Sustained Immune Tolerance Induction in Enzyme Replacement Therapy-Treated CRIM-Negative Patients with Infantile Pompe Disease

BACKGROUND: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of /=51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values o

Acro-cardio-facial syndrome

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor

Missense variant contribution to USP9X-female syndrome

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.Lachlan A. Jolly … Alison E. Gardner, Mark A. Corbett, Luis A. Pérez-Jurado, Marie Shaw … Jozef Gec

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

Role of elosulfase alfa in mucopolysaccharidosis IVA

Debra S Regier, Pranoot Tanpaiboon Division of Genetics and Metabolism, Children’s National Medical Center, Washington, DC, USA Abstract: Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive lysosomal storage disease which results in a striking skeletal phenotype, but does not negatively impact the intellect of the patient. MPS IVA has a phenotypic continuum that ranges from a severe and rapidly progressing form to a slowly progressive form. The clinical diagnosis is often made in the preschool years based on abnormal bone findings on physical examination and dysplasia on radiographic imaging. Supportive care has been the mainstay in caring for patients. Orthopedic physicians often form the core of the care team due to the early and severe skeletal abnormalities; however, systemic disease is common and requires aggressive monitoring and management. Interdisciplinary care teams often consist of medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. With the US Food and Drug Administration’s approval of elosulfase alfa, patients >5 years of age now have access to this medication from the time of diagnosis. The clinical trial with once weekly intravenous dosing (2.0 mg/kg per week) showed improvement in the 6-minute walk test. The composite end point analysis to evaluate the combining changes from baseline in 6-minute walk test, 3-minute stair climb test, and respiratory function showed that at a dose of 2.0 mg/kg per week, subjects performed better when compared to placebo. This indication was clinically meaningful in the treatment group. The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Currently, clinical trials are underway to determine the efficacy and safety in MPS IVA patients <5 years of age. Keywords: mucopolysaccharidosis type IVA, elosulfase alfa, enzyme replacement therapy, Morquio syndrome, lysosomal storage disease, keratan sulfat

Role of elosulfase alfa in mucopolysaccharidosis IVA

Debra S Regier, Pranoot Tanpaiboon Division of Genetics and Metabolism, Children’s National Medical Center, Washington, DC, USA Abstract: Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive lysosomal storage disease which results in a striking skeletal phenotype, but does not negatively impact the intellect of the patient. MPS IVA has a phenotypic continuum that ranges from a severe and rapidly progressing form to a slowly progressive form. The clinical diagnosis is often made in the preschool years based on abnormal bone findings on physical examination and dysplasia on radiographic imaging. Supportive care has been the mainstay in caring for patients. Orthopedic physicians often form the core of the care team due to the early and severe skeletal abnormalities; however, systemic disease is common and requires aggressive monitoring and management. Interdisciplinary care teams often consist of medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. With the US Food and Drug Administration’s approval of elosulfase alfa, patients >5 years of age now have access to this medication from the time of diagnosis. The clinical trial with once weekly intravenous dosing (2.0 mg/kg per week) showed improvement in the 6-minute walk test. The composite end point analysis to evaluate the combining changes from baseline in 6-minute walk test, 3-minute stair climb test, and respiratory function showed that at a dose of 2.0 mg/kg per week, subjects performed better when compared to placebo. This indication was clinically meaningful in the treatment group. The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Currently, clinical trials are underway to determine the efficacy and safety in MPS IVA patients <5 years of age. Keywords: mucopolysaccharidosis type IVA, elosulfase alfa, enzyme replacement therapy, Morquio syndrome, lysosomal storage disease, keratan sulfat

Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects

BACKGROUND: Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model. METHODS: Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections. RESULTS: Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model. CONCLUSION: Our findings identify Slit-Robo as a significant pathway in human heart development and CHD