Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.

Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate the underlying mechanisms of repeat instability, which occurs both somatically and intergenerationally, we created a novel mouse model of familial ALS/FTD that harbors 96 copies of G4C2 repeats at a humanized C9orf72 locus. In mouse embryonic stem cells, we observed two modes of repeat expansion. First, we noted minor increases in repeat length per expansion event, which was dependent on a mismatch repair pathway protein Msh2. Second, we found major increases in repeat length per event when a DNA double- or single-strand break (DSB/SSB) was artificially introduced proximal to the repeats, and which was dependent on the homology-directed repair (HDR) pathway. In mice, the first mode primarily drove somatic repeat expansion. Major changes in repeat length, including expansion, were observed when SSB was introduced in one-cell embryos, or intergenerationally without DSB/SSB introduction if G4C2 repeats exceeded 400 copies, although spontaneous HDR-mediated expansion has yet to be identified. These findings provide a novel strategy to model repeat expansion in a non-human genome and offer insights into the mechanism behind C9orf72 G4C2 repeat instability.

Quantifying ventilation by X-ray velocimetry in healthy adults.

RATIONALE: X-ray velocimetry (XV) has been utilized in preclinical models to assess lung motion and regional ventilation, though no studies have compared XV-derived physiologic parameters to measures derived through conventional means. OBJECTIVES: To assess agreement between XV-analysis of fluoroscopic lung images and pitot tube flowmeter measures of ventilation. METHODS: XV- and pitot tube-derived ventilatory parameters were compared during tidal breathing and with bilevel-assisted breathing. Levels of agreement were assessed using the Bland-Altman analysis. Mixed models were used to characterize the association between XV- and pitot tube-derived values and optimize XV-derived values for higher ventilatory volumes. MEASUREMENTS AND MAIN RESULTS: Twenty-four healthy volunteers were assessed during tidal breathing and 11 were reassessed with increased minute ventilation with bilevel-assisted breathing. No clinically significant differences were observed between the two methods for respiratory rate (average Δ: 0.58; 95% limits of agreement: -1.55, 2.71) or duty cycle (average Δ: 0.02; 95% limits of agreement: 0.01, 0.03). Tidal volumes and flow rates measured using XV were lower than those measured using the pitot tube flowmeter, particularly at the higher volume ranges with bilevel-assisted breathing. Under these conditions, a mixed-model based adjustment was applied to the XV-derived values of tidal volume and flow rate to obtain closer agreement with the pitot tube-derived values. CONCLUSION: Radiographically obtained measures of ventilation with XV demonstrate a high degree of correlation with parameters of ventilation. If the accuracy of XV were also confirmed for assessing the regional distribution of ventilation, it would provide information that goes beyond the scope of conventional pulmonary function tests or static radiographic assessments.

Patient and Clinician Recommendations to Improve Communication and Understanding of Lung Cancer Screening Results.

BACKGROUND: Patient understanding of chest low-dose CT (LDCT) scan results for lung cancer screening (LCS) may impact outcomes. RESEARCH QUESTION: What are patient- and clinician-identified gaps in understanding and communication of LCS results and how might communication be improved through a patient-oriented tool? STUDY DESIGN AND METHODS: We performed a mixed-methods study of participants recruited from a multisite LCS program to understand knowledge gaps after receiving LCS results and to guide development of a commonly asked questions (CAQ) after LCS information sheet. Initial patient surveys assessed understanding and reactions to LCS results (n = 190). We then conducted patient interviews and focus group discussions (n = 31) to understand experiences receiving LDCT scan results and reactions to results letters and the proposed CAQ; we also interviewed clinicians (n = 6) for feedback on these resources. We summarized survey responses and used thematic analysis to identify major themes in focus groups and interviews. RESULTS: Of 190 survey respondents (43% response rate), although 88% agreed that they "understood" their LCS results, only 55% reported understanding what a lung nodule is. Approximately two-thirds thought it was "very important" to receive more information regarding lung nodules and incidental lung and heart disease. In interviews and focus groups, although patients believed that brief results letters for normal LDCT scan results generally were acceptable, most found letters explaining abnormal LDCT scan and incidental findings to be concerning and not a substitute for discussion with their clinician. Nearly all patients expressed that the CAQ sheet provided helpful information on nodules, results reporting and incidental findings, and helped them form questions to ask their clinicians. INTERPRETATION: We identified patient-reported information needs regarding LCS results and developed a CAQ information sheet that was refined with patient and clinician input. The CAQ may represent a simple and feasible way to improve LCS results reporting and to augment clinician-patient discussions.

Preclinical Four-Dimensional Functional Lung Imaging and Quantification of Regional Airflow: A New Standard in Lung Function Evaluation in Murine Models.

The current standard for lung function evaluation in murine models is based on forced oscillation technology, which provides a measure of the total airway function but cannot provide information on regional heterogeneity in function. Limited detection of regional airflow may contribute to a discontinuity between airway inflammation and airflow obstruction in models of asthma. Here, we describe quantification of regional airway function using novel dynamic quantitative imaging and analysis to quantify and visualize lung motion and regional pulmonary airflow in four dimensions (4D). Furthermore, temporo-spatial specific ventilation (ml/ml) is used to determine ventilation heterogeneity indices for lobar and sublobar regions, which are directly compared to ex vivo biological analyses in the same sublobar regions. In contrast, oscillation-based technology in murine genetic models of asthma have failed to demonstrate lung function change despite altered inflammation, whereas 4D functional lung imaging demonstrated diminished regional lung function in genetic models relative to wild-type mice. Quantitative functional lung imaging assists in localizing the regional effects of airflow. Our approach reveals repeatable and consistent differences in regional airflow between lung lobes in all models of asthma, suggesting that asthma is characterized by regional airway dysfunctions that are often not detectable in composite measures of lung function. 4D functional lung imaging technology has the potential to transform discovery and development in murine models by mapping out regional areas heterogeneously affected by the disease, thus deciphering pathobiology with greater precision.

Spin in Abstracts of Systematic Reviews and Meta-analyses of Melanoma Therapies: Cross-sectional Analysis.

BACKGROUND: Spin is defined as the misrepresentation of a study's results, which may lead to misperceptions or misinterpretation of the findings. Spin has previously been found in randomized controlled trials and systematic reviews of acne vulgaris treatments and treatments of various nondermatological conditions. OBJECTIVE: The purpose of this study was to quantify the presence of spin in abstracts of systematic reviews and meta-analyses of melanoma therapies and identify any related secondary characteristics of these articles. METHODS: We used a cross-sectional approach on June 2, 2020, to search the MEDLINE and Embase databases from their inception. To meet inclusion criteria, a study was required to be a systematic review or meta-analysis pertaining to the treatment of melanoma in human subjects, and reported in English. We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) definition of systematic reviews and meta-analyses. Data were extracted in a masked, duplicate fashion. We conducted a powered bivariate linear regression and calculated odds ratios for each study characteristic. RESULTS: A total of 200 systematic reviews met the inclusion criteria. We identified spin in 38% (n=76) of the abstracts. The most common type of spin found was type 3 (selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention), occurring 40 times; the least common was type 2 (title claims or suggests a beneficial effect of the experimental intervention not supported by the findings), which was not present in any included abstracts. We found that abstracts pertaining to pharmacologic interventions were 3.84 times more likely to contain spin. The likelihood of an article containing spin has decreased annually (adjusted odds ratio 0.91, 95% CI 0.84-0.99). No significant correlation between funding source or other study characteristics and the presence of spin was identified. CONCLUSIONS: We have found that spin is fairly common in the abstracts of systematic reviews of melanoma treatments, but the prevalence of spin in these abstracts has been declining from 1992-2020.

Evaluation of Industry Relationships Among Authors of Systematic Reviews and Meta-analyses Regarding Ménières Disease.

OBJECTIVES: To quantify the presence of conflicts of interest (COI) in SRs and MAs of Ménières disease treatment and identify any related secondary characteristics of these articles. METHODS: A search was conducted on May 28, 2020 to search MEDLINE and Embase databases for SRs or MAs pertaining to Ménières disease published between September 1, 2016 and June 2, 2020. A risk of bias assessment was performed using the Cochrane Collaboration risk of bias assessment criteria. RESULTS: A total of 13 systematic reviews conducted by 49 authors met the inclusion criteria. Of the 49 authors, 7 (14.3%) were found to have some form of COI. Of these 7 authors, 1 (14.3%) completely disclosed all COI within the SR, 1 (14.3%) disclosed one or more COI but were found to have an additional undisclosed COI, and 5 (71.4%) were found to have only undisclosed COI. One of 2 industry funded SRs (50%) had a high risk of bias, and 1 (50%) of the non-industry sponsored SRs were found to have a high risk of bias. CONCLUSIONS: Overall authors of SRs pertaining to Ménières disease appear to be properly disclosing COI at higher rates than other fields of medicine; however, further room for improvement has been noted.

Patient Identification of Lung Cancer Screening Follow-Up Recommendations and the Association with Adherence.

Rationale: Adherence to follow-up lung cancer screening (LCS) in real-world settings is suboptimal. Patient understanding of screening results and anticipated follow-up may be crucial to adherence. Objectives: To determine patient factors associated with identification of follow-up recommendations as a measure of patient understanding of screening results after LCS, and to determine whether misidentification of follow-up is associated with lower adherence to recommendations. Methods: We performed a prospective study of patients in the University of Washington/Seattle Cancer Care Alliance LCS registry who underwent an initial LCS examination between June 2017 and September 2019. We mailed potential participants a survey after the initial LCS examination, with additional data abstracted from the electronic health record and LCS registry. Participants were asked to identify the timing and next step for their follow-up, with answers corresponding to the lung imaging reporting and data system (Lung-RADS) recommendations. We examined associations between incorrect identification of recommended follow-up and patient-level characteristics, self-perceived benefit/harm of LCS, LCS knowledge, Lung-RADS score, and patient-reported method of LCS results communication (letter, telephone, or in-person). We used multivariable logistic regression to evaluate associations with incorrect identification of recommendations and assessed incorrect identification of recommendations as a potential mechanism for poor adherence in a separate regression model. Results: One hundred eighty-eight participants completed the survey (response rate 44%); 47% misidentified their follow-up recommendation. Those with Lung-RADS scores ⩾3 had higher odds of incorrectly identifying follow-up recommendations than those with scores <3, as did those with lower educational attainment. However, there was no significant association between incorrect identification of follow-up and ultimate adherence to follow-up. Conclusions: Understanding of LCS follow-up appears to be poor, especially among those with lower education levels and positive findings. Among survey responders, incorrect identification of follow-up was not associated with poor adherence, suggesting that other factors, such as provider interventions, may be driving adherence behavior. These results can inform efforts to target improved patient education regarding follow-up for LCS.

Superlatives in news articles reporting non-FDA approved indications for use of cannabis and cannabis products with a focus on psychiatric disorders: a cross-sectional analysis.

The exaggerated language used in news articles to describe the benefits of cannabis for conditions without FDA indications may mislead the public and healthcare providers. Thus, this study's objective was to investigate the use of exaggerated language in news articles focused on cannabis and cannabis-derived products. Using a cross-sectional study design, we searched Google News from March 3, 2020, and September 3, 2019 for 11 prespecified superlative terms along with the search terms "cannabis," "cannabidiol," "pot," "marijuana," "weed," and "CBD." Articles were evaluated for these exaggerative terms describing cannabis and cannabis-derived products along with additional news article characteristics. Screening and data extraction occurred in a masked, duplicate fashion. We identified 612 superlative terms in 374 different news articles focused on cannabis and cannabis-derived products from 262 news outlets. Only 26 (of 374, 7.0%) news articles provided clinical data. In total, superlative terms were used to describe cannabis and cannabis-derived products for the treatment of 91 medical conditions, of which only 2 are FDA approved. The most common psychiatric disorder indicated was anxiety disorder appearing in 88 news articles. Superlatives in news articles covering the treatment of psychiatric illnesses with cannabis and cannabis-derived products are common.

Advances in the Diagnosis and Treatment of Krabbe Disease.

Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in 1970, a diagnosis could be made by measuring GALC activity in leukocytes and cultured cells. After the purification of GALC in 1993, the cDNA and genes were cloned. Over 260 disease-causing variants as well as activity lowering benign variants have been identified. While some pathogenic variants can be considered "severe," others can be considered "mild." The combination of alleles determines the type of Krabbe disease a person will have. To identify patients earlier, newborn screening (NBS) has been implemented in several states. Low GALC activity in this screening test may indicate a diagnosis of Krabbe disease. Second tier testing as well as neuro-diagnostic studies may be required to identify those individuals needing immediate treatment. Treatment of pre-symptomatic or mildly symptomatic patients at this time is limited to hematopoietic stem cell transplantation. Treatment studies using the mouse and dog models have shown that combining bone marrow transplantation with intra-venous gene therapy provides the best outcomes in terms of survival, behavior, and preservation of normal myelination in the central and peripheral nervous systems. With earlier diagnosis of patients through newborn screening and advances in treatment, it is hoped that more patients will have a much better quality of life.

Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT?

Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for pre-symptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four- and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.

United States internet searches for "infertility" following COVID-19 vaccine misinformation.

CONTEXT: On December 1, 2020, Drs. Wolfgang Wodarg and Micheal Yeadon petitioned to withhold emergency use authorization of the BNT162b2 messenger ribonucleic acid vaccine for coronavirus disease 2019 (COVID-19) manufactured by BioNTech and Pfizer, raising concern for female infertility risks but acknowledging the lack of evidence. The European Medicines Agency and the US Food and Drug Administration ultimately issued emergency use authorizations, but misinformation claiming that COVID-19 vaccines cause female infertility began circulating on social media, potentially influencing public perception and medical decision making among pregnant patients or those seeking to become pregnant. OBJECTIVES: To determine the potential influence misinformation may have had on public interest in infertility related topics, as analyzed through internet search statistics in the US. METHODS: The Google Trends tool was used to analyze results for the search terms "infertility," "infertility AND vaccine," and "infertility AND COVID vaccine" in the US from February 4, 2020 to February 3, 2021. We applied autoregressive integrated moving average models to forecast expected values, comparing them with actual observed values. RESULTS: At peak interest (100), the forecasted relative search volumes interest for the search terms "infertility," "infertility AND vaccine," and "infertility AND COVID vaccine" were 45.47 (95% CI, 33.27-57.66; p<0.001), 0.88 (95% CI, 2.87-4.63; p<0.001), and 0.29 (95% CI, -2.25-2.82; p<0.001). The actual relative search volumes at peak searching represented 119.9, 11,251, and 34,900% increases, respectively, when compared with forecasted values. CONCLUSIONS: COVID-19 vaccine misinformation corresponded with increased internet searches for topics related to infertility in the US. Dispelling misinformation and informing patients about the risks and benefits of COVID-19 vaccination may prevent unnecessary vaccine hesitancy or refusal, contributing to successful vaccination efforts.

Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.

OBJECTIVE: To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD). METHODS: KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD. RESULTS: Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%. CONCLUSION: The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.

Publication Trends and Their Relationship With Academic Success Among Dermatology Residents: Cross-sectional Analysis.

BACKGROUND: Involvement in scholarly activities is considered to be one of the foundational pillars of medical education. OBJECTIVE: This study aims to investigate publication rates before, during, and after residency to determine whether research productivity throughout medical training correlates with future academic success and research involvement. METHODS: We successfully identified a list of 296 graduates from 25 US dermatology residency programs from the years 2013-2015. The publication history for each graduate was compiled using Scopus, PubMed, and Google Scholar. The Pearson correlation test and linear regression were used to assess the relationship between research productivity and continued academic success after residency graduation. RESULTS: Before residency, graduates published a mean of 1.9 (SD 3.5) total publications and a mean of 0.88 (SD 1.5) first-author publications. During residency, graduates published a mean of 2.7 (SD 3.6) total publications and a mean of 1.39 (SD 2.0) first-author publications. Graduates who pursued a fellowship had more total publications (t294=-4.0; P<.001), more first-author publications (t294=-3.9; P<.001), and a higher h-index (t294=-3.8; P=.002). Graduates who chose to pursue careers in academic medicine had more mean total publications (t294=-7.5; P<.001), more first-author publications (t294=-5.9; P<.001), and a higher mean h-index (t294=-6.9; P<.001). Graduates with one or more first-author publications before residency were 1.3 times more likely to pursue a career in academic medicine (adjusted odds ratio 1.3, 95% CI 1.1-1.5). Graduates who pursued a fellowship were also 1.9 times more likely to pursue a career in academic medicine (adjusted odds ratio 1.9, 95% CI 1.2-3.2). CONCLUSIONS: Our results suggest that research productivity before and during residency training are potential markers for continued academic success and research involvement after completing dermatology residency training.

Chemical mutagenesis of a GPCR ligand: Detoxifying "inflammo-attraction" to direct therapeutic stem cell migration.

A transplanted stem cell's engagement with a pathologic niche is the first step in its restoring homeostasis to that site. Inflammatory chemokines are constitutively produced in such a niche; their binding to receptors on the stem cell helps direct that cell's "pathotropism." Neural stem cells (NSCs), which express CXCR4, migrate to sites of CNS injury or degeneration in part because astrocytes and vasculature produce the inflammatory chemokine CXCL12. Binding of CXCL12 to CXCR4 (a G protein-coupled receptor, GPCR) triggers repair processes within the NSC. Although a tool directing NSCs to where needed has been long-sought, one would not inject this chemokine in vivo because undesirable inflammation also follows CXCL12-CXCR4 coupling. Alternatively, we chemically "mutated" CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions. This synthetic dual-moity CXCR4 agonist not only elicited more extensive and persistent human NSC migration and distribution than did native CXCL 12, but induced no host inflammation (or other adverse effects); rather, there was predominantly reparative gene expression. When co-administered with transplanted human induced pluripotent stem cell-derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex (including as electrophysiologically-active cortical neurons) where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone. Such a "designer" cytokine receptor-agonist peptide illustrates that treatments can be controlled and optimized by exploiting fundamental stem cell properties (e.g., "inflammo-attraction").

The Lysosomal Diseases Testing Laboratory: A review of the past 47 years.

Lysosomal disorders are diseases that involve mutations in genes responsible for the coding of lysosomal enzymes, transport proteins, activator proteins and protein processing enzymes. These defects lead to the storage of specific metabolites within lysosomes resulting in a great variety of clinical features depending on the tissues with the storage, the storage products and the extent of the storage. The methods for rapidly diagnosing patients started in the late 1960's when the enzyme defects were identified eliminating the need for tissue biopsies. The first requests for diagnostic help in this laboratory came in 1973. In that year, patients with Krabbe disease and Niemann-Pick type A were diagnosed. Since that time samples from about 62 000 individuals have been received for diagnostic studies, and 4900 diagnoses have been made. The largest number of diagnosed individuals had metachromatic leukodystrophy and Krabbe disease because of our research interest in leukodystrophies. A number of new disorders were identified and the primary defects in other disorders were clarified. With new methods for diagnosis, including newborn screening, molecular analysis, microarrays, there is still a need for biochemical confirmation before treatment is considered. With new treatments, including gene therapy, stem cell transplantation, enzyme replacement used alone or in combination becoming more available, the need for rapid, accurate diagnosis is critical.

Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease.

Introduction: Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. This results in defective myelination in the peripheral and central nervous systems due to low GALC activity. Treatment at this time is limited to hematopoietic stem cell transplantation (HSCT) in pre-symptomatic individuals. While this treatment extends the lives of treated individuals, most have difficulty walking by the end of the first decade due to peripheral neuropathy. Studies in the murine model of KD, twitcher (twi) combining bone marrow transplantation (BMT) with AAVrh10-mGALC showed a great extension of life from 40 days to about 400 days, with some living a full life time. Methods: In order to find the optimum conditions for dosing and timing of this combined treatment, twi mice were injected with five doses of AAVrh10-mGALC at different times after BMT. Survival, as well as GALC expression were monitored along with studies of sciatic nerve myelination and possible liver pathology. Results: Dosing had a pronounced effect on survival and measured GALC activity. There was window of time after BMT to inject the viral vector and see similar results, however delaying both the BMT and the viral injection shortened the lifespans of the treated mice. Lowering the viral dose too much decreased the correction of the sciatic nerve myelination. There was no evidence for hepatic neoplasia. Conclusion: These studies provide the conditions optimum for successfully treating the murine model of KD. There is some flexibility in dosing and timing to obtain a satisfactory outcome. These studies are critical to the planning of a human trial combining the "standard of care", HSCT, with a single iv injection of AAVrh10-GALC.

Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study.

OBJECTIVES: Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS: We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS: Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION: The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.