Case series of patients under biweekly treatment with laronidase: a report of a single center experience / Série de casos de pacientes em tratamento com laronidase quinzenal: relato da experiência de um centro

ABSTRACT Objective: To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of laronidase of 1.2 mg/kg every other week. Methods: We participated in a dose-optimization trial for laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. Results: Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event. Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.

RESUMO Objetivo: Descrever a manutenção dos níveis de glicosaminoglicano (GAG) excretados na urina e da estabilização clínica em pacientes com mucopolissacaridose do tipo I (MPS I) com o uso da laronidase num regime de dose alternativo de 1,2 mg/kg a cada duas semanas. Método: Alguns pacientes do nosso serviço participaram de um estudo de otimização de dose da laronidase para o tratamento da MPS I no qual foram comparados quatro esquemas terapêuticos: 0,58 mg/kg/semana, 1,2 mg/kg a cada duas semanas, 1,2 mg/kg/semana e 1,8 mg/kg a cada duas semanas. Após o término do estudo, todos os pacientes passaram a receber a terapia de reposição enzimática (TRE) na dose padrão de bula, que é de 0,58 mg/kg/semana, e nesse regime alguns pais se queixaram da dificuldade em comparecer ao centro todas as semanas, além da dificuldade de se obter acesso para punção venosa. Com base nessas queixas, oito pacientes passaram a receber a TRE no regime alternativo de 1,2 mg/kg a cada duas semanas. Foi feito o estudo retrospectivo de dados de prontuário de pacientes com MPS I que fizeram TRE com laronidase nas doses 0,58 mg/kg/semana e 1,2 mg/kg a cada duas semanas. Resultados: Os pacientes mantiveram-se clinicamente estáveis, não apresentaram aumento dos níveis de GAG urinários nem eventos adversos durante o regime alternativo de dose. Conclusões: A mudança para o esquema de 1,2 mg/kg de laronidase a cada duas semanas foi segura e não acarretou piora clínica nos pacientes que já estavam em TRE na dose padrão.

CASE SERIES OF PATIENTS UNDER BIWEEKLY TREATMENT WITH LARONIDASE: A REPORT OF A SINGLE CENTER EXPERIENCE.

OBJECTIVE: To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of laronidase of 1.2 mg/kg every other week. METHODS: We participated in a dose-optimization trial for laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. RESULTS: Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event.Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.

Oxidative stress assessment by glutathione peroxidase activity and glutathione levels in response to selenium supplementation in patients with Mucopolysaccharidosis I, II and VI.

We assessed levels of plasma selenium (Se), selenoproteins and their change after Se supplementation in patients with mucopolysaccharidosis (MPS) types I, II and VI. This was done in a retrospective study of the medical records of 30 patients with MPS I (n=13), MPS II (n=9) and MPS VI (n=8) who were being treated with enzyme replacement therapy. As part of routine nutritional monitoring, Se levels were measured, revealing that 28 patients (93.3%) had values below the normal range. Therefore, they received supplementation for 12 months, and Se was measured after 6 and 12 months. Glutathione peroxidase (GPx) activity, total glutathione (GSHt), oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured at baseline and 6 months after Se supplementation. The mean GSHt at baseline was 7.90 ± 2.36 µmol/g Hb, and after Se supplementation it was 5.76 ± 1.13 µmol/g Hb; GSH/GSSG was 2.3 ± 1.16 at baseline and 0.58 ± 0.38 after supplementation. GPx activity was 16.46 ± 3.31 U/g Hb at baseline and 4.53 ± 4.92 U/g Hb after Se supplementation. The difference was shown to be statistically significant by paired t-test. In conclusion, our study demonstrated that oxidative stress parameters were altered by Se supplementation in patients with MPS I, II and VI who were previously deficient in Se.

A New Mutation in IDS Gene Causing Hunter Syndrome: A Case Report.

RATIONALE: Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked multisystem disorder, caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The clinical manifestations of this disease are severe skeletal deformities, airway obstruction, cardiomyopathy, and neurologic deterioration. PATIENT: The patient was 5 years and 6 months boy, with developmental delay, hearing loss, hepatosplenomegaly, and skeletal dysplasia. He was diagnosed with mucopolysaccharidosis type II based on clinical manifestations, biochemical and genetic analysis. OUTCOMES: The patient carries a new mutation (c.879-1210_1007-218del) in hemizygosis in the IDS gene, which was defined as pathogenic according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and as responsible for the mucopolysaccharidosis type II phenotype in the patient.

Short stature as a presenting symptom of attenuated Mucopolysaccharidosis type I: case report and clinical insights.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) results in significant disease burden and early treatment is important for optimal outcomes. Recognition of short stature and growth failure as symptoms of MPS I among pediatric endocrinologists may lead to earlier diagnosis and treatment. CASE PRESENTATION: A male patient first began experiencing hip pain at 5 years of age and was referred to an endocrinologist for short stature at age 7. Clinical history included recurrent respiratory infections, sleep apnea, moderate joint contractures, mild facial dysmorphic features, scoliosis, and umbilical hernia. Height was more than - 2 SD below the median at all time points. Growth velocity was below the 3rd percentile. Treatment for short stature included leuprolide acetate and recombinant human growth hormone. The patient was diagnosed with MPS I and began enzyme replacement therapy with laronidase at age 18. CONCLUSIONS: The case study patient had many symptoms of MPS I yet remained undiagnosed for 11 years after presenting with short stature. The appropriate path to MPS I diagnosis when patients present with short stature and/or growth failure plus one or more of the common signs of attenuated disease is described. Improved awareness regarding association of short stature and growth failure with attenuated MPS I is needed since early identification and treatment significantly decreases disease burden.

Lysosomal Acid Lipase Deficiency: Report of Five Cases across the Age Spectrum.

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive lysosomal storage disorder caused by mutations in the LIPA gene that leads to premature organ damage and mortality. We present retrospective data from medical records of 5 Brazilian patients, showing the broad clinical spectrum of the disease.

Alternative laronidase dose regimen for patients with mucopolysaccharidosis I: a multinational, retrospective, chart review case series.

BACKGROUND: Enzyme replacement therapy (ERT) with laronidase (recombinant human α-L-iduronidase, Aldurazyme®) is indicated for non-neurological signs and symptoms of mucopolysaccharidosis type I (MPS I). The approved laronidase dose regimen is weekly infusions of 0.58mg/kg, however, patients and caregivers may have difficulty complying with the weekly regimen. We examined clinical outcomes, tolerability, compliance, and satisfaction in a series of patients who switched to every other week infusions. METHODS: This multinational, retrospective, chart review case series analyzed data from 20 patients who had undergone ERT with laronidase 0.58mg/kg weekly for more than one year, and who then switched to 1.2mg/kg every other week. RESULTS: The majority of patients had attenuated MPS I phenotypes (9 with Hurler-Scheie and 8 with Scheie syndromes) and 3 patients had severe MPS I (Hurler syndrome). Most patients presented with organomegaly (17/20), umbilical and/or inguinal hernia (16/20), cardiac abnormalities (17/20), musculoskeletal abnormalities (19/20), and neurological and/or developmental deficits (15/20). Following laronidase treatment, signs stabilized or improved. No deterioration or reversal of clinical outcome was noted in any patient who switched from the weekly dose of 0.58mg.kg to 1.2mg/kg every other week. There were no safety issues during the duration of every other week dosing. Patient compliance and satisfaction with the dosing regimen were greater with every other week dosing than weekly dosing. CONCLUSIONS: An alternative dose regimen of 1.2mg/kg laronidase every other week was well tolerated and clinically similar to the standard dose for patients who were stabilized with weekly 0.58 mg/kg for one year or more. When an individualized approach to laronidase therapy is necessary, every other week dosing may be an alternative for patients with difficulty receiving weekly infusions.

Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships.

BACKGROUND: Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. METHODS: This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. RESULTS: Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. CONCLUSIONS: These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.

Novel GAA mutations in patients with Pompe disease.

Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in the GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 13 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of the Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates.

Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: from our experience of 4 cases including an autopsy case.

We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM *606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condition at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family's permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hypertension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of specific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound cardiography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction.