Therapy for the mucopolysaccharidoses

Abstract Better understanding of disease pathophysiology, improved supportive care and availability of diseasespecific treatments for some of the mucopolysaccharidosis (MPS) disorders have greatly improved the outlook for patients with MPS disorders. Optimal management of these multisystemic disorders involves a multidisciplinary team and regular, comprehensive follow-up. Enzyme replacement therapy (ERT) is now available for MPS I (Hurler, HurlerScheie and Scheie syndromes) (laronidase), MPS II (Hunter syndrome) (idursulfase) and MPS VI MaroteauxLamy (galsulfase), and is in development for MPS IV (Morquio syndrome) and MPS VII (Sly syndrome). Benefits of ERT can include improved walking ability, improved respiration and enhanced quality of life. Haematopoietic stem cell transplantation (HSCT) can preserve cognition and prolong survival in very young children with the most severe form of MPS I, and is under investigation for several other MPS disorders. Better tissue matching techniques, improved graft-vs-host prophylaxis and more targeted conditioning regimens have improved morbidity and mortality associated with HSCT

Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable

Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias.

International audienceBACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 mumol/L versus 70 mumol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 mumol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 mumol/mmol of creatinine versus 34.6 mumol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 mumol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients

Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function : Update of 34 patients

BackgroundTransaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. MethodsWe performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. Results and conclusionsMost patients (n =22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype-phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.Peer reviewe

Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies.</p> <p>Methods</p> <p>A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus.</p> <p>Results</p> <p>Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT.</p> <p>Conclusions</p> <p>This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.</p

Glycogen Storage Disease Type Ia:Current Management Options, Burden and Unmet Needs

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.</p

LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

International audienceAutosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement ∆pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study.

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5&nbsp;years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0&nbsp;mg/kg/every other week (qow), elosulfase alfa 2.0&nbsp;mg/kg/week (weekly) or placebo for 24&nbsp;weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95&nbsp;% CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95&nbsp;% CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95&nbsp;% CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95&nbsp;% CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24&nbsp;weeks in both regimens. In the weekly dose group, 22.4&nbsp;% of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3&nbsp;% of all infusions in this group) over 6&nbsp;months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants

PurposeThe purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.MethodsInvestigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.ResultsRecords for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).ConclusionsThese data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458