RESUMO
BACKGROUND: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients. Recently, it has been shown that 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediate of the de novo pathway, accumulates in LND fibroblasts maintained with RPMI containing physiological levels (25 nM) of folic acid (FA), which strongly differs from FA levels of regular cell culture media (2200 nM). However, RPMI and other standard media contain non-physiological levels of many nutrients, having a great impact in cell metabolism that does not precisely recapitulate the in vivo behavior of cells. METHODS: We prepared a new culture medium containing physiological levels of all nutrients, including vitamins (Plasmax-PV), to study the potential alterations of LND fibroblasts that may have been masked by the usage of non-physiological media. We quantified ZMP accumulation under different culture conditions and evaluated the activity of two known ZMP-target proteins (AMPK and ADSL), the mRNA expression of the folate carrier SLC19A1, possible mitochondrial alterations and functional consequences in LND fibroblasts. RESULTS: LND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND. CONCLUSIONS: A complete physiological cell culture medium reveals new alterations in Lesch-Nyhan disease. This work emphasizes the importance of using physiological cell culture conditions when studying a metabolic disorder.
Assuntos
Síndrome de Lesch-Nyhan , Humanos , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/metabolismo , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Ácido FólicoRESUMO
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
Assuntos
Ataxia Cerebelar , Deficiência Intelectual , Humanos , Mutação/genética , Síndrome , Deficiência Intelectual/genética , Ataxia Cerebelar/genética , Fenótipo , Espasticidade Muscular/genética , Cátions , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.
Assuntos
Ácido Fólico/análise , Síndrome de Lesch-Nyhan/etiologia , Purinas/metabolismo , Trifosfato de Adenosina/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/metabolismo , Técnicas de Cultura de Células , Meios de Cultivo Condicionados/química , Fibroblastos/metabolismo , Humanos , Hipoxantina Fosforribosiltransferase/metabolismo , Síndrome de Lesch-Nyhan/metabolismo , Ribonucleotídeos/metabolismoRESUMO
Pathogenic variants in the AP4B1 gene lead to a rare form of hereditary spastic paraplegia (HSP) known as SPG47. We report on a patient with a clinical suspicion of complicated HSP of the lower limbs with intellectual disability, as well as a novel homozygous noncanonical splice site variant in the AP4B1 gene, in which the effect on splicing was validated by RNA analysis. We sequenced 152 genes associated with HSP using Next-Generation Sequencing (NGS). We isolated total RNA from peripheral blood and generated cDNA using reverse transcription-polymerase chain reaction (RT-PCR). A region of AP4B1 mRNA was amplified by PCR and the fragments obtained were purified from the agarose gel and sequenced. We found a homozygous variant of uncertain significance in the AP4B1 gene NM_006594.4: c.1511-6C>G in the proband. Two different AP4B1 mRNA fragments were obtained in the patient and his carrier parents. The shorter fragment was the predominant fragment in the patient and revealed a deletion with skipping of the AP4B1 exon 10. The patient's longer fragment corresponded to an insertion of the last five nucleotides of AP4B1 intron 9. We confirmed that this variant affects the normal splicing of RNA, sustaining the molecular diagnosis of SPG47 in the patient.
Assuntos
Paraplegia Espástica Hereditária , Complexo 4 de Proteínas Adaptadoras , Subunidades beta do Complexo de Proteínas Adaptadoras , Homozigoto , Humanos , Íntrons , Mutação , Linhagem , RNA , RNA Mensageiro/genética , Paraplegia Espástica Hereditária/genéticaRESUMO
OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Gota , Proteínas de Neoplasias/genética , Ácido Úrico/sangue , Adulto , Idade de Início , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Gota/sangue , Gota/epidemiologia , Gota/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Exacerbação dos SintomasRESUMO
PURPOSE: Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was to describe macrocytic erythrocytes as another common aspect of the phenotype. METHODS: The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly. RESULTS: Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia. CONCLUSION: These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.
Assuntos
Anemia Macrocítica/etiologia , Síndrome de Lesch-Nyhan/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Síndrome de Lesch-Nyhan/sangue , Estudos Longitudinais , Masculino , Fenótipo , Adulto JovemRESUMO
X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT-deficiency carrier females. As a group, 75% of HPRT-deficiency carrier females presented skewed XCI. Moreover, skewed XCI is significantly more frequent in LND carriers (83%) than in LNV (0-50%, depending on the phenotype severity). The ratios of the preferentially inactivated allele of carrier females were significantly higher than the ratios of the preferentially inactivated allele of noncarrier females (89.4±15, n=52 vs 65.2±12, n=52; P<0.0001). For carrier diagnosis, the presence of skewed XCI presents a sensitivity of 75% with a specificity of 85%. In LND families, the presence of skewed XCI is more sensitive for carrier diagnosis than in LNV families; however, we believe that this test is not accurate for carrier diagnostic purposes.
Assuntos
Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/genética , Inativação do Cromossomo X/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , FenótipoRESUMO
Lesch-Nyhan disease (LND) is a genetic disorder that has characteristic metabolic, neurologic, and behavioral features. There are multiple behavioral problems including impulsivity, aggressiveness, and severe recurrent self-injurious behavior (SIB). This last behavior varies considerably across subjects and may encompass self-biting, self-hitting, scratching, head banging, and other injurious actions. Current treatments for SIB involve behavioral extinction, sedatives, physical restraints, and removal of teeth. Because these interventions do not reliably control SIB, better treatments are urgently needed. Animal studies have suggested that D1-dopamine receptor antagonists such as ecopipam may suppress SIB. These observations have led to proposals that such drugs might provide effective treatment for in LND. The current study describes the results of a double-blind, three-period, crossover trial of a single dose of ecopipam in subjects with LND. The study was designed for 20 patients, but it was terminated after recruitment of only 10 patients, because interim analysis revealed unanticipated side effects. These side effects were most likely related to starting with a single large dose without any titration phase. Despite the limited data due to early termination, the drug appeared to reduce SIB in most cases. Subjects who completed the trial were eligible to continue the drug in an open-label extension phase lasting a year, and one patient who elected to continue has maintained a striking reduction in SIB for more than a year with no apparent side effects. These results suggest ecopipam could be a useful treatment for SIB in, but further studies are needed to establish an appropriate dosing regimen.
Assuntos
Benzazepinas/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Síndrome de Lesch-Nyhan/tratamento farmacológico , Adolescente , Benzazepinas/efeitos adversos , Criança , Estudos Cross-Over , Antagonistas de Dopamina/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Tamanho da Amostra , Resultado do Tratamento , Adulto JovemRESUMO
Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.
Assuntos
Estudos de Associação Genética , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/fisiopatologia , Mutação/genética , Animais , HumanosRESUMO
OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (ß = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; ß = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; ß = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (ß = 0.07 [95% CI -2.32, 2.45] in European women; ß = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; ß -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (ß = -2.42 [95% CI -3.37, -1.46] and ß = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (ß = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.
Assuntos
Gota , População das Ilhas do Pacífico , Feminino , Humanos , Masculino , Predisposição Genética para Doença , Gota/genética , Fatores de Risco , População EuropeiaRESUMO
Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances.
Assuntos
Síndrome de Lesch-Nyhan/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D5/metabolismo , Adenosina/metabolismo , Adolescente , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Dopamina/metabolismo , Humanos , Síndrome de Lesch-Nyhan/etiologia , Síndrome de Lesch-Nyhan/genética , Linfócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Serotonina/metabolismo , Adulto JovemRESUMO
Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.
Assuntos
Gota/genética , Hiperuricemia/genética , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/diagnóstico , Comportamento Autodestrutivo/genética , Humanos , Síndrome de Lesch-Nyhan/genéticaRESUMO
BACKGROUND: Lesch-Nyhan disease (LND) is a disease of purine metabolism linked to chromosome X due to the absence or near-absence of enzyme hypoxanthine-guanine phosphoribosyltransferase. Patients with LND have a compulsive autoaggressive behavior that consists of self-mutilation by biting. METHODS: The objective of this study was to explore the safety and efficacy of botulinum toxin (BoNT) injected into the masticatory muscles and biceps brachii to reduce self-mutilation in patients with LND. We retrospectively analyzed six patients with LND who were treated with BoNT to prevent automutilatory behavior. RESULTS: The patient ages when started on treatment with BoNT were 4, 4.5, 6.6, 7.9, 13.9, and 32.3 years. Patients received a mean number of injections of 20, ranging from 3 to 29, over a period that ranged from 1.5 to 7.1 years. The maximum total dose of Botox was 21.3 units/kg mean and the maximum total dose of Dysport was 37.5 units/kg mean. A total of 119 injections were performed. Of these 113 (95%) were partially or completely effective. Only three of 119 injections (2.5%) produced adverse effects. CONCLUSIONS: Botulinum toxin is useful and safe for the treatment of self-biting behavior in patients with LND.
Assuntos
Toxinas Botulínicas/farmacologia , Síndrome de Lesch-Nyhan/tratamento farmacológico , Músculos da Mastigação/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fármacos Neuromusculares/farmacologia , Automutilação/tratamento farmacológico , Adolescente , Braço , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/efeitos adversos , Criança , Feminino , Humanos , Masculino , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/efeitos adversos , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1ß) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1ß mutations are found in only approximately 45% of FJHN probands, indicating the involvement of other genetic loci in approximately 55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1ß and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a approximately 5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a approximately 5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.
Assuntos
Cromossomos Humanos Par 2/genética , Loci Gênicos , Genoma Humano , Feminino , Heterogeneidade Genética , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/genética , Humanos , Hiperuricemia/genética , Nefropatias/genética , Falência Renal Crônica/genética , Masculino , Linhagem , Ácido Úrico/sangue , Ácido Úrico/metabolismoRESUMO
Lesch-Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine-guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype-phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype-phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.
Assuntos
Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Predisposição Genética para Doença , Humanos , Hipoxantina Fosforribosiltransferase/metabolismo , Lactente , Recém-Nascido , Fenótipo , Mutação Puntual , Ácido Úrico/metabolismo , Adulto JovemRESUMO
Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.
Assuntos
Síndrome de Lesch-Nyhan , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Discinesias/metabolismo , Discinesias/fisiopatologia , Humanos , Síndrome de Lesch-Nyhan/metabolismo , Síndrome de Lesch-Nyhan/fisiopatologia , Síndrome de Lesch-Nyhan/psicologia , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Ácido Úrico/metabolismo , Adulto JovemRESUMO
X-linked myotubular myopathy (XLMTM; OMIM 310400) is a centronuclear congenital muscular disorder of X-linked recessive inheritance. Although female carriers are typically asymptomatic, affected heterozygous females have been described. Here, we describe the case of a sporadic female patient with suspicion of centronuclear myopathy and a heterozygous large deletion at Xq28 encompassing the MAMLD1, MTM1, MTMR1, CD99L2, and HMGB3 genes. The deletion was first detected using a custom next generation sequencing (NGS)-based multigene panel and finally characterized by comparative genomic hybridization array and multiplex ligation probe assay techniques. In this patient we have confirmed, by MTM1 mRNA quantification, a MTM1 gene expression less than the expected 50 percent in patient muscle. The significant 20% reduction in MTM1 mRNA expression in muscle, precludes low level of the normal myotubularin protein as the cause of the phenotype in this heterozygous female. We have also found that BIN1 expression in patient muscle biopsy was significantly increased, and postulate that BIN1 expression will be increased in XLMTM patient muscle as an attempt to maintain muscle function.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Deleção Cromossômica , Miopatias Congênitas Estruturais/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Cromossomos Humanos X/genética , Feminino , Heterozigoto , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/metabolismo , Miopatias Congênitas Estruturais/patologia , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Gout is the most common arthritis and it is associated to urate monosodium crystals deposits in articulations, kidney and soft tissue. The urate monosodium crystals deposit initiates an inflammatory response; mediated by NLRP3 inflammasome, with the release of interleukin 1ß. Toll-like receptor 4 (TLR4) is involved in this response. Although serum urate level is a strong predictor of incident gout, only about half of those with serum urate concentrations ≥10mg/dL develop clinically evident gout over 15 years. Therefore, it has been postulated that other factors, including genetic or immunity related factors, seems to be necessary to the apparition of the acute gout flare beside hyperuricemia. The association of TLR4 single nucleotide polymorphism (SNP) rs2149356 and gout risk is controversial with different results according to different populations.Methods: We have analyzed rs2149356 polymorphism of TLR4 gene in DNA extracted from 125 well characterized Caucasian gouty patients and 300 Caucasian health controls, by automated DNA sequencing.Results: Allele frequency distribution in control samples were CC: 0.467 (140); CA 0.437 (131); and AA 0.097 (29).Allele distribution in gouty patients were CC: 0.512 (64); CA: 0.392 (49); and AA: 0.096 (12). No significant association was found between TRL4 rs2149356 polymorphism and risk of gout in the analyzed population.Conclusions: Allele frequency for rs2149356 in our population was similar to other population of European ancestry, and in these populations; the polymorphism was not related to gouty risk.
Assuntos
Predisposição Genética para Doença/genética , Gota/genética , Polimorfismo de Nucleotídeo Único , Receptor 4 Toll-Like/genética , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , EspanhaRESUMO
INTRODUCTION: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. METHODS: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). RESULTS: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. CONCLUSION: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.
RESUMO
We report on a 16-day-old male with metabolic acidosis, hyperuricemia, hyperuricosuria, and nephrocalcinosis caused by Lesch-Nyhan syndrome. Activity of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme in lysed erythrocytes was undetectable, and molecular DNA analysis confirmed the presence of a 4-base pair deletion at the 5' end of intervening sequence 8 in the HPRT1 gene, a change that affects a 5' splice site consensus sequence. Rasburicase, a urate oxidase enzyme, was administered on day 26 of life, with an endovenous dose of 0.20 mg/kg/d for 3 days. Plasma urate concentrations normalized (2.96 mg/dL) at 38 days of life. Kidney function was preserved in our patient. In summary, rasburicase proved to be a safe and effective treatment in a patient with Lesch-Nyhan syndrome with uric acid nephropathy in the neonatal period.