RESUMO
Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, cutis laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
Assuntos
Cútis Laxa/genética , Antígenos de Histocompatibilidade Menor/genética , Mutação de Sentido Incorreto , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pele/patologia , Sequência de Aminoácidos , Animais , Criança , Cútis Laxa/patologia , Feminino , Glicosilação , Homozigoto , Humanos , Camundongos , Camundongos Knockout , Linhagem , Fosfatidilinositóis/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/deficiênciaRESUMO
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and â¼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.
Assuntos
Alelos , Perda Auditiva Neurossensorial/genética , Hipoglicemia/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Proteínas Ribossômicas/genética , Sequência de Aminoácidos , Pré-Escolar , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Fibroblastos/metabolismo , Perda Auditiva Neurossensorial/complicações , Humanos , Hipoglicemia/complicações , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/complicações , Proteínas Mitocondriais/química , Fosforilação Oxidativa , Subunidades Proteicas/genética , RNA Ribossômico/genética , Proteínas Ribossômicas/químicaRESUMO
Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.
Assuntos
Cútis Laxa/genética , Mutação de Sentido Incorreto , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Alelos , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glicosilação , Complexo de Golgi/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Conformação Proteica , Transporte Proteico , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: To define phenotypic groups and identify predictors of disease severity in patients with phosphoglucomutase-1 deficiency (PGM1-CDG). STUDY DESIGN: We evaluated 27 patients with PGM1-CDG who were divided into 3 phenotypic groups, and group assignment was validated by a scoring system, the Tulane PGM1-CDG Rating Scale (TPCRS). This scale evaluates measurable clinical features of PGM1-CDG. We examined the relationship between genotype, enzyme activity, and TPCRS score by using regression analysis. Associations between the most common clinical features and disease severity were evaluated by principal component analysis. RESULTS: We found a statistically significant stratification of the TPCRS scores among the phenotypic groups (P < .001). Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score. Principal component analysis identified 5 variables that contributed to 54% variance in the cohort and are predictive of disease severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth. CONCLUSIONS: We established a scoring algorithm to reliably evaluate disease severity in patients with PGM1-CDG on the basis of their clinical history and presentation. We also identified 5 clinical features that are predictors of disease severity; 2 of these features can be evaluated by physical examination, without the need for specific diagnostic testing and thus allow for rapid assessment and initiation of therapy.
Assuntos
Doença de Depósito de Glicogênio/diagnóstico , Fenótipo , Índice de Gravidade de Doença , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Genótipo , Doença de Depósito de Glicogênio/enzimologia , Doença de Depósito de Glicogênio/genética , Humanos , Masculino , Mutação , Fosfoglucomutase/deficiência , Fosfoglucomutase/genética , Exame Físico , Análise de Componente Principal , Análise de Regressão , Adulto JovemRESUMO
Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all reported P5CS patients. So far 10 patients were described with mutations in ALDH18A1. Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly.
Assuntos
Tecido Adiposo/patologia , Aldeído Desidrogenase/genética , Cútis Laxa/genética , Mutação/genética , Doenças Retinianas/genética , Família Aldeído Desidrogenase 1 , Pré-Escolar , Cútis Laxa/complicações , Cútis Laxa/patologia , Humanos , Masculino , Retinal Desidrogenase , Doenças Retinianas/complicações , Doenças Retinianas/patologiaRESUMO
Glycosylation is the posttranslational coupling of sugar chains to proteins or lipids. Proper glycosylation is essential for normal protein structure, function, and trafficking. Mutations in the glycosylation pathway lead to a phenotypically heterogeneous group of metabolic disorders, the congenital disorders of glycosylation (CDG). Some of these conditions, including PMM2-CDG, frequently present with recognizable skin abnormalities such as abnormal fat distribution, skin wrinkling, or peau d'orange, whereas others, such as COG7-CDG and ATP6V0A2-CDG, have been described in association with cutis laxa: wrinkled, inelastic, and sagging skin. Ichthyosis is also common in several types of CDG. ALG8-CDG is a severe disorder characterized by dysmorphic features, failure to thrive, protein-losing enteropathy, neurologic and ophthalmologic problems, and developmental delay. We reviewed the clinical features in all nine previously reported patients diagnosed with ALG8-CDG with a special focus on their skin signs. Three of the nine patients had abnormal fat distribution and skin wrinkling. As the spectrum of CDG presenting with skin signs expands further, we suggest screening for CDG in all patients presenting with any type of central nervous involvement and wrinkled skin, cutis laxa, severe ichthyosis, or abnormal fat distribution.
Assuntos
Tecido Adiposo/patologia , Glucosiltransferases/genética , Envelhecimento da Pele/genética , Envelhecimento da Pele/patologia , Dermatopatias , Tecido Adiposo/metabolismo , Evolução Fatal , Glucosiltransferases/metabolismo , Glicosilação , Humanos , Lactente , Masculino , Dermatopatias/congênito , Dermatopatias/genética , Dermatopatias/patologiaRESUMO
Cutis laxa is an inherited or acquired disease characterized by redundant, sagging and inelastic skin. In inherited cutis laxa an abnormal synthesis of extracellular matrix proteins occurs due to genetic defects coding for diverse extracellular matrix components. Recently, different inborn errors of metabolism have been found to be associated with cutis laxa as well. In some of these metabolic conditions the pathomechanism of cutis laxa remains unknown. Cutis laxa can be inherited in an autosomal dominant, autosomal recessive and X-linked recessive inheritance pattern. Besides the skin abnormalities, in most inherited forms multiple organ systems are involved, leading to a severe, in some forms even lethal, multisystem disorder. To date no effective treatment is available for cutis laxa. This chapter focuses on inherited forms of cutis laxa, offering a practical guideline for clinicians, biochemist and geneticist to diagnose and differentiate between the different forms of cutis laxa, and providing a concise theoretical reference.
Assuntos
Proteínas de Transporte/genética , Cútis Laxa/genética , Proteínas da Matriz Extracelular/genética , Proteínas Mitocondriais/genética , Mutação , Pele/metabolismo , Cútis Laxa/classificação , Cútis Laxa/diagnóstico , Cútis Laxa/patologia , Regulação da Expressão Gênica , Humanos , Padrões de Herança , Linhagem , Guias de Prática Clínica como Assunto , Pele/patologia , Terminologia como AssuntoRESUMO
Cutis laxa (CL) is a connective tissue disorder, characterized by loose, inelastic, sagging skin. Both acquired and inherited (dominant, recessive, and X-linked) forms exist. Here, we describe a new phenotype, which overlaps with other known CL syndromes. Our patient has a unique combination of features in association with sagging, inelastic, wrinkled skin, including cataract, severe cardiomyopathy, abnormal fat distribution, improvement of skin-wrinkling with age, and white matter abnormalities but no significant histologic collagen or elastin abnormalities. Mutation analysis of known CL genes was negative. We suggest that our patient has a novel syndrome, with the main features of CL, intellectual disability, abnormal fat distribution, cardiomyopathy, and cataract.
Assuntos
Cardiomiopatias/genética , Catarata/genética , Cútis Laxa/genética , Adolescente , Distribuição da Gordura Corporal , Humanos , Masculino , Mutação , Fenótipo , Envelhecimento da Pele/genéticaRESUMO
Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.
Assuntos
Agenesia do Corpo Caloso , Cútis Laxa , Epilepsia , Adolescente , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Agenesia do Corpo Caloso/patologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Cútis Laxa/diagnóstico , Cútis Laxa/genética , Cútis Laxa/metabolismo , Cútis Laxa/patologia , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Feminino , Glicosilação , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Masculino , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Estudos Prospectivos , Pirrolina Carboxilato Redutases/genética , Pirrolina Carboxilato Redutases/metabolismo , delta-1-Pirrolina-5-Carboxilato RedutaseRESUMO
OBJECTIVE: To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation. METHODS: Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast. RESULTS: We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP-sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP-sialic acid in vitro. CONCLUSION: We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.
Assuntos
Ácido N-Acetilneuramínico do Monofosfato de Citidina/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Proteínas de Transporte de Nucleotídeos/genética , Adolescente , Western Blotting , Criança , Análise Mutacional de DNA , Feminino , Glicosilação , Transtornos Hemorrágicos/genética , Transtornos Hemorrágicos/metabolismo , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Congenital disorders of glycosylation (CDG) are a rapidly growing family of inborn errors. Screening for CDG in suspected cases is usually performed in the first year of life by serum transferrin isoelectric focusing or mass spectrometry. Based on the transferrin analysis patients can be biochemically diagnosed with a type 1 or type 2 transferrin pattern, and labeled as CDG-I, or CDG-II. The diagnosis of CDG is frequently delayed due to the highly variable phenotype, some cases showing single organ involvement and others mimicking syndromes, like skeletal dysplasia, cutis laxa syndrome, or congenital muscle dystrophy. The aim of our study was to evaluate perinatal abnormalities and early discriminative symptoms in 58 patients consecutively diagnosed with diverse CDG-subtypes. Neonatal findings and clinical features in the first months of life were studied in 36 children with CDG-I and 22 with CDG-II. Maternal complications were found in five, small for gestational age in nine patients. Five children had abnormal neonatal screening results for hypothyroidism. Congenital microcephaly and neonatal seizures were common in CDG-II. Inverted nipples were uncommon with 5 out of 58 children. Dysmorphic features were mostly nonspecific, except for cutis laxa. Early complications included feeding problems, cardiomyopathy, thrombosis, and bleeding. Cases presenting in the neonatal period had the highest mortality rate. Survival in CDG patients is highly dependent on early intervention therapy. We recommend low threshold screening for glycosylation disorders in infants with neurologic symptoms, even in the absence of abnormal fat distribution. Growth retardation and neonatal bleeding increase suspicion for CDG.
Assuntos
Anormalidades Múltiplas/genética , Defeitos Congênitos da Glicosilação/genética , Convulsões/genética , Anormalidades Múltiplas/mortalidade , Defeitos Congênitos da Glicosilação/mortalidade , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Gravidez , Complicações na Gravidez/genética , Convulsões/mortalidadeRESUMO
Glycoproteins are essential in the production, transport, storage and regulation of thyroid hormones. Altered glycosylation has a potential impact on thyroid function. Abnormal thyroid function tests have been described in patients with congenital disorders of glycosylation. We evaluated the reliability of biochemical markers and investigated thyroid function in 18 PMM2-CDG patients. We propose an expectative therapeutic approach for neonates with thyroid abnormalities in CDG.
Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/terapia , Neuraminidase/farmacologia , Fosfotransferases (Fosfomutases)/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/enzimologia , Feminino , Seguimentos , Glicosilação , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Testes de Função Tireóidea , Tireotropina/metabolismo , Adulto JovemRESUMO
We found that the missense mutation p.Pro1205Leu in the PHKA2 gene is a common cause of hepatic phosphorylase-kinase deficiency in Dutch patients, suggesting a founder-effect. Most patients presented with isolated growth delay and diarrhea, prior to the occurrence of hepatomegaly, delaying diagnosis. Tetraglucoside excretion correlated with disease severity and was used to follow compliance. The clinical presentation and therapeutic requirements in the same mutation carriers were variable, and PhK deficiency necessitated tube-feeding in some children.
Assuntos
Mutação de Sentido Incorreto , Fosforilase Quinase/deficiência , Fosforilase Quinase/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Efeito Fundador , Estudos de Associação Genética , Hepatomegalia/genética , Humanos , Lactente , Masculino , FenótipoRESUMO
Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG's diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions.
Assuntos
Defeitos Congênitos da Glicosilação/classificação , Defeitos Congênitos da Glicosilação/diagnóstico , Pediatria/métodos , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Prognóstico , Projetos de PesquisaRESUMO
Cutis laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of cutis laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited cutis laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with cutis laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of cutis laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic cutis laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing cutis laxa we offer a practical approach for the differential diagnosis of metabolic cutis laxa syndromes.