Caso familiar com diagnóstico para doença de Fabry / Familiar case with diagnostics for Fabry disease

A doença de Fabry é uma enfermidade genética ligada ao cromossomoX e de caráter progressivo, causada pela deficiênciaparcial ou total da enzima alfa galactosidase A (?-Gal A). Habitualmenteo diagnóstico é tardio em função das complicaçõespatológicas provocadas pela deficiência da enzima. OBJETIVO:Neste estudo, descrevemos os aspectos clínicos de um caso familiaratravés do acompanhamento ao longo de 3 anos, duranteo tratamentopela reposição enzimática. MÉTODOS: O métodoadotado foi indutivo, relacionado ao estudo de caso familiarde pacientes com doença de Fabry. Quanto à natureza das informações,a pesquisafoi qualitativa, utilizando-se, quanto aoseu objetivo, à pesquisa exploratória. Com relação as fonte deinformação e procedimento de coleta, a pesquisa caracteriza-secomo sendo bibliográfica e documental. A amostra foi compostapor três pacientesque realizamacompanhamento quinzenalpara aplicação de terapia de reposição enzimática. O critério deinclusão para a pesquisa partiu do pressuposto de se considerarque a doença de Fabry é uma afecção rara e que a família estudadacontempla com riqueza manifestações clínicas, capazesde caracterizar a doença de Fabry. RESULTADOS: Os principaissintomas clínicos relatados pelos pacientes foram: crisede dor generalizada, fadiga, acroparestesia, febre, mialgia, dorabdominal, hipohidrose, intolerância ao frio, calor e ao exercíciofísico. Esses sintomas segundo os pacientes surgiram nainfância e foram amenizados após o uso da terapia de reposiçãoenzimática, propiciando uma melhor qualidade de vida para osmesmos. Também, se observou sinais específicos desta patologianos pacientes, como córnea verticillata e angioqueratoma. Atravésda genotipagem se verificou a semelhança da mutação entre os pacientes do estudo, demonstrando padrão típico de herançarecessiva ligada ao cromossomo X. CONCLUSÃO: Os pacientesdeste estudo apresentaram quadro clínico semelhante,sendoque a sintomatologia iniciou na infância. Córnea verticillata eangioqueratoma umbilical foram sinais encontrados nos pacientes do sexo masculino e são considerados manifestações clínicas frequentes desta patologia. A herança encontrada nesta amostra tem um padrão típico de herança recessiva ligada ao cromossomo X. Desta forma, apesar de ser uma afecção rara na população em geral, o diagnóstico precoce e a terapia de reposição enzimática permitem a evolução clínica favorável e a melhoria da qualidade de vida do paciente.(AU)

Fabry disease is a genetic disorder linked to the X chromosomeand progressive, caused by partial or total deficiency of alphagalactosidase A (?-Gal A). Usually the diagnosis is delayed dueto the pathological complications caused by deficiency of theenzyme. OBJECTIVE: In this study, we describe the clinicalaspects of a family case by monitoring for over three years,during the treatment by enzyme replacement. METHODS:The method adopted was inductive, related to the study of afamily case with patients with Fabry disease. About the nature ofthe information, the research was qualitative, using, as its goal,the exploratory research. Regarding the source of informationand collection procedure, the research is characterized asbibliographical and documentary. The sample was composed ofthree patients submitted to biweekly monitoring for applicationof enzyme replacement therapy. The inclusion criterion forthe research assumed to consider that Fabry disease is a raredisease and that the studied family contemplates with wealththe clinical manifestations, able to characterize the Fabrydisease. RESULTS: The main clinical symptoms related bypatients were: generalized pain crisis, fatigue, acroparesthesia,fever, myalgia, abdominal pain, hypohidrosis, intolerance tocold, heat and exercise. These symptoms according to patientsemerged in childhood and were alleviated after the use ofenzyme replacement therapy, providing a better quality of lifefor them. Also, we found specific signs of this disease in patients,as verticillata cornea and angiokeratoma. By genotyping, it wasfound the similarity of the mutation among patients in thestudy, showing typical pattern of recessive inheritance linkedto chromosome X. CONCLUSION: The patients in this study showed similar clinical condition, and the symptoms began inchildhood. Verticillata cornea and umbilical angiokeratomasigns were found in male patients and are considered commonclinical manifestations of this pathology. The heritage found inthis sample has a typical pattern of recessive inheritance linkedto chromosome X. Thus, despite being a rare disease in generalpopulation, early diagnosis and enzyme replacement therapyallow favorable clinical evolution and improved patient qualityof life.(AU)

[Variability in the clinical presentation of Pompe disease: development following enzyme replacement therapy]. / Variabilidad en la presentación clínica en la enfermedad de Pompe: evolución tras terapia de reemplazo enzimático.

INTRODUCTION: Pompe disease is a generalized progressive disease caused by a deficiency of the lysosome enzyme acid alpha-glucosidase (GAA). We present three cases with different clinical symptomatology and treated with enzyme replacement therapy (ERT) with positive evolution. CASE REPORTS: Case 1: three-month old male, with weakness and rejecting meals; mild hepatomegaly, discrete macroglossia and muscular hypotony; and increased muscular enzymes. Case 2: five-month old male, with delayed motor development, severe neurosensory deafness, and respiratory disorder of difficult evolution; muscular hypotony; and mild increase in creatine kinase. Case 3: 22-year old male, with progressive dyspnea, with history of increased creatine kinase and transaminases, and hypercholesterolemia. He suffered from severe respiratory failure requiring endotraqueal intubation Muscular biopsy showed glycogen storage suggestive of Pompe disease. In the three cases, the EMG showed a characteristic pattern with pseudomyotonic discharges and the deficiency in GAA was confirmed in lymphocytes. One single mutation was observed in one case and two in the other two cases. Every patient received ERT showing a favorable evolution; with disappearance of cardiac disorders in case 1, improvement in motor development in both infants and no longer need for mechanical ventilation in case 3. CONCLUSION: Pompe disease has a wide variability in clinical expression. ERT achieves a good response, especially in infant forms of the disease. The survival of treated patients with these Pompe disease forms will allow knowing further the course of the disease.

TITLE: Variabilidad en la presentacion clinica en la enfermedad de Pompe: evolucion tras terapia de reemplazo enzimatico.Introduccion. La enfermedad de Pompe es un trastorno generalizado progresivo producido por el deficit de la enzima alfa-glucosidasa acida (AGA) de los lisosomas. Se presentan tres casos manifestados de forma muy diferente y tratados con terapia enzimatica sustitutiva (TES), con evolucion favorable. Casos clinicos. Caso 1: varon de 3 meses, con debilidad y rechazo de la alimentacion, hepatomegalia leve, ligera macroglosia e hipotonia, y aumento de las enzimas musculares. Caso 2: varon de 5 meses, con retraso del desarrollo motor, sordera neurosensorial grave, trastornos respiratorios de repeticion de evolucion torpida, hipotonia y leve elevacion de la creatincinasa. Caso 3: varon de 22 años con disnea progresiva, con antecedentes de elevacion de la creatincinasa y las transaminasas, e hipercolesterolemia. Sufrio insuficiencia respiratoria grave que preciso intubacion endotraqueal. La biopsia muscular presento depositos de glucogeno sugestivos de la enfermedad. En los tres casos, el estudio electromiografico dio un patron caracteristico, con descargas pseudomiotonicas, y se confirmo el deficit de AGA en los linfocitos. Se encontro una mutacion en un caso y dos mutaciones en los otros dos. Todos recibieron TES con evolucion favorable: desaparicion de las alteraciones cardiacas en el caso 1, mejoria en los hitos motores en los dos casos infantiles y retirada del respirador en el caso 3. Conclusion. La enfermedad de Pompe tiene una amplia variabilidad en la expresion clinica. La TES consigue una buena respuesta, especialmente en las formas infantiles. La supervivencia a largo plazo de las formas infantiles tratadas permitira conocer mas aspectos del curso de la enfermedad.

The role of antibodies in enzyme treatments and therapeutic strategies.

Substitution of the defective lysosomal enzyme in lysosomal storage disorders (LSDs) often elicits antibody formation towards the infused protein. Aside from Gaucher disease, antibodies often lead to infusion associated reactions and a reduced biochemical response. In Pompe disease, antibody titer is predictive of clinical outcome, but this is less apparent in other LSDs and warrants further study. Few laboratories are capable of enzyme-antibody determination: often physicians need to rely on the enzyme manufacturer for analysis. Currently, laboratories employ different antibody assays which hamper comparisons between cohorts or treatment regimens. Assay standardisation, including measurement of antibody-related enzyme inhibition, is therefore urgently needed. Successful immunomodulation has been reported in Pompe and in Gaucher disease, with variable success. Immunomodulation regimens that contain temporary depletion of B-cells (anti-CD20) are most used. Bone marrow transplantation in MPS-I results in disappearance of antibodies. No other clinical studies have been conducted in humans with immunomodulation in other LSDs.

BAFF blockade prevents anti-drug antibody formation in a mouse model of Pompe disease.

Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid α-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in association with enzyme replacement therapy using recombinant human GAA in Gaa(-/-) mice. BAFF blockade delayed antibody production and increased GAA activity within tissues with protection from anaphylaxis. Anti-BAFF also resolved antibody formation during an immune response and precluded the maturation of antibody secreting cells from entering the bone marrow compartment. This treatment modality may therefore be a viable alternative for the clinical management of antibody formation for Pompe disease and has potential use against antibody formation in other protein replacement therapies.

[Variability in the clinical presentation of Pompe disease in infancy: two case reports and response to treatment with human recombinant enzyme]. / Variabilidad en la presentacion clinica de la enfermedad de Pompe infantil: presentacion de dos casos y respuesta al tratamiento con enzima recombinante humana.

INTRODUCTION: Pompe disease/glycogen storage disease type II is a congenital metabolic disorder. It is an autosomal recessive disease where there is a deficiency of acid alpha-glucosidase (GAA), an enzyme required for lysosomal glycogen degradation. We describe two infantile onset cases with heterogeneous presentations. CASE REPORTS: The first case is a newborn with maintained bradycardia, a cardiologic study revealed severe biventricular hypertrophy. The second case is a 14 months old patient with motor delay and arreflexic hypotonia. Creatine kinase, lactate dehydrogenase, glutamic-oxaloacetic transaminase and glutamic-pyruvic trans aminase were high. The electromyogram showed myopathic alteration and the muscle biopsy vacuolar myopathy with glycogen accumulation. In both of them, GAA activity was decreased and the genetic exam of the GAA gene revealed heterozygous mutations already described in Pompe disease. They started enzyme replacement therapy at 1 month old and 18 months old respectively, improving the cardiomyopathy hypertrophy, motor wise however less advance was seen. At the present time, the patients are 9 months and 5 years old respectively, the last one has a Gross Motor Function Measure (GMFM) III level. CONCLUSION: GAA is the only authorized option for Pompe disease treatment; the effects observed are similar to the ones described in the literature, with excellent outcome in the hypertrophic cardiomyopathy but less effective in the skeletal muscle.

TITLE: Variabilidad en la presentacion clinica de la enfermedad de Pompe infantil: presentacion de dos casos y respuesta al tratamiento con enzima recombinante humana.Introduccion. La enfermedad de Pompe o glucogenosis tipo II es un error innato del metabolismo, de herencia autosomica recesiva, causado por un deficit de la enzima lisosomal alfa-glucosidasa acida (GAA), que ocasiona un acumulo multisistemico de glucogeno. Describimos dos casos de inicio temprano (infantil) con diferentes formas de presentacion. Casos clinicos. El primer caso se trata de un neonato que presento una bradicardia mantenida desde el nacimiento, lo que motivo el estudio cardiologico, en el que se evidencio una hipertrofia biventricular grave. El segundo caso se trata de un niño de 14 meses con retraso motor e hipotonia con arreflexia. En la analitica destacaban una creatincinasa, lactato deshidrogenasa, transaminasa glutamico oxalacetica y transaminasa glutamico piruvica elevadas. El electromiograma mostro signos de afectacion miopatica, y la biopsia muscular, una miopatia vacuolar con deposito de glucogeno. En ambos, la actividad de la GAA estaba disminuida y el analisis genetico del gen GAA evidencio que eran portadores heterocigotos de mutaciones descritas en la enfermedad de Pompe. Iniciaron tratamiento con enzima recombinante humana al mes y a los 18 meses de vida, respectivamente, con mejoria evidente de la miocardiopatia hipertrofica, aunque mas limitada a nivel motor. En la actualidad tienen, respectivamente, 9 meses y 5 años, y este ultimo presenta un nivel III de la escala GMFM (Gross Motor Function Measure). Conclusion. La GAA recombinante humana es la unica opcion terapeutica autorizada para estos pacientes. Los efectos que hemos observado son similares a los descritos en otros casos, con una excelente evolucion de la miocardiopatia hipertrofica y un efecto variable sobre la musculatura esqueletica.

Gingival overgrowth in Pompe disease: a case report.

Pompe disease, or glycogen storage disease type 2, is a rare inheritable metabolic disease caused by a deficiency of the lysosomal enzyme acid α-glucosidase. Patients with the classic infantile form of Pompe disease present with symptoms during the first 3 months after birth, and most will die within their first year. Recently, enzyme replacement therapy (ERT) with recombinant human α-glucosidase became commercially available for Pompe disease. This is a case report of an 8-year-old girl with the infantile form of Pompe disease who is one of the longest survivors through ERT. The patient was tetraplegic when she started ERT. At age 3 years, she developed massive gingival overgrowth and could not close her mouth, prompting a reduction of the gingival overgrowth surgically. We expected that massive accumulation of glycogen would explain the gingival overgrowth. However, histopathology of the gingiva tissue showed marked glycogen accumulation in smooth muscle cells of the arteries, but the glycogen content in fibroblasts did not exceed that of control individuals. Further, there was an increase of immature collagen in the connective tissue, and signs of a mild chronic inflammation. We concluded that glycogen storage is not a direct causative factor of gingival overgrowth in our patient. Chronic inflammation, dryness of the gingiva, or even the minimal glycogen accumulation in the fibroblasts may have played a role.