Methylmalonic aciduria and homocystinuria, cblC type, the most prevalent disorder of cobalamin (cbl) metabolism, results from genetic variants in the MMACHC gene. Although public databases document numerous splice variants of this gene, experimental evidence confirms pathogenicity for only a limited proportion.

In symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver failure, malabsorption and growth failure, and systemic inflammation, such as hemophagocytic lymphohistiocytosis, typically leading to death by 6 months of age if untreated. Sebelipase alfa (KANUMA®; Alexion, AstraZeneca Rare Disease, Boston, MA) is a recombinant human LAL (a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme) approved for the treatment of LAL-D in infants with rapidly progressive disease as well as in children and adults with LAL-D. Previous studies showed that enzyme replacement therapy (ERT) with sebelipase alfa led to survival with improved growth and development, hematologic parameters, and liver parameters and was well tolerated. We report long-term outcomes in 29 patients with rapidly progressive LAL-D who were symptomatic in infancy using patient data from the International LAL-D Registry, an ongoing observational, multicenter, international registry (NCT01633489) that collects data on patients with LAL-D. Among these 29 patients treated with sebelipase alfa, 41 % were male, and 28 % had participated in clinical trials with sebelipase alfa. Median age (Q1, Q3) was 2.3 months (1.8, 3.1) at the start of ERT. Patients received a starting ERT dose of ≤1 mg/kg or ≥3 mg/kg per week. In patients who had participated in clinical trials of sebelipase alfa, the starting dose was driven by the clinical trial protocol and was between 0.2 and 1.0 mg/kg per week. Overall, 27 of 29 (93 %) patients survived during the median observation time (Q1, Q3) of 6.2 years (3.5, 8.4). At baseline, 11 patients had abnormally low weight-for-age z scores (<-2); for 5 of these patients, weight stabilized after 6 to 12 months of treatment (z scores between -2 and 2). Adverse events occurred in 23 (79 %) patients. Eleven (38 %) patients experienced adverse events potentially related to sebelipase alfa, which were generally not severe and most resolved. Four patients among 7 tested developed antidrug antibodies, and 3 had positive results for neutralizing antidrug antibodies. These results confirmed the dramatic survival and metabolic benefit associated with sebelipase alfa ERT in patients with symptomatic, rapidly progressive LAL-D.

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disease caused by the deficiency of the glycogen branching enzyme encoded by GBE1. GSD IV can present with variable age of onset and severity of disease processes involving liver, central and peripheral nerves, muscles, and heart. Adult Polyglucosan Body Disease (APBD) is now increasingly recognized as a continuum of the GSDIV spectrum. If the clinical disease presentation includes progressive liver failure, treatment may require liver transplant to prevent morbidity and mortality. The variable presentation of GSD IV, including the hepatic phenotypes, creates diagnostic and treatment challenges. Here we describe a girl presenting with hypotonia and hepatomegaly at age 4 years; genetic analysis revealed compound heterozygosity in GBE1: c.1621A>G p.(Asn541Asp) and c.1655C>T p.(Pro552Leu). Based on her presentation and genotypes, her phenotypic prognosis was not immediately clear. She was monitored closely for liver disease progression including, synthetic dysfunction, cholestasis, or cirrhosis, but her liver function proved stable over time. Recent analysis suggested that liver disease progression is a spectrum and some develop a progressive/severe hepatic form and others stabilize with an attenuated hepatic form. Previous reviews of GSD IV genotype-phenotype correlations have not adequately addressed the prediction of hepatic phenotype based on GBE1 genotypes. We performed an updated comprehensive literature search and genotype-phenotype analysis, while updating the GBE1 genotypes according to the HGVS nomenclature. Our detailed and comprehensive review of GSDIV adds to the previously published literature available on GSD IV genotypes (Li et al. 2010, Iijima 2018, Souza et al. 2021).

Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; NCT03292887) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS.

Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmune disorders (e.g. systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocystosis (HLH)). Recently, one case of allogeneic hematopoietic stem cell transplantation (allo-HSCT) reversing SLE and HLH in a LPI patient was reported. We present 21 years of follow-up in a second LPI patient having undergone allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for HLH.

Carriers of the mitochondrial variant m.3243A>G have a high risk of diabetes mellitus and frequently report gastrointestinal symptoms, suggesting a dual endocrine and exocrine pancreas dysfunction. Whether changes in pancreatic morphology, abdominal or ectopic fat distribution contribute to these conditions, remains unknown.

The cblG inborn error of vitamin B metabolism is associated with pathogenic variants in the MTR gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 potentially causal MTR variants published.

MEHMO syndrome (OMIM#300148) is a rare, X-linked, multisystemic condition that predominantly involves endocrinologic and neurologic dysfunctions. Initial naming of the syndrome emphasizes the presentation of Mental disability, Epileptic seizures, Hypogonadism/Hypogenitalism, Microcephaly, and Obesity. This review provides a synthesis of the genetics, genotypes, and phenotypes of publicly available information on EIF2S3 and MEHMO syndrome. Identification and confirmation of variants in the gene EIF2S3 as the genetic underpinning of the syndrome's pathophysiology and reports of additional cases suggest a consideration for a re-definition of the acronym and a re-classification of the condition along with others as eIF2-related neuroendocrinopathies. This would allow for more standardized and encompassing characterization of the group of eIF2-related disorders, that in turn would support and continue to spur further research progress in basic pathophysiology, disease diagnosis and monitoring, and biomarker and therapeutic discoveries.

In Gaucher disease (GD), clinical management is complicated by heterogeneity and the lack of standardized guidelines for treatment initiation. As patients are being identified pre-symptomatically or as mildly affected through carrier and newborn screening programs, timing of treatment is an increasingly important issue. This study evaluated the utility of plasma lyso-GL1 as an objective biomarker to inform treatment decisions. Retrospective data were analyzed from 240 GD patients with lyso-GL1 levels measured primarily at a single laboratory between June 2018 and September 2023. The study population included both adult (n = 194, 80.8 %) and pediatric (n = 46, 19.2 %) patients predominantly diagnosed with type 1 GD (n = 234, 97.5 %) and self-identified as Jewish (82.1 %). Among 25 patients who initiated GD-specific treatment during the study period with available pre-treatment lyso-GL1 data, the median age at treatment initiation was 33 years. In this group, the median baseline lyso-GL1 was 91.6 ng/mL, which declined to 19.5 ng/mL following treatment with a median follow-up of 2.9 years. In contrast, untreated patients had a median baseline lyso-GL1 of 14.2 ng/mL, which increased to 17.0 ng/mL over a similar follow-up period. Logistic regression and receiver operating characteristic analysis identified a lyso-GL1 threshold of 78.9 ng/mL that effectively discriminated treatment status in GD1 patients, with an area under the curve of 0.865, sensitivity of 73 %, and specificity of 96 %. The predictive performance of this identified threshold was comparable to that reported in a previous study, underscoring the reproducibility and potential utility of lyso-GL1 as a reliable and objective biomarker to guide treatment initiation in Gaucher disease.

Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterised by glycosaminoglycan (GAG) accumulation, leading to progressive multisystem disease. Cardiovascular complications, including arterial wall stiffness, and valvular dysfunction, are major causes of morbidity and mortality. Conventional cardiovascular risk tools are unreliable in MPS, and the role of vascular imaging remains underdefined.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are organic acidurias that can present with metabolic acidosis and hyperammonemia, often leading to frequent hospital admission. While recent studies have provided guidelines for management and diagnosis of these conditions, there is a lack of research detailing the frequency and reasons for hospital admission in the first three years of life.

Well-recognized challenges in rare disease diagnosis include limited awareness of rare diseases among healthcare providers and barriers to accessing genetic testing. Less well understood are the ways in which communication between parents of undiagnosed children and providers may impact access to diagnosis, as well as quality of care broadly. We sought to characterize key dynamics of communication between parents of undiagnosed children and healthcare providers during the diagnostic odyssey.

Nutrition management of urea cycle disorders (UCDs) focuses on limiting dietary protein and providing adequate energy to ensure appropriate growth and prevent catabolism. Dietary protein intakes are recommended to patients; however, assessment of actual protein intake is challenging as standard assessment methods are recognized to be inaccurate, time-consuming, and cumbersome. A new dietary collection method utilizes a smartphone camera; participants take photos of meals and snacks for remote analysis by a registered dietitian. This food photography method using the mFood app was compared to traditional 3-day diet records in individuals with UCDs and reported energy intake for both were validated against an objective gold-standard measurement of total energy expenditure (TEE) by doubly labeled water. In weight-stable adults, energy intake is approximately equal to TEE. Eight individuals ≥16 years old participated in a randomized crossover design study. In this cohort, protein intake was 13 % and 15 % of energy for 3-day diet records and mFood, respectively. There was no statistical difference in gram intake of the macronutrients between the two methods. Compared to TEE, participants reported 16 % lower total energy intake by 3-day diet records and 22 % lower energy intake by mFood, demonstrating limited benefit to using mFood. We highlight the importance of utilizing consistent nutrient analysis methods to compare dietary assessments within a population. mFood, although not superior to traditional dietary collection methods, was preferred by the majority of participants and offers a novel method for collecting nutrition information in individuals with UCD who frequently find this task cumbersome.

Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S, EC 3.1.6.13), due to pathological variants of the I2S gene (IDS). Clinically, MPS II is a chronic progressive multisystem developmental and degenerative disorder, typically associated with manifestations in early childhood. Intravenous enzyme replacement therapy has been available since 2006, with improved outcomes seen with early initiation of therapy. Newborn screening for MPS II in a public health setting has been ongoing in Taiwan since 2015 and in some states of the USA since 2017. These developments prompted a successful nomination of MPS II to be included as a core screening condition on the US Federal Recommended Uniform Screening Panel (RUSP), which was approved by the US Secretary of Health and Human Services on August 2, 2022. With the promise of expanded public health screening for MPS II, there was a perceived need for a set of consensus recommendations on MPS II newborn screening, the clinical confirmation of screened positive cases, and their clinical management. To this end an international expert panel of 21 members from 8 countries was convened to conduct a modified Delphi consensus on the evaluation and follow-up of newborns who screened positive for MPS II, the results of which are presented.

This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex-stratified survival outcomes to explore differences in symptom development. Findings were compared with international cohorts to contextualize the Danish results.

Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case of a pregnant woman with MPI-CDG and the management of D-mannose therapy during pregnancy. D-mannose was discontinued at 6 weeks' gestation, due to the potential fetal toxicity observed particularly in animal models, but severe digestive symptoms and hypoglycemia relapsed. We decided to readminister D-mannose therapy at 10 weeks' gestation although data on teratogenecity in humans are lacking. Symptoms resolved rapidly when D-mannose was resumed. Monitoring of transferrin glycoforms profile and coagulation parameters allowed to gradually increase D-mannose dosage throughout pregnancy. The patient delivered at 38 weeks' gestation after an intrauterine growth retardation was noted. The infant was 2.390 kg at birth with a low Apgar score but rapidly recovered. Low dose D-mannose treatment administered from 10 weeks' gestation could be a safe option for women with MPI-CDG.

High-resolution urine oligosaccharide screening with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been clinically available for 10 years and has been used to help diagnose a wide spectrum of disorders. The untargeted nature of MALDI-TOF MS analysis gives it broad clinical utility. Here we report characteristic profiles for several disorders that had not previously been described using this method, including lysosomal disorders, congenital disorders of glycosylation, and glycogen storage disorders. In addition, we review the clinical performance of the assay in our laboratory and provide basic test performance information for each condition. A total of 4445 analyses performed with 4145 unique patient samples generated 139 confirmed and presumptive positive results and 16 false-positive results. The disorder with the highest rate of false positivity was Pompe disease, which has an oligosaccharide profile similar to that seen in formula-fed infants. The positive predictive value of urine oligosaccharide screening with MALDI-TOF MS was 89.7 % across all conditions. For 10 of the 16 conditions detected during the study period, no false-positive results occurred. No known false-negative results were reported for any of the targeted conditions. Urine oligosaccharide analysis with MALDI-TOF MS, which uses an accessible specimen type and offers quick turnaround time, is an effective initial screening method for patients with a clinical presentation suggestive of a lysosomal disorder.

Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns. Advances in genetic testing have enabled earlier diagnoses, creating opportunities to better define the natural history of disease in infancy and early childhood. We conducted a longitudinal, observational study of 21 male patients (ages 0-48 months) with genetically confirmed BTHS evaluated at the Barth Syndrome Interdisciplinary Clinic at Kennedy Krieger Institute. Data collected included perinatal history, growth, feeding, cardiac function, hematologic findings, gross motor development, quality of life, and pain assessment. Gross motor skills were assessed via milestone acquisition and the Peabody Developmental Motor Scales (PDMS-2/3). Quality of life was evaluated using the PedsQL™ parent-proxy questionnaire. The most common presenting features were cardiomyopathy (n = 10) and failure to thrive (n = 6), with an average age at diagnosis of 5.5 months, which was significantly earlier than historical cohorts. Eighteen patients developed cardiac dysfunction, 25 % required heart transplantation, and one death occurred due to cardiopulmonary arrest. Feeding difficulties were frequent, with 16 patients affected and 7 requiring gastrostomy tubes. Growth delay was common, though height/weight ratios were often preserved. Neutropenia was present in 19 patients, with variable severity and infection risk. Gross motor development was delayed, particularly for standing and walking, with progressive deficits on PDMS subtests. Quality of life scores indicated substantial impairment, especially in fatigue and general functioning domains. Pain was rarely reported. We conclude that infants and toddlers with BTHS present with significant cardiac, growth, and developmental abnormalities. Earlier diagnosis facilitated by genetic testing allows for earlier intervention and monitoring. These findings highlight the need for proactive cardiac surveillance, nutritional support, and early therapeutic interventions to optimize outcomes, and they provide critical endpoints for future clinical trials in this young age group.

Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol. Individuals with NPC1 manifest progressive neurodegeneration. Identification and characterization of proximal biomarkers is essential for developing therapeutic interventions. Increased levels of 24(S)-hydroxycholesterol (24(S)OHC) after intrathecal administration of adrabetadex reflect correction of the biochemical defect in neurons. In this study, we show that 24(S)OHC remains a robust proximal biomarker in individuals treated with IT adrabetadex for over four years.

GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to d-serine that modulates NMDAR activity, has shown therapeutic potential for GRIN2B loss-of-function (LoF) variants.