RESUMO
BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of ß-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII. METHODS: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022. RESULTS: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died. CONCLUSIONS: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.
Assuntos
Terapia de Reposição de Enzimas , Glucuronidase , Mucopolissacaridose VII , Proteínas Recombinantes , Humanos , Mucopolissacaridose VII/tratamento farmacológico , Glucuronidase/uso terapêutico , Glucuronidase/metabolismo , Masculino , Pré-Escolar , Feminino , Criança , Terapia de Reposição de Enzimas/métodos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Lactente , Estudos Longitudinais , AdolescenteRESUMO
Abstract Isolated sulfite oxidase deficiency (ISOD) is a devastating, neurometabolic disorder caused by mutations in the SUOX gene necessary for the final step in the sulfur-containing amino acid catabolic pathway. Patients classically present in the neonatal period with neurologic manifestations. Biochemical findings include elevated sulfocysteine, low cystine and undetectable homocysteine with normal uric acid levels. Other associated biochemical markers include elevated plasma alpha-aminoadipic semialdehyde and piperideine-6-carboxylic acid. We report a patient with classic neonatal onset ISOD (refractory seizures, hypertonicity, brain abnormalities, pathogenic SUOX mutations). Her clinical course was marked by extreme irritability, prompting the use of a low methionine and cystine diet to decrease toxic metabolites thought to be contributing to her symptoms. Biochemical markers and extreme irritability improved with dietary treatment (methionine=30mg/kg/day). She died of sepsis in early infancy, precluding long term follow-up. This case reviews the potential benefits and limitations of diet therapy in this rare disorder.
RESUMO
OBJECTIVES: FG syndrome is an X-linked recessive mental retardation syndrome with ano-rectal anomalies, constipation, and occasional urinary incontinence. Because tethered spinal cord syndrome (TCS) has similar symptoms, we evaluated imaging for TCS in patients with FG syndrome. STUDY DESIGN: Patients were recruited from the International FG Syndrome Support Group, and an FG Syndrome Consensus Group reviewed clinical histories, medical records, and photographs of each responding patient. Results of cranial and spinal imaging studies were available for 12 patients. RESULTS: Of 12 boys with FG syndrome, 6 had hypoplasia of the corpus callosum, and 3 of these had TCS (all with constipation and urinary symptoms). The other 9 did not have urinary symptoms. After surgical untethering, bowel and bladder symptoms improved. CONCLUSIONS: Tethered spinal cord syndrome occurred in 25% of patients with FG syndrome associated with hypoplasia of the corpus callosum and causing bowel and bladder incontinence. A high index of suspicion is necessary for early diagnosis, and timely intervention results in significant improvement in symptomatology.
Assuntos
Canal Anal/anormalidades , Constipação Intestinal/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Defeitos do Tubo Neural/genética , Incontinência Urinária/genética , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Masculino , Fenótipo , SíndromeRESUMO
OBJECTIVES: To determine if infants of diabetic mothers (IDM) are at increased risk for dysplastic ears and the oculoauriculo-vertebral spectrum (OAVS). STUDY DESIGN: Cases of IDM with dysplastic external ears seen at Cedars-Sinai Medical Center were combined with case series in medical literature describing similar patients. Data from a large congenital birth defects registry in Spain were analyzed, and odds ratios (OR) for infants born to either a gestational or preconceptionally diabetic mother to have one of the studied malformations were calculated with 95% confidence intervals. RESULTS: Among the 30 patients in the case series, 50.0% (15) had hemifacial microsomia; 46.7% (14) had hearing loss; 33.3% (10) had facial nerve palsy; 33.3% (10) had vertebral anomalies; 36.7% (11) had cardiovascular defects, of which 45% (5) were conotruncal defects; 26.7% (8) had renal anomalies; 13.3% (4) had limb defects (all radial ray hypoplasia); 10% (3) had DiGeorge sequence; 6.7% (2) had laterality defects; and 6.7% (2) had imperforate anus. Within the cases from the birth defects registry, the odds ratio for OAVS in infants of mothers with gestational diabetes mellitus was 2.28 (95% CI, 1.03-4.82, P =.03), and the OR for ear anomalies in these infants was 1.21 (95% CI, 0.94-1.56, P =.13). When infants of mothers with preconceptionally diagnosed type 1 or 2 diabetes were considered, the OR for OAVS was 1.50 (95% CI, 0.08-9.99, P =.49), and the OR for dysplastic ears was 0.94 (95% CI, 0.48-1.81, P =.85). CONCLUSIONS: Our data indicate that OAVS occurs with a higher incidence in IDM than in the general population. Associated problems include hearing loss, athymia, and cardiac, renal, and limb malformations. Therefore, we recommend that an IDM with features consistent with OAVS undergo a workup including hearing evaluation, skeletal survey, echocardiogram, renal ultrasonogram, and immunodeficiency workup if clinically indicated. Furthermore, noting that most of these defects occur in structures of neural crest origin, we hypothesize that poorly controlled maternal diabetes interferes with cephalic neural crest cell migration.