RESUMO
The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1-6.0 points) in all the IQ index scores (p < 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood-brain barrier in order to treat this CNS phenotype.
Assuntos
Encéfalo , Cognição , Doença de Depósito de Glicogênio Tipo II , Imageamento por Ressonância Magnética , Humanos , Masculino , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/patologia , Feminino , Lactente , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Pré-Escolar , Adolescente , Criança , Estudos Longitudinais , Adulto Jovem , Progressão da Doença , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Terapia de Reposição de Enzimas , AdultoRESUMO
BACKGROUND: Though enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome. METHODS: Eight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated. RESULTS: All eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3-5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation. CONCLUSIONS: Our data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.
Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Criança , Pré-Escolar , Reações Cruzadas/fisiologia , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Resultado do Tratamento , Ventiladores MecânicosRESUMO
Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome. In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO(2) in 17 children and 75 adults with Pompe disease (mean age 42.7 years, range 5-76 years). Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness. Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p<0.001), they used mechanical ventilation more often than females (p=0.042) and the decline over the course of the disease was significantly different between males and females (p=0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6 years, range 0.5-4.2 years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p=0.09), VC in supine position of 1.2% points (p=0.049), MIP of 3.2% points (p=0.018) and MEP of 3.8% points (p<0.01). We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk.
Assuntos
Progressão da Doença , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Pulmão/fisiopatologia , Adolescente , Adulto , Idoso , Capnografia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Prognóstico , Espirometria , Decúbito Dorsal , Resultado do Tratamento , Capacidade Vital/fisiologia , Adulto JovemRESUMO
Pompe disease is a rare inherited metabolic and neuromuscular disorder, presenting as a spectrum, with the classic infantile form on one end and the more slowly progressive non-classic form on the other end. While being a hallmark in classic infantile Pompe disease, cardiac involvement in non-classic Pompe disease seems rare. Vascular abnormalities, such as aneurysms and arterial dolichoectasia, likely caused by glycogen accumulation in arterial walls, have been reported in non-classic Pompe patients. With this first systematic review on cardiovascular disease in non-classic Pompe disease, we aim to gain insight in the prevalence and etiology of cardiovascular disease in these patients. Forty-eight studies (eight case-control studies, 15 cohort studies and 25 case reports/series) were included. Fourteen studies reported cardiac findings, 25 studies described vascular findings, and nine studies reported both cardiac and vascular findings. Severe cardiac involvement in non-classic Pompe disease patients has rarely been reported, particularly in adult-onset patients carrying the common IVS1 mutation. There are indications that intracranial dolichoectasia and aneurysms are more prevalent in non-classic Pompe patients compared to the general population. To further investigate the prevalence of cardiovascular disease in non-classic Pompe patients, larger case-control studies that also study established cardiovascular risk factors should be conducted.
Assuntos
Doenças Cardiovasculares/complicações , Doença de Depósito de Glicogênio Tipo II/complicações , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Enzyme replacement therapy for Pompe disease received market authorization in 2006. To implement this costly treatment in the Netherlands in the most sensible way, a multidisciplinary expert committee was installed. We evaluated decision making in adult patients in relation to the European POmpe Consortium stop criteria. Of 125 adult Pompe patients, 111 started treatment; subsequently treatment stopped in 24 patients (21%). In 10 patients, treatment was discontinued for medical or personal reasons, as defined in the six stop criteria (median treatment duration: 2.1 years, range: 0.3-14.6 years). Three of these patients continued follow-up (follow-up: 1.3-8.0 years), these patients did not display a more rapid decline after discontinuation. In 14 of 24 patients, therapy ended at time of death. In 10 patients death was related to Pompe disease (median treatment duration: 7.2 years, range: 0.4-10.3 years). All 10 patients were severely affected at start of treatment, treatment had elicited positive effects in eight. The European POmpe Consortium guidelines worked well in decision making on stopping treatment. However, (re)evaluation of the rationale for continuation of treatment in advanced disease stage is not addressed. We suggest to add this to the treatment evaluation and to handle treatment decisions in a multidisciplinary expert team.
Assuntos
Tomada de Decisão Clínica , Terapia de Reposição de Enzimas/normas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Avaliação de Processos e Resultados em Cuidados de Saúde , Guias de Prática Clínica como Assunto/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos ProspectivosRESUMO
BACKGROUND: Enzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT. METHODS: In this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head). RESULTS: Median age at start of ERT was 3.2 months (0.1-5.8 months), median age at study end was 5.6 years (2.9-18.2 years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit. CONCLUSIONS: We found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Debilidade Muscular , Animais , Criança , Estudos de Coortes , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , Coelhos , Resultado do Tratamento , alfa-Glucosidases/uso terapêuticoRESUMO
To determine the rate of disease progression in patients with late-onset Pompe disease, we collected longitudinal data on pulmonary function and skeletal muscle strength in 16 patients whose symptoms had started in childhood or adulthood. The mean duration of follow-up was 16 years (range 4-29 years). During the follow-up period, eight patients (50%) became wheelchair bound and three (19%) became ventilator dependent. At a group level, pulmonary function deteriorated by 1.6% per year, and proximal muscle weakness progressed gradually. At the individual level, however, the rate and extent of progression varied highly between patients. In two thirds of patients, pulmonary function and muscle strength declined simultaneously and to the same extent. The remaining one third of patients showed a variable, sometimes rapidly progressive course, leading to early respirator or wheelchair dependency. These individual differences, especially in pulmonary dysfunction, indicate the need for regular monitoring every 6-12 months depending on the rate of disease progression.
Assuntos
Doença de Depósito de Glicogênio Tipo II/epidemiologia , Debilidade Muscular/epidemiologia , Paralisia Respiratória/epidemiologia , Atividades Cotidianas , Adulto , Idade de Início , Idoso , Comorbidade , Efeitos Psicossociais da Doença , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/normas , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Paralisia Respiratória/fisiopatologia , Fatores de Tempo , Ventiladores Mecânicos/estatística & dados numéricos , Cadeiras de Rodas/estatística & dados numéricosRESUMO
Enzyme analysis for Pompe disease in leukocytes has been greatly improved by the introduction of acarbose, a powerful inhibitor of interfering alpha-glucosidases, which are present in granulocytes but not in lymphocytes. Here we show that the application of acarbose in the enzymatic assay employing the artificial substrate 4-methylumbelliferyl-alpha-D: -glucoside (MU-alphaGlc) is insufficient to clearly distinguish patients from healthy individuals in all cases. Also, the ratios of the activities without/with acarbose only marginally discriminated Pompe patients and healthy individuals. By contrast, when the natural substrate glycogen is used, the activity in leukocytes from patients (n = 82) with Pompe disease is at most 17% of the lowest control value. The use of artificial substrate in an assay with isolated lymphocytes instead of total leukocytes is a poor alternative as blood samples older than one day invariably yield lymphocyte preparations that are contaminated with granulocytes. To diagnose Pompe disease in leukocytes we recommend the use of glycogen as substrate in the presence of acarbose. This assay unequivocally excludes Pompe disease. To also exclude pseudo-deficiency of acid alpha-glucosidase caused by the sequence change c.271G>A (p.D91N or GAA2; homozygosity in approximately 1:1000 caucasians), a second assay employing MU-alphaGlc substrate plus acarbose or DNA analysis is required.
Assuntos
Acarbose/metabolismo , Glucana 1,4-alfa-Glucosidase/análise , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Glicogênio/metabolismo , Leucócitos/enzimologia , Acarbose/farmacologia , Técnicas de Diagnóstico Neurológico , Glucana 1,4-alfa-Glucosidase/antagonistas & inibidores , Glucana 1,4-alfa-Glucosidase/metabolismo , Glicogênio/farmacologia , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Recém-Nascido , Leucócitos/patologia , Especificidade por SubstratoRESUMO
BACKGROUND: Glycogen storage disease type II or Pompe disease is a neuromuscular disorder caused by deficiency of lysosomal acid alpha- glucosidase. Classic infantile Pompe disease results in massive left ventricular (LV) hypertrophy and failure. Although Pompe disease is often included in the differential diagnosis of LV hypertrophy the true frequency of cardiac involvement in adults with Pompe disease is not known. METHODS: Forty-six consecutive adult patients (mean age 48 +/- 12, 22 men) with Pompe disease were included. Each patient underwent a clinical examination, electrocardiography, and rest and low-dose dobutamine (in 20 patients) two-dimensional echocardiography including contrast and tissue Doppler imaging. RESULTS: All patients had limited exercise tolerance; a rollator walking aid was used in seven patients (15%), a wheelchair in 13 patients (28%), and assisted ventilation in 14 patients (30%). Prior to this study, one patient was known with permanent atrial fibrillation, His-bundle ablation and a VVI pacemaker and another patient was known with fluid retention. The first patient had increased LV end-diastolic diameter, impaired LV ejection fraction, low systolic mitral annular velocities and diastolic dysfunction grade II. The patient with fluid retention was wheelchair bound and dependent on 24-h assisted ventilation and showed right ventricular and LV hypertrophy (septum 16 mm, posterior wall 15 mm). LV hypertrophy was not seen in any of the other patients. One woman of advanced age had isolated low systolic mitral annular velocities. Mean global systolic LV function, including contractile reserve, was not decreased in patients with Pompe disease. Eight patients (17%) had mild diastolic dysfunction grade I, related to hypertension in four and advanced age in seven. CONCLUSIONS: In adult patients with Pompe disease without objective signs of cardiac affection by 12-leads electrocardiography or physical examination, echocardiographic screening for LV hypertrophy seems not effective.
Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Cardiopatias/complicações , Adulto , Idoso , Estudos de Casos e Controles , Dobutamina , Ecocardiografia , Ecocardiografia Doppler de Pulso , Tolerância ao Exercício , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND AND OBJECTIVE: Pompe disease is an inherited metabolic disorder caused by deficiency of acid alpha-glucosidase. All affected neonates have a severe hypertrophic cardiomyopathy, leading to cardiac failure and death within the first year of life. We investigated the presence and extent of cardiac involvement in children and adults with Pompe disease with the common c.-32-13T>G genotype to determine the usefulness of cardiac screening in these patients with relatively 'milder' phenotypes. METHODS: Cardiac dimensions and function were evaluated through echocardiography, electrocardiography and Holter monitoring. The total group comprised 68 patients with Pompe disease, of whom 22 patients had disease onset before the age of 18. RESULTS: Two patients (3%) had cardiac abnormalities possibly related to Pompe disease: Electrocardiography showed a Wolff-Parkinson-White pattern in an 8-year-old girl, and one severely affected adult patient had a mild hypertrophic cardiomyopathy. This hypertrophy did not change during treatment with recombinant human alpha-glucosidase. In addition, four adult patients showed minor cardiac abnormalities which did not exceed the prevalence in the general population and were attributed to advanced age, hypertension or pre-existing cardiac pathology unrelated to Pompe disease. CONCLUSIONS: Cardiac involvement is rare in Pompe patients with the common c.-32-13T>G genotype. The younger patients were not more frequently affected than the adults. Electrocardiographic evaluation appears to be appropriate as initial screening tool. Extensive cardiac screening seems indicated only if the electrocardiogram is abnormal or the patient has a history of cardiac disease.
Assuntos
Glucana 1,4-alfa-Glucosidase/genética , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Cardiopatias/etiologia , Mutação/genética , Adulto , Fatores Etários , Idoso , Criança , Eletrocardiografia/métodos , Saúde da Família , Feminino , Genótipo , Cardiopatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia/métodosRESUMO
Respiratory muscle weakness frequently occurs in patients with neuromuscular disease. Measuring respiratory function with standard pulmonary function tests provides information about the contribution of all respiratory muscles, the lungs and airways. Imaging potentially enables the study of different respiratory muscles, including the diaphragm, separately. In this review, we provide an overview of imaging techniques used to study respiratory muscles in neuromuscular disease. We identified 26 studies which included a total of 573 patients with neuromuscular disease. Imaging of respiratory muscles was divided into static and dynamic techniques. Static techniques comprise chest radiography, B-mode (brightness mode) ultrasound, CT and MRI, and are used to assess the position and thickness of the diaphragm and the other respiratory muscles. Dynamic techniques include fluoroscopy, M-mode (motion mode) ultrasound and MRI, used to assess diaphragm motion in one or more directions. We discuss how these imaging techniques relate with spirometric values and whether these can be used to study the contribution of the different respiratory muscles in patients with neuromuscular disease.
Assuntos
Diafragma/diagnóstico por imagem , Doenças Neuromusculares/diagnóstico por imagem , Músculos Respiratórios/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , UltrassonografiaRESUMO
Pompe disease (glycogen storage disease type II, acid maltase deficiency) is a progressive metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase. This leads to an accumulation of glycogen in various tissues of the body, most notably in skeletal muscle. The disease has an autosomal recessive inheritance with a predicted frequency of 1 :40.000. Pompe disease is a continuous spectrum but for clinical practice different subtypes are recognized. The classic infantile form of the disease occurs in infants (shortly after birth) and is characterized by generalized hypotonia, failure to thrive, and cardiorespiratory failure. Patients usually die within the first year of life. The non-classic or late-onset form of the disease may occur at any age in childhood or adulthood. It presents predominantly as a slowly progressive proximal myopathy, with or without respiratory failure. Enzyme replacement therapy (ERT) is under study as treatment for the disease. The first results with recombinant human alpha-glucosidase are promising and a registered therapy seems near. Beneficial effects of ERT have been reported both in patients with the classic infantile form as well as in patients with the non-classic or late-onset form of the disease. The best therapeutic results are achieved when ERT is started early in the course of symptom development and before irreversible muscular damage has occurred. Detailed knowledge about the natural course of the disease becomes more and more essential to determine the indication and timing of treatment.
Assuntos
Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , alfa-Glucosidases/uso terapêutico , Animais , Glucana 1,4-alfa-Glucosidase/deficiência , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , alfa-Glucosidases/deficiênciaRESUMO
We constructed a patient-based interval scale using Rasch analysis, specifically suited to quantify the effects of Pompe disease on patient's ability to carry out daily life activities and their social participation: Rasch-built Pompe-specific Activity scale. Between July 2005 and April 2011, 186 patients aged 16 or older, participated to develop this scale. External construct validity was determined through correlations with the MRC sumscore and Rotterdam Handicap Scale. Furthermore, test-retest reliability was determined in a subgroup of 44 patients. Finally, individual person-level responsiveness was used to determine the proportion of patients demonstrating significant improvement or deterioration during their natural disease course, or during treatment with enzyme replacement therapy. Of the original 49 items, 31 were removed after investigation of model fit, internal reliability, threshold examination, item bias, and local dependency. The remaining 18 items were ordered on a linearly weighted scale and demonstrated good discriminative ability (Person Separation Index 0.96), external construct validity (intraclass correlation coefficient (ICC) for MRC sumscore 0.82, and for the Rotterdam handicap scale 0.86), reliability of person's location (ability comparison: ICC 0.95), and responsiveness. We therefore conclude that the R-PAct scale enables us to accurately detect limitations in activities and social participation throughout the entire disease spectrum in patients with Pompe disease.
Assuntos
Atividades Cotidianas , Avaliação da Deficiência , Doença de Depósito de Glicogênio Tipo II/psicologia , Comportamento Social , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Pompe disease is a rare neuromuscular disorder caused by deficiency of acid α-glucosidase. Treatment with recombinant human α-glucosidase recently received marketing approval based on prolonged survival of affected infants. The current open-label study was performed to evaluate the response in older children (age 5.9-15.2 years). The five patients that we studied had limb-girdle muscle weakness and three of them also had decreased pulmonary function in upright and supine position. They received 20-mg/kg recombinant human α-glucosidase every two weeks over a 3-year period. No infusion-associated reactions were observed. Pulmonary function remained stable (n = 4) or improved slightly (n = 1). Muscle strength increased. Only one patient approached the normal range. Patients obtained higher scores on the Quick Motor Function Test. None of the patients deteriorated. Follow-up data of two unmatched historical cohorts of adults and children with Pompe disease were used for comparison. They showed an average decline in pulmonary function of 1.6% and 5% per year. Data on muscle strength and function of untreated children were not available. Further studies are required.
Assuntos
Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/terapia , Músculo Esquelético/fisiopatologia , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid alpha-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T-->G is the most common mutation in adults. OBJECTIVE: To delineate the disease variation among patients with this mutation and to define the c.-32-13T-->G haplotypes in search for genotype-phenotype correlations. METHODS: We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T-->G mutation. RESULTS: All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid alpha-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T-->G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T-->G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T-->G encountered in the major GAA core haplotype (DRHGEIVT). CONCLUSION: Patients with the same c.-32-13T-->G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.