Journal of Inherited Metabolic Disease最新文献

Adenylosuccinate lyase deficiency (ADSLD) is a rare neurological disorder characterized by psychomotor retardation, autistic behaviors, and seizures, with no specific treatment available. ADSL catalyzes the transformation of succinylaminoimidazole carboxamide ribotide (SAICAr) to AICAR, and succinyl-AMP (S-AMP) to AMP. The pathogenesis of the disease is primarily attributed to the toxicity of elevated SAICAr concentrations. Allopurinol, used primarily for hyperuricemia, inhibits purine synthesis and may reduce SAICAr levels. We hypothesized that administering allopurinol could decrease SAICAr levels and lead to clinical improvement. A Phase II, prospective trial evaluated the efficacy of allopurinol in patients with ADSLD over 12 months. Eight participants (four children, four young adults) with developmental delay and high SAICAr levels received Zyloric (10–20 mg/kg/day, maximum 400 mg/day for children and 900 mg/day for adults). The study assessed changes in adaptive and cognitive functioning, behavior, and urinary levels of SAICAr and succinyl-adenosine (S-Ado). Results showed clinical improvements in younger, less cognitively impaired patients, indicated by better Vineland Adaptive Behavior Scale (VABS II) scores and reduced hyperactivity on the Aberrant Behavior Checklist (ABC) and Conners Rating Scale-Revised (CRSR). These improvements correlated with significant decreases in urinary SAICAr levels and an increased S-Ado/SAICAr ratio. No changes were observed in older or noncompliant patients. Allopurinol had no effect on epilepsy but was well tolerated. Allopurinol showed behavioral and developmental benefits in younger ADSLD patients, suggesting that it may be a viable treatment option.

Hypophosphatasia (HPP) is a rare, inherited monogenic disorder that is typically caused by variants in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Genetic testing for ALPL variant(s) to confirm the diagnosis in patients with suspected HPP is a standard practice based on availability. This review attempts to improve the current understanding of the genetics of HPP as it addresses five key related topics: (1) HPP patterns of inheritance and the relationship between HPP genotype and phenotype, (2) how the disease can manifest (including specific genotypes) in heterozygotes, (3) potential reasons why some patients have persistently low alkaline phosphatase activity yet lack an ALPL variant, (4) the implications of and resources for variants of uncertain significance (VUS), and (5) recent information on genetic testing in fetuses and newborns. We summarize pertinent information applicable in daily clinical practice, with the objective of preventing missed, delayed, or incorrect HPP diagnoses and improving patient care.

Classic isovaleric aciduria (cIVA) is a rare inherited metabolic disorder characterized by recurrent life-threatening metabolic decompensations and neurocognitive impairment in untreated patients. This meta-analysis aims to assess the impact of early diagnosis by newborn screening (NBS) on mortality and neurocognitive outcome. A systematic literature search for articles published until 2022 was conducted following PRISMA protocol guidelines. We investigated effects on clinical outcomes and survival, analyzing outcome parameters using meta-analytical measures and estimating effect sizes with a random-effects model. Overall, 20 studies were included, reporting on 240 individuals with cIVA. Individuals identified by NBS presented with a lower frequency of neurological symptoms (13.0% vs. 44.9%; p = 0.0040) and developmental delay (6.1% vs. 51.2%; p < 0.0001), and had a lower mortality rate (1.1% vs. 10.9%; p = 0.0320). The quality of healthcare systems did not have a measurable impact on neurocognitive outcome and mortality. Despite the beneficial effect of NBS on clinical outcome and mortality, it could not reliably prevent the manifestation of neonatal decompensation in all individuals with cIVA identified by NBS. Early diagnosis through NBS is essential for the timely initiation of therapy and for improving outcomes and survival rates in individuals with cIVA.

The introduction of nitisinone (NTBC) and newborn screening for Tyrosinemia type 1 (TT1) enabled preemptive treatment of patients, thereby significantly improving outcomes by preventing liver, kidney, and neurological issues. Treatment goals have shifted from emergency treatment to long-term care. To evaluate the risk of developing complications with aging, due to TT1 itself or its treatment, long-term follow-up is essential. In 2014, an overview of TT1 management practices in Europe was published. Within the Metabolic European Reference Network's subnetwork on amino-and-organic acidurias (MetabERN-AOA), we considered it important to give an update on current TT1 management practices in Europe. An online survey study was performed among members of the MetabERN-AOA subnetwork, and participants of a workshop on TT1 at the European Metabolic Group Meeting of Nutricia. Findings were compared to existing data from the aforementioned publication from 2014 and previously published recommendations. Thirty-two centers (16 European countries) completed the survey. Both consistencies and inconsistencies in TT1 management were seen. Inconsistencies were observed in the frequency and methods of follow-up, dosing of NTBC, and target ranges of biochemical markers. Compared to 2014, key differences included an increased number of patients detected by newborn screening, lower NTBC dosing, and a shift from interest in mainly hepatic to hepatic and neurocognitive outcomes. These results align with trends seen in TT1 recommendations over the years. In addition to numerous consistencies, many aspects in TT1 management still differ widely across Europe, suggesting the need for uniform guidance in clinical management beyond existing recommendations.

Neutropenia in Glycogen Storage Disease Type Ib (GSDIb) and G6PC3 deficiency results from defects in metabolite repair, leading to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Treatment currently relies on inhibitors of SGLT2, the renal sodium-glucose co-transporter, which indirectly enhances urinary excretion of 1,5-anhydroglucitol (1,5-AG), the precursor of the toxic 1,5-AG6P that accumulates in neutrophils and is at the origin of these patients' neutropenia. In this context, a detailed understanding of the formation, intestinal absorption, renal reabsorption, and metabolism of 1,5-AG is essential. Here, we review the current knowledge of these mechanisms, their role in the pathophysiology of 1,5-AG6P–related neutropenia, and explore potential strategies to improve treatment outcomes.

In 2007, the Dutch newborn screening (NBS) program was expanded to include C5-OH as a marker to screen for three inborn errors of metabolism (IEMs): 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) and holocarboxylase synthetase deficiency (HLCSD). This study evaluates the effectiveness of C5-OH as an NBS marker by analyzing data from neonates screened in the Dutch NBS program from 2007 to 2023 and by reviewing the literature on various IEMs detected by an elevated NBS C5-OH concentration worldwide. Of the 126 neonates referred on the basis of elevated C5-OH concentrations in the Netherlands, 46 were true positive cases. No missed cases in the Netherlands have been reported so far, resulting in a positive predictive value of 38.3% and a negative predictive value of 100%. Strikingly, there was notable overlap between C5-OH concentrations of true and false positive cases. The systematic review included 58 articles and showed that C5-OH concentrations of patients with different IEMs reported in the literature were insufficiently distinctive to differentiate between these diseases. While C5-OH can be used to detect patients with 3-MCCD, HCLSD, and HMGCLD, its value is limited by the overlap of C5-OH concentrations between affected and unaffected neonates and among patients with different diseases. This emphasizes the need for improvement of the screening strategy and potentially the use of additional markers to increase its specificity.

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease characterized by hepatosplenomegaly, pulmonary dysfunction, dyslipidemia, and growth deficits. Olipudase alfa (recombinant-human ASM) is the only treatment for non-central-nervous-system ASMD manifestations in children and adults. An open-label long-term study followed 4 to 8 years of olipudase alfa treatment in 20 children and adolescents with ASMD (baseline age (years) 1.5–17.5). At final assessments, splenomegaly and hepatomegaly were reduced relative to baseline (mean percent decrease in spleen and liver volumes 78% ± 1.2% and 59.8% ± 1.5%, respectively). Baseline splenomegaly was severe (spleen volume > 15 MN [multiples of normal]) or moderate (5–15 MN) (n = 12 and n = 8, respectively) versus mild/absent (< 5 MN) (n = 12) or moderate (n = 8) at final assessment. Baseline hepatomegaly was severe (liver volume > 2.5 MN) (n = 10) or moderate (1.25–2.5 MN) (n = 10) versus mild/absent (< 1.25 MN) (n = 19) or moderate (n = 1) at final assessment. Among nine individuals able to perform assessments, diffusing capacity of the lung for carbon monoxide (DL_CO) impairment was severe (< 40%) (n = 1), moderate (40%–60%) (n = 4), or mild (60%–80%) (n = 4) at baseline versus absent (n = 4), mild (n = 4) or moderate (n = 1) at final assessment. Mean percent increase in DL_CO was 53.7% ± 6.5%. At baseline, 10/20 children had clinical short stature (height Z-scores ≤ − 2) at baseline versus 0/20 at the final assessment. Atherogenic lipid profiles and liver function tests normalized within 2 years and remained stable. Adverse events were mostly mild or moderate, with 4 individuals experiencing 7 serious adverse events, all recovered/resolved. Interpretation: Enzyme replacement therapy with olipudase alfa in children and adolescents with chronic ASMD was well-tolerated with clinically meaningful improvements in multiple disease parameters.

Trial Registration: NCT02004704.