos , Estudos Retrospectivos
7.
Mol Genet Metab ; 136(3): 190-198, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34998670

RESUMO

Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.


Assuntos
Adenilossuccinato Liase , Erros Inatos do Metabolismo da Purina-Pirimidina , Adenilossuccinato Liase/deficiência , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Transtorno Autístico , Humanos , Inosina Monofosfato , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Purinas
8.
J Inherit Metab Dis ; 45(2): 215-222, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34687058

RESUMO

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.


Assuntos
Fígado Gorduroso , Deficiência de Frutose-1,6-Difosfatase , Hipoglicemia , Animais , Seguimentos , Frutose , Deficiência de Frutose-1,6-Difosfatase/complicações , Deficiência de Frutose-1,6-Difosfatase/diagnóstico , Frutose-Bifosfatase/metabolismo , Hepatomegalia , Humanos , Hipoglicemia/complicações , Fígado/metabolismo , Camundongos , Transaminases
9.
J Inherit Metab Dis ; 45(4): 848-861, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35460084

RESUMO

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.


Assuntos
Homocistinúria , Estudos de Coortes , Homocisteína , Homocistinúria/diagnóstico , Homocistinúria/tratamento farmacológico , Humanos , Recém-Nascido , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/diagnóstico , Transtornos Psicóticos , Estudos Retrospectivos
10.
Ann Neurol ; 85(3): 385-395, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30635937

RESUMO

OBJECTIVE: SLC13A3 encodes the plasma membrane Na+ /dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 carbon dicarboxylates as well as N-acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes, and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a urinary excretion of α-ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) were observed. Extensive workup was unsuccessful, and a genetic cause was suspected. METHODS: Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher. RESULTS: WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by reverse transcriptase polymerase chain reaction performed in muscle tissue (c.1016 + 3A > G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild-type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate, and NAA. INTERPRETATION: SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy, for which SLC13A3 deficiency is a novel differential diagnosis. ANN NEUROL 2019;85:385-395.


Assuntos
Ácido Aspártico/análogos & derivados , Ácidos Cetoglutáricos/metabolismo , Leucoencefalopatias/genética , Simportadores/genética , Adolescente , Ácido Aspártico/líquido cefalorraquidiano , Ácido Aspártico/metabolismo , Pré-Escolar , Feminino , Células HEK293 , Humanos , Ácidos Cetoglutáricos/líquido cefalorraquidiano , Ácidos Cetoglutáricos/urina , Leucoencefalopatias/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Linhagem , Infecções Respiratórias , Ácido Succínico/metabolismo , Simportadores/metabolismo , Tonsilite , Sequenciamento do Exoma
11.
Am J Hum Genet ; 98(2): 310-21, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833332

RESUMO

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.


Assuntos
Complexo de Golgi/genética , Homeostase , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Clonagem Molecular , Retículo Endoplasmático/metabolismo , Exoma , Feminino , Fibroblastos/citologia , Glicosilação , Complexo de Golgi/metabolismo , Células HeLa , Heterozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
Genet Med ; 21(9): 2025-2035, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30723320

RESUMO

PURPOSE: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.


Assuntos
Alopecia/genética , Colesterol/metabolismo , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transferases Intramoleculares/genética , Idade de Início , Alopecia/complicações , Alopecia/patologia , Criança , Pré-Escolar , Colesterol/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Lanosterol/genética , Lanosterol/metabolismo , Masculino , Mutação , Linhagem , Fenótipo , Esqualeno/análogos & derivados , Esqualeno/metabolismo , Sequenciamento do Exoma
13.
Metab Brain Dis ; 33(3): 875-884, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29435807

RESUMO

To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females.


Assuntos
Arginina/uso terapêutico , Creatina/uso terapêutico , Glicina/uso terapêutico , Deficiência Intelectual/tratamento farmacológico , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Adolescente , Adulto , Criança , Pré-Escolar , Creatinina/metabolismo , Feminino , Genótipo , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras/deficiência , Fenótipo , Convulsões/metabolismo , Resultado do Tratamento , Adulto Jovem
16.
J Med Genet ; 53(12): 820-827, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27439707

RESUMO

BACKGROUND: Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. METHODS: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. RESULTS: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. CONCLUSIONS: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.


Assuntos
Variações do Número de Cópias de DNA , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Anormalidades Craniofaciais , Análise Mutacional de DNA , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Epilepsia/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/metabolismo , Pessoa de Meia-Idade , Linhagem , Fenótipo , Síndrome
17.
Mol Genet Metab ; 118(3): 185-189, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27233227

RESUMO

Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9-mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild.


Assuntos
Acil-CoA Desidrogenases/genética , Cardiopatias/genética , Ácido Láctico/sangue , Mutação , Acil-CoA Desidrogenases/metabolismo , Adulto , Criança , Feminino , Predisposição Genética para Doença , Cardiopatias/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Estudos Retrospectivos , Riboflavina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
19.
Am J Med Genet A ; 170(11): 2927-2933, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27333055

RESUMO

X-chromosome exome sequencing was performed to identify the genetic cause of syndromic intellectual disability in two unrelated families with suspected X-linked inheritance. In both families, affected males presented with severe intellectual disability, microcephaly, growth retardation, and epilepsy. A missense mutation (c.777T>G p.(Ile259Met)) and a frameshift mutation (c.1394_1397del p.(Ile465Serfs*4)) were identified in the EIF2S3 gene in the hemizygous state in affected patients, and in the heterozygous states female obligate carriers. A missense mutation in EIF2S3, coding for the gamma-subunit of the translation initiation factor eIF2, was reported once in a family presenting with similar clinical features. Morpholino-based knockdown of the zebrafish EIF2S3 ortholog (eif2s3) recapitulates the human microcephaly and short stature phenotype, supporting the pathogenicity of the identified variants. Our data confirm that EIF2S3 mutation is implicated in a rare, but recognizable, form of syndromic intellectual disability. © 2016 Wiley Periodicals, Inc.


Assuntos
Epilepsia/genética , Fator de Iniciação 2 em Eucariotos/genética , Estudos de Associação Genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , Mutação , Adolescente , Alelos , Sequência de Aminoácidos , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/diagnóstico , Exoma , Fácies , Feminino , Técnicas de Silenciamento de Genes , Genes Ligados ao Cromossomo X , Genótipo , Transtornos do Crescimento/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico , Linhagem , Fenótipo , Síndrome , Peixe-Zebra
20.
PLoS Genet ; 9(12): e1003989, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348268

RESUMO

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Complexo de Golgi/genética , Deficiência Intelectual/genética , Manosidases/genética , Adolescente , Sequência de Aminoácidos , Criança , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Exoma/genética , Feminino , Estudos de Associação Genética , Glicosilação , Complexo de Golgi/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Manosidases/deficiência , Mutação
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