RESUMO
Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new hematopoietic stem cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof of concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon-optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard vs. a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof of concept for the clinical translation of this approach for the treatment of Hunter syndrome.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Humanos , Animais , Camundongos , Mucopolissacaridose II/terapia , Mucopolissacaridose II/tratamento farmacológico , Iduronato Sulfatase/genética , Iduronato Sulfatase/metabolismo , Terapia Genética , Sistema Nervoso Central/metabolismo , Lentivirus/genética , Lentivirus/metabolismo , Células-Tronco Hematopoéticas/metabolismoRESUMO
The Lysosomal Storage disease known as Mucopolysaccharidosis type II, is caused by mutations affecting the iduronate-2-sulfatase required for heparan and dermatan sulfate catabolism. The central nervous system (CNS) is mostly and severely affected by the accumulation of both substrates. The complexity of the CNS damage observed in MPS II patients has been limitedly explored. The use of mass spectrometry (MS)-based proteomics tools to identify protein profiles may yield valuable information about the pathological mechanisms of Hunter syndrome. In this further study, we provide a new comparative proteomic analysis of MPS II models by using a pipeline consisting of the identification of native protein complexes positioned selectively by using a specific antibody, coupled with mass spectrometry analysis, allowing us to identify changes involving in a significant number of new biological functions, including a specific brain antioxidant response, a down-regulated autophagic, the suppression of sulfur catabolic process, a prominent liver immune response and the stimulation of phagocytosis among others.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Humanos , Mucopolissacaridose II/genética , Proteômica , Iduronato Sulfatase/genética , Iduronato Sulfatase/metabolismo , Glicosaminoglicanos/metabolismo , Encéfalo/metabolismoRESUMO
BACKGROUND: Bow Hunter's syndrome (BHS), also known as rotational vertebral artery occlusion (RVAO), is a rare condition characterized by dynamic vertebrobasilar insufficiency due to position-dependent occlusion of the vertebral artery (VA). In the existing literature, most cases of BHS are attributed to osteophytic compression originating from the occipital condyle or within the transverse foramen, often accompanied by anatomical abnormalities of the VA. However, cases presenting solely with VA anomalies in the absence of any cervical vertebral structural abnormality are rare. This case report presents a unique instance of BHS in a 56-year-old male, attributed to the anomalous origin of the right VA and the absence of the left VA, without cervical structural abnormalities. CASE PRESENTATION: The patient exhibited symptoms like episodic dizziness and vertigo, which were exacerbated by rightward head rotation and alleviated upon returning to a neutral position. Diagnostic evaluation, including digital subtraction angiography, revealed that the right VA originated from the right common carotid artery and compression-induced stenosis of the right VA during head rotation. Conservative management, including avoidance of certain head movements and anti-arteriosclerosis medication, led to symptom resolution over a two-year follow-up period. CONCLUSIONS: This report contributes to the understanding of BHS by highlighting a rare vascular anomaly presentation and incorporates a review of 14 similar case reports in the literature describing that an anatomical abnormality of the VA is mainly responsible for the pathology of BHS in the absence of cervical vertebral anomalies, thus emphasizing the need for careful diagnostic and management strategies.
Assuntos
Artéria Vertebral , Insuficiência Vertebrobasilar , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Vertebral/anormalidades , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/patologia , Insuficiência Vertebrobasilar/complicações , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/diagnósticoRESUMO
Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Criança , Humanos , Recém-Nascido , Estados Unidos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/genética , Triagem Neonatal , Ácido Idurônico , Iduronato Sulfatase/uso terapêutico , Glicosaminoglicanos , Terapia de Reposição de Enzimas/métodosRESUMO
We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase activity in dried blood spots between December 12, 2017 and April 30, 2022. A total of 76 infants were referred for diagnostic testing, 0.01% of the screened population. Of these, eight cases of MPS II were diagnosed for an incidence of 1 in 73,290. At least four of the eight cases detected had an attenuated phenotype. In addition, cascade testing revealed a diagnosis in four extended family members. Fifty-three cases of pseudodeficiency were also identified, for an incidence of 1 in 11,062. Our data suggest that MPS II may be more common than previously recognized with a higher prevalence of attenuated cases.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Lactente , Recém-Nascido , Humanos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose II/genética , Triagem Neonatal , Incidência , FamíliaRESUMO
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS-/- NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Humanos , Animais , Camundongos , Mucopolissacaridose II/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Iduronato Sulfatase/genética , GlicosaminoglicanosRESUMO
Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disease caused by a disease-associated variant in the IDS gene, which encodes iduronate 2-sulfatase (IDS). We aimed to characterize the clinical characteristics and genotypes of the largest cohort of Chinese patients with MPS II and so gain a deeper understanding of natural disease progression. Patients with confirmed MPS II and without treatment were included. The disease was classified as severe in patients with neurological impairment, and as attenuated in patients aged >6 years without neurological impairment. Of the 201 male patients, 78.1% had severe MPS II. Cognitive regression occurred before age 6 years in 94.3% of patients. Of 122 IDS variants identified, 37 were novel. Among the large gene alteration types identified, only the frequency of IDS-IDS2 recombination was significantly higher in severe versus attenuated MPS II (P = 0.032). Some identified point variants could inform the understanding of genotype-phenotype correlations. In conclusion, this study showed that classification of the disease as attenuated should only be made in patients aged >6 years. Our findings expand the understanding of the genotype-phenotype relationship, inform the diagnostic process, and provide an indication of the likely prognosis.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Masculino , Humanos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/genética , Estudos Retrospectivos , Iduronato Sulfatase/genética , Genótipo , MutaçãoRESUMO
Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, lysosomal disorder caused by mutations in a gene encoding iduronate-2-sulfatase (IDS). IDS deficiency results in an accumulation of glycosaminoglycans (GAGs) and secondary accumulations of other lipids in lysosomes. Symptoms of MPS II include a variety of soft and hard tissue problems, developmental delay, and deterioration of multiple organs. Enzyme replacement therapy is an approved treatment for MPS II, but fails to improve neuronal symptoms. Cell-based neuronal models of MPS II disease are needed for compound screening and drug development for the treatment of the neuronal symptoms in MPS II. In this study, three induced pluripotent stem cell (iPSC) lines were generated from three MPS II patient-derived dermal fibroblast cell lines that were differentiated into neural stem cells and neurons. The disease phenotypes were measured using immunofluorescence staining and Nile red dye staining. In addition, the therapeutic effects of recombinant human IDS enzyme, delta-tocopherol (DT), and hydroxypropyl-beta-cyclodextrin (HPBCD) were determined in the MPS II disease cells. Finally, the neural stem cells from two of the MPS II iPSC lines exhibited typical disease features including a deficiency of IDS activity, abnormal glycosaminoglycan storage, and secondary lipid accumulation. Enzyme replacement therapy partially rescued the disease phenotypes in these cells. DT showed a significant effect in reducing the secondary accumulation of lipids in the MPS II neural stem cells. In contrast, HPBCD displayed limited or no effect in these cells. Our data indicate that these MPS II cells can be used as a cell-based disease model to study disease pathogenesis, evaluate drug efficacy, and screen compounds for drug development.
Assuntos
Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/uso terapêutico , Linhagem Celular , Terapia de Reposição de Enzimas , Glicosaminoglicanos/metabolismo , Humanos , Iduronato Sulfatase/uso terapêutico , Células-Tronco Pluripotentes Induzidas/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Modelos Neurológicos , Mucopolissacaridose II/patologia , Células-Tronco Neurais/patologia , Fenótipo , Proteínas Recombinantes/uso terapêutico , Tocoferóis/uso terapêuticoRESUMO
PURPOSE: To describe a case of retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome. METHODS: Fundus photography, total field electroretinogram, ultrasound, computerized visual field examination, biochemical examination and genetic testing were obtained. RESULTS: The fundus exam showed diffuse arteriolar attenuation, optic disc with regular contours, and pigment agglomerates like "bone spicules" in the middle periphery. Ultrasound examination revealed scleral thickening and short axial diameter in both eyes. The total field electroretinogram exam showed a subnormal result with greater impairment of the scotopic phase of the exam. Computerized visual field examination demonstrated a diffuse reduction in retinal sensitivity in the periphery. Biochemical examination showed increased urine glycosaminoglycan excretion and iduronate-2-sulphatase activity (IDS) deficiency in leukocytes, confirming the type II mucopolysaccharidosis. Molecular analysis revealed a novel missense mutation (p.A77D) in the IDS gene. CONCLUSION: The case report is about a patient presented an attenuated form of the syndrome, with no cognitive impairment. Ophthalmologic follow-up is still an important part of multidisciplinary treatment for Hunter's syndrome.
Assuntos
Microftalmia , Mucopolissacaridose II , Retinose Pigmentar , Humanos , Mucopolissacaridose II/complicações , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/terapia , Microftalmia/complicações , Microftalmia/diagnóstico , Microftalmia/genética , Eletrorretinografia , Retinose Pigmentar/complicações , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Mutação de Sentido IncorretoRESUMO
Bow Hunter's syndrome is a rare disorder usually producing transient ischemic symptoms as a result of dynamic compression of the vertebral artery during head turning. We report a case of a 14 year old male presenting with stroke due to occlusion of vertebral artery due to rotatory atlanto-axial subluxation. The patient presented with sudden onset vertigo and ataxia. History revealed led mild torticollis since childhood which was never investigated. MRI and MRA showed infarcts in the bilateral cerebellar hemispheres and the occipital lobes with a hypoplastic left vertebral artery and kinking of the right vertebral artery at the cranio-vertebral junction due to rotatory atlanto-axial subluxation. The patient was successfully treated by C1 lateral mass and C2 sub-facetal screw with rod fixation. Bow-Hunter's syndrome producing transient ischemia is well reported but stroke in the vertebro-basilar territory in a 14 year old due to rotatory atlanto-axial subluxation is uncommon, and to the best of our knowledge, this is the eighth such reported case.
Assuntos
Luxações Articulares , Mucopolissacaridose II , Acidente Vascular Cerebral , Insuficiência Vertebrobasilar , Masculino , Humanos , Criança , Adolescente , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/etiologia , Insuficiência Vertebrobasilar/cirurgia , Artéria Vertebral/cirurgia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/cirurgia , Luxações Articulares/diagnóstico por imagem , Luxações Articulares/etiologia , Luxações Articulares/cirurgiaRESUMO
BACKGROUND: Bow hunter's syndrome (BHS), also known as rotational vertebral artery occlusion syndrome, is rare. Occasionally, it combines with dissection/pseudoaneurysm of the ipsilateral VA. METHODS: We report a case of BHS combined with ipsilateral VA dissection/pseudoaneurysm and review eight similar cases reported in the literature. Their aetiology, clinical and imaging features, treatment, and prognosis were analysed. RESULTS: Nine patients (seven male, two female; average age 22.0 ± 4.5 years) were enrolled. Visual symptoms comprised the most common clinical finding (66.7%, 7/9). Clinical symptoms were not related to neck rotation in seven patients (77.8%). Eight patients (88.9%) had multiple, scattered, new and old infarctions of the posterior circulation revealed on computed tomography/magnetic resonance imaging (CT/MRI) scans. Dissection/pseudoaneurysm was found in the ipsilateral VA - usually subtle and localised in the atlas, axis, and occipital bone - in all nine patients. Seven patients (66.7%) had special causes for the syndrome (i.e. congenital bone dysplasia). Altogether, 87.5% (7/8) experienced recurrence with cerebral infarction after antithrombotic therapy alone. Aetiologically targeted treatment, including surgical decompression or vertebral fixation, was performed in seven patients (77.8%). CONCLUSION: Young patients presenting with cryptogenic stroke in the posterior circulation and localised, subtle dissection/pseudoaneurysm of the ipsilateral VA around the atlanto-axial joint should undergo carotid ultrasonography with a neck rotation test or dynamic CT angiography/MR angiography/digital subtraction angiography, if necessary, to rule out/diagnose BHS.
Assuntos
Falso Aneurisma , Mucopolissacaridose II , Dissecação da Artéria Vertebral , Insuficiência Vertebrobasilar , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/cirurgia , Insuficiência Vertebrobasilar/complicações , Insuficiência Vertebrobasilar/diagnóstico por imagem , Mucopolissacaridose II/complicações , Mucopolissacaridose II/patologia , Falso Aneurisma/complicações , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/cirurgia , SíndromeRESUMO
We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko's lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or "pebbling" of the skin that are observed in MPS II.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Masculino , Humanos , Criança , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/genética , Iduronato Sulfatase/genética , Pele , Mutação de Sentido Incorreto , EsplenomegaliaRESUMO
PURPOSE: Intrathecal (IT) idursulfase-IT for the treatment of cognitive impairment is being investigated in pediatric patients with neuronopathic mucopolysaccharidosis II (MPS II) in addition to intravenous idursulfase. In this article, we report the findings for 54 months of idursulfase-IT treatment in an ongoing phase I/II extension trial (NCT01506141). METHODS: A total of 15 male participants with neuronopathic MPS II (aged 3-11 years at enrollment) who were previously treated with intravenous idursulfase entered the extension study. Idursulfase-IT 10 mg or 30 mg was administered monthly via an IT drug delivery device or lumbar puncture, if indicated. The primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics, cerebrospinal fluid glycosaminoglycan levels, and cognitive function. RESULTS: In total, 15 participants received a median (range) of 50 (18-55) idursulfase-IT doses. Idursulfase-IT was generally well tolerated; there were no life-threatening adverse events (AEs) or deaths. Most serious AEs were related to the IT drug delivery device; only 2 serious AEs were related solely to idursulfase-IT. After treatment with idursulfase-IT, cerebrospinal fluid glycosaminoglycans were decreased in all participants; these decreases were maintained. Cognitive function was stabilized in 3 of 4 testable participants at month 55. CONCLUSION: These long-term results support the clinical development of idursulfase-IT for patients with MPS II with cognitive impairment.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Criança , Terapia de Reposição de Enzimas/métodos , Glicosaminoglicanos , Humanos , Iduronato Sulfatase/farmacocinética , Iduronato Sulfatase/uso terapêutico , Masculino , Mucopolissacaridose II/tratamento farmacológicoRESUMO
Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Quimioterapia Combinada , Humanos , Mucopolissacaridose II/diagnóstico , Resultado do TratamentoRESUMO
In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Terapia de Reposição de Enzimas/métodos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Brasil/epidemiologia , Criança , Quimioterapia Combinada , Feminino , Humanos , Masculino , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose II/genética , Mucopolissacaridose II/patologia , Receptores da Transferrina/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Bow Hunter's syndrome is a rare cause of posterior circulation ischemia, produced by the mechanical and reversible occlusion of the vertebral artery during cephalic rotation. Diagnosis requires clinical suspicion and careful inspection of images with three-dimensional reconstruction. The study of choice is dynamic digital subtraction angiography (DSA). Treatment alternatives are: medical, surgical or endovascular. We report the case of an 8-year-old boy with recurrent infarctions of the posterior circulation secondary to the dissection of the vertebral artery, in association with an occipital bone spur. Dynamic DSA was negative. Conservative initial management was elected with cervical immobilization and anticoagulation, but due to persistence of symptoms, surgical decompression was decided. The patient did not repeat symptoms postoperatively and returned to his usual life. This is the first case reported to our knowledge of a surgical pediatric patient with asymptomatic atypical compression of VA secondary to BHS, whose dynamic angiography was negative, suggesting an alternative mechanism of the syndrome.
Assuntos
Mucopolissacaridose II , Insuficiência Vertebrobasilar , Masculino , Humanos , Criança , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/etiologia , Insuficiência Vertebrobasilar/cirurgia , Mucopolissacaridose II/complicações , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/cirurgia , Descompressão Cirúrgica/métodos , Angiografia DigitalRESUMO
Bow hunter's syndrome is the mechanical compression of the vertebral artery due to cervical rotation, resulting in ischemic symptoms in the vertebrobasilar artery territory. However, some cases present without typical symptoms and exhibit compression of the non-dominant side of the vertebral artery. We encountered a case of posterior circulation embolism due to a subtype of bow hunter's syndrome in a 74-year-old man. Although the right vertebral artery was not visualized on time-of-flight magnetic resonance angiography in the neutral position, duplex ultrasonography and time-of-flight magnetic resonance angiography in the left cervical rotation position showed blood flow in the right vertebral artery. In this case, blood flow in the contralateral vertebral artery was normal, and typical bow hunter's syndrome symptoms did not occur. In a case of posterior circulation embolism with undetermined etiology, wherein the routine duplex ultrasonography and time-of-flight magnetic resonance angiography results were inconclusive, additional testing with head positioning led to the diagnosis of a subtype of bow hunter's syndrome.
Assuntos
Embolia , Mucopolissacaridose II , Idoso , Embolia/diagnóstico , Humanos , Masculino , Mucopolissacaridose II/complicaçõesRESUMO
Background: Mucopolysaccharidoses (MPS) are rare, metabolic lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs). We report a case that was discovered to be Mucopolysaccharidosis Type II and was presented to the hospital with signs and symptoms of congenital diaphragmatic hernia. The hernia was repaired, and the patient was discharged on BiPAP and High-flow Oxygen. Case Presentation: A vaginally delivered male child was presented to the hospital with a fever, cough, and shortness of breath. He has a history of recurrent chest infections treated as pneumonia. The child was born to a mother with a pregnancy complicated with gestational diabetes and the presence of polyhydramnios. Screening tests during the pregnancy reported no congenital anomalies. The patient was admitted, and a chest X-ray was performed and revealed cardiomegaly, pulmonary infiltrates consistent with pneumonia and bowel herniation noted through the right hemidiaphragm. A Computed Tomography (CT) scan of the thorax and Barium swallow was done, and Pneumonia and Congenital diaphragmatic hernia was confirmed. Genetic testing was done because the patient has coarse facial features, developmental delay, hypotonia and skeletal abnormalities. Iduronate-2-sulfatase enzyme levels were significantly low, all the other enzymes were normal in range, and the diagnosis of Type II Mucopolysaccharidosis was established. The patient was stabilized and operated on for diaphragmatic hernia repair. No enzyme-replacement therapy (ERT) was given because it is not available in Jordan. He was discharged on high-flow Oxygen and bilevel positive airway pressure (BiPAP). Conclusion: Depending on the typical presentation to suspect Mucopolysaccharidosis is not always the key to diagnose it. MPS is a multi-organ disorder and rare presentations should not be disregarded.
RESUMO
Mucopolysaccharidoses are a group of rare lysosomal accumulation diseases caused by a deficiency of the lysosomal enzyme and the accumulation of mucopolysaccharides in various organs and tissues. Children with mucopolysaccharidosis type II (Hunter syndrome) develop multisystem dysfunction, including severe airway obstruction. At the same time, 34% of patients already at an early age (2-3 years) undergo surgical manipulations related to ENT organs (tonsillectomy, adenotomy). The article describes a clinical case of diagnosis of type II mucopolysaccharidosis by a pediatric otorhinolaryngologist. The main manifestations of the disease are discussed in detail, including the presence of indications for adenotomy at the age of 2 years, episodes of otitis media, which served as diagnostic markers for suspected orphan disease mucopolysaccharidosis type II. The leading role of the pediatric otorhinolaryngologist in the early diagnosis of the rare disease mucopolysaccharidosis type II is substantiated.
Assuntos
Mucopolissacaridose II , Otite Média , Criança , Pré-Escolar , Glicosaminoglicanos , Humanos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/cirurgiaRESUMO
Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.