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CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5–18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS. Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS. Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

The results of the International Collaborative Study of Maternal phenylketonuria have shown that dietary phenylalanine restriction of women with hyperphenylalaninemia during pregnancy decreases the incidence of mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation in their offspring. The best results are achieved when treatment is initiated before conception. Psychosocial problems are the most pervasive obstacle to the achievement of optimum dietary treatment. Novel, nondietary approaches to the treatment of maternal phenylketonuria are under development.

OBJECTIVES. The prevalence and identification of hypertriglyceridemia in youths will likely will increase in the future as a consequence of childhood obesity and increased screening for dyslipidemias. We sought to review our clinical experience with hypertriglyceridemia, evaluate factors associated with increased triglyceride levels, and review treatment options to provide guidance for management. METHODS. Clinical review of data for all patients who had ≥1 elevated triglyceride level (>4 mmol/L [>350 mg/dL]) while being monitored in a specialized lipid disorders clinic was performed. RESULTS. The study population consisted of 76 patients with 761 clinic visits. Hypertriglyceridemia was secondary to lifestyle factors for 13 patients. The rest had primary hypertriglyceridemia, with 32 patients having familial combined hypertriglyceridemia and hypercholesterolemia (type II), 25 patients having primary hypertriglyceridemia (type IV), 4 patients having familial lipase deficiency (type I), and 2 patients having hyperlipoproteinemia E2/E2 phenotype (type III). Triglyceride levels were highest in type I and III hypertriglyceridemia (>10 mmol/L [>900 mg/dL]), followed by type IV and adiposity-related hypertriglyceridemia (>4 mmol/L [>350 mg/dL]) and finally type II familial combined hypertriglyceridemia and hypercholesterolemia (>2 mmol/L [>180 mg/dL]). A total of 34 patients received 37 trials of drug therapy as part of triglyceride level management (bile acid–binding resins, n = 12; fibrates, n = 19; statins, n = 6). Triglyceride levels were found to decrease over time with the use of fibrates, to increase with the use of bile acid–binding resins, and not to change with the use of statins. CONCLUSIONS. Lifestyle modifications remain the primary therapeutic avenue for the management of pediatric hypertriglyceridemia. We propose an algorithm for the management of this heterogeneous population to guide clinicians in their treatment decisions.

Juvenile gm2 gangliosidosis (jGM2), also called subacute GM2 gangliosidosis (Online Mendelian Inheritance in Man [OMIM] No. 230700), is a rare and heterogeneous autosomal recessive disorder characterized by progressive neurologic deterioration that mainly affects motor and spinocerebellar function. It is a lysosomal storage disease caused by deficiency of β-hexosaminidase A, combined deficiency of β-hexosaminidases A and B, or deficiency of the noncatalytic GM2 activator. The enzyme β-hexosaminidase is comprised of 2 major isoenzymes, β-hexosaminidase A and β-hexosaminidase B. β-Hexosaminidase A is made up of 2 nonidentical subunits, α and β, that are encoded by the genes HEXA (15q23-q24) and HEXB (5q13), respectively, which are associated into the heterodimeric isoenzyme. It catalyzes the removal of the β-N-acetylgalactosamine residue from the nonreducing terminal of the oligosaccharide of GM2 ganglioside. β-Hexosaminidase B comprises 2 identical β subunits (β2). It does not catalyze the degradation of GM2 ganglioside. Mutations of the HEXA gene encoding the α subunit cause deficiency of the β-hexosaminidase A and result in the well-known form of GM2 gangliosidosis called Tay-Sachs disease (OMIM No. 272800). Mutations of the HEXB gene, encoding the β-subunit, cause deficiency of both enzymes (β-hexosaminidase A and β-hexosaminidase B), leading to Sandhoff disease (OMIM No. 268800), which is, in clinical aspects, virtually indistinguishable from Tay-Sachs disease. Deficiency of the GM2 activator protein, which mediates the interaction between the water-soluble β-hexosaminidase A and its membrane-embedded substrate, GM2 ganglioside, causes the AB variant of GM2 gangliosidosis (OMIM No. 272750).1,2 In the general population, the Tay-Sachs variant (TSV) of GM2 gangliosidosis is rare, with a prevalence of 1 in 201 000 live births and incidence of 1 in 222 000 live births.3 The Sandhoff variant (SV) prevalence and incidence rates have been reported as 1 in 384 000 and 1 in 422 000 live births, respectively.3 The TSV carrier frequency is much higher in the Ashkenazi Jewish (1 in 30) and eastern Quebec French Canadian (1 in 14) populations compared with that in the general population (1 in 300).4 Community-based TSV carrier screening programs in these at-risk populations have had a dramatic effect on birth prevalence, which is now lower than that in the general population.5,6 The classical infantile form of GM2 gangliosidosis is characterized by the onset of symptoms before the age of 6 months and progresses rapidly to death by 3 to 5 years of age.7 Juvenile or subacute and the adult, also called late-onset or chronic, subtypes of this condition present later in childhood or in adulthood and progress more slowly.1,8–22 The juvenile and adult forms of GM2 gangliosidosis differ from each other primarily by the impact of the disease on intelligence, which is minimal through much of the course of the adult or chronic variant. Several case reports and a small number of case series have been reported.11,13,20,21 However, few studies have provided accurate descriptions of the natural clinical course of jGM2 in larger groups of patients.21,23 We report here a series of 21 cases of juvenile or subacute GM2 gangliosidosis followed at 2 medical centers. We also review a collection of 134 previously reported cases of jGM2.* The focus of our analysis is on initial symptomatology, age of onset, and severity of symptoms during the course of the disease. We also report on the spectrum of HEXA and HEXB mutations identified in patients with the TSV and SV, respectively, and make some generalizations concerning genotype-phenotype correlations.