Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.

Clinical, neuroimaging, and genetic features of L-2-hydroxyglutaric aciduria in Arab kindreds.

BACKGROUND AND OBJECTIVES: L-2-hydroxyglutaric aciduria is a neurometabolic disorder with autosomal recessive mode of inheritance in which patients exhibit elevated L-2-hydroxyglutaric acid in body fluids, central nervous system manifestations, and increased risk of brain tumor formation. Mutations in L2HGDH gene have been described in L-2-hydroxyglutaric aciduria patients of different ethnicities. The present study was conducted to perform a detailed clinical, imaging and genetic analysis. DESIGN AND SETTINGS: A cross-sectional clinical genetic study of 16 L-2-hydroxyglutaric aciduria patients from 4 Arab consanguineous families examined at the metabolic clinic of the hospital. PATIENTS AND METHODS: Genomic DNA was isolated from the blood of 12 patients and 10 unaffected family members, and the L2HGDH gene was sequenced. DNA sequences were compared to the L2HGDH reference sequence from GenBank. RESULTS: All patients exhibit characteristic clinical, biochemical, and imaging features of L-2-hydroxyglutaric aciduria, and 4 patients exhibited increased incidence of brain tumors. The sequencing of the L2HGDH gene revealed the c.1015delA, c.1319C > A, and c.169G > A mutations in these patients. These mutations encode for the p.Arg339AspfsX351, p.Ser440Tyr, and p.Gly57Arg changes in the L2HGDH protein, respectively. The c.169G > A mutation, which was shown to have a common origin in Italian and Portuguese patients, was also discovered in Arab patients. Finding of the homozygous c.159T SNP associated with the c.169G > A mutation in Arab patients points to an independent origin of this mutation in Arab population. CONCLUSION: The detailed description of clinical manifestations and L2HGDH mutation in this study is useful for diagnosis of L-2-hydroxyglutaric aciduria in Arab patients. While reoccurrence of an L2HGDH mutation in L-2-hydroxyglutaric aciduria patients of different ethnicity is extremely rare, the c.169G mutation has an independent origin in Arab patients. It is likely that this mutation may also be present in patients of other ethnicities.

Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay.

Sodium leak channel, nonselective (NALCN) is a voltage-independent and cation-nonselective channel that is mainly responsible for the leaky sodium transport across neuronal membranes and controls neuronal excitability. Although NALCN variants have been conflictingly reported to be in linkage disequilibrium with schizophrenia and bipolar disorder, to our knowledge, no mutations have been reported to date for any inherited disorders. Using linkage, SNP-based homozygosity mapping, targeted sequencing, and confirmatory exome sequencing, we identified two mutations, one missense and one nonsense, in NALCN in two unrelated families. The mutations cause an autosomal-recessive syndrome characterized by subtle facial dysmorphism, variable degrees of hypotonia, speech impairment, chronic constipation, and intellectual disability. Furthermore, one of the families pursued preimplantation genetic diagnosis on the basis of the results from this study, and the mother recently delivered healthy twins, a boy and a girl, with no symptoms of hypotonia, which was present in all the affected children at birth. Hence, the two families we describe here represent instances of loss of function in human NALCN.

The development of genetic counseling services and training program in Saudi Arabia.

In 2005 the first Saudi genetic counseling training program was established by the Department of Medical Genetics at King Faisal Specialist Hospital and Research Center (KFSH&RC) in the Kingdom of Saudi Arabia. The program has graduated five genetic counselors with high diploma-level degree. This brief report describes the development of the genetic counseling training program and the factors that led to its establishment. Special emphasis is made to unique cultural practices including consanguinity, religious influence, and termination of pregnancy. This report also describes the current status of the genetic counseling services offered by KFSH&RC and availability of genetic testing.