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Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.

Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case–control study evaluated 40 cases who progressed to ESRD during 8–12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry–based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid–derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.

Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon postmortem investigation. Previously, we reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL] (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.

Background Propionic acidemia (PA) is a rare disease resulting in toxic accumulation of metabolites that cause metabolic decompensation events (MDEs). Natural history characterization of PA is limited partly due to its rarity and complexity. This study examined clinical events in participants with PA and their correlation with biomarkers to better understand the disease. Methods Participants diagnosed with PA (early- versus late-onset) were evaluated every 6 months from baseline to month 36. Outcome measures included annualized MDEs and changes in 3-hydroxypropionic acid (3-HP), 2-methylcitrate (2-MC), and propionylcarnitine (C3) concentrations. Blood samples were collected at each visit and during MDEs for plasma biomarker analyses. Relative risk (RR) was calculated based on MDE rates and biomarker levels. Results Most participants (n/ N  = 49/50, 98.0%) reported MDEs. Annualized MDE rates were highest in participants aged 0 to ≤ 1 and > 1 to ≤ 2 versus > 12 to ≤ 18 years (2.6 and 2.4, respectively, vs 0.2) and for early-onset versus late-onset PA (1.2 vs 0.3). A 50% decrease in plasma biomarkers was associated with a statistically significant reduction in RR of MDEs for 3-HP (RR: 0.7, 95% CI: 0.6–0.9; p  < 0.01) and a substantial reduction for C3 (RR: 0.6, 95% CI: 0.4–0.9; p  = 0.017); no effect was observed for 2-MC. Conclusions MDE rates were higher in the youngest participants (0 to ≤ 2 years) versus participants aged > 12 years, and with early- versus late-onset PA. Lower concentrations of 3-HP and C3 were associated with a reduced MDE risk. These findings may guide biomarker or clinical endpoints in future treatment trials.

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut ⁻/⁻ mice as a stable transgene under the control of an albumin (INS-Alb- Mut) promoter. Mut ⁻/⁻;Tg ᴵᴺS⁻ᴬˡᵇ⁻ᴹᵘᵗ mice, although completely rescued from neonatal lethality that was displayed by Mut ⁻/⁻ mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut ⁻/⁻;Tg ᴵᴺS⁻ᴬˡᵇ⁻ᴹᵘᵗ kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut ⁻/⁻;Tg ᴵᴺS⁻ᴬˡᵇ⁻ᴹᵘᵗ mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17–5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.

Background Galactose epimerase (GALE) deficiency is a rare hereditary disorder of galactose metabolism with only a few cases described in the literature. This study aims to present the data of patients with GALE deficiency from different countries included through the Galactosemia Network to further expand the existing knowledge and review the current diagnostic strategy, treatment and follow-up of this not well characterized entity. Methods Observational study collecting medical data from December 2014 to April 2022 of 22 not previously reported patients from 14 centers in 9 countries. Patients were classified as generalized or non-generalized based on their genotype, enzyme activities in different tissues and/or clinical picture and professional judgment of the treating physician. Results In total 6 patients were classified as generalized and 16 as non-generalized. In the generalized group, acute neonatal illness was reported in 3, cognitive and developmental delays were present in 5 and hearing problems were reported in 3. Four generalized patients were homozygous for the genetic variant NM_001008216.2:c.280G > A (p.Val94Met). In the non-generalized group, no clearly related symptoms were found. Ten novel genetic variants were reported in this study population. Conclusion The phenotypic spectrum of GALE deficiency ranges from asymptomatic to severe. The generalized patients have a phenotype that is in line with the 9 described cases in the literature and prescribing dietary interventions is the cornerstone for treatment. In the non-generalized group, treatment advice is more difficult. To be able to offer proper counseling, in addition to red blood cell enzyme activity, genetic studies, transferrin glycoform analysis and enzymatic measurements in fibroblasts are recommended. Due to lack of facilities, additional enzymatic testing is not common practice in many centers nor a tailored long-term follow-up is performed.

Objective The developmental and epileptic encephalopathies (DEE) are associated with serious and lifelong neurological conditions and risk of early mortality. Here, we describe the chronic treatment of a boy with PLCB1‐related DEE with enteral myo‐inositol supplementation as an add‐on therapy to standard antiseizure medications that had been ineffective, and present novel findings in our lethal Slc5a3 knockout mouse model to substantiate our hypothesis for a novel role of myo‐inositol in prenatal life. Methods Myo‐inositol levels were measured in plasma, urine, and cerebrospinal fluid (CSF) using stable isotope dilution and selected ion monitoring gas chromatography/mass spectrometry. Brain function and structure were monitored with magnetic resonance spectroscopy, magnetic resonance imaging, and electroencephalograms. Safety studies were performed according to Food and Drug Administration requirements. Results Treatment was well tolerated without any adverse events. There was an improvement in seizure burden and stabilization of brain atrophy that was most evident in the first and second years of life. Myo‐inositol administration to the pregnant Slc5a3 carrier mice increased the myo‐inositol content in the CSF of the Slc5a3 knockout pups, which prevented their death. Interpretation High‐dose enteral myo‐inositol supplementation was safely used in a patient with epileptic encephalopathy due to PLCB1 deletion, increasing CSF levels and improving seizures and brain atrophy. The hypothesized mechanism involves restoring a fetal‐like state with increased membrane potential, thereby reducing neuronal firing. Based on our experience, we encourage the exploration of high‐dose myo‐inositol in clinical trials involving infants with severe epileptic encephalopathy.

We report two patients with PMM2‐CDG who developed end stage renal disease (ESRD). Renal abnormalities of clinical significance have only been reported in about 6% of patients with PMM2‐CDG and have rarely been reported as the cause of death. Given the recurrent episodes of acute kidney injury associated with hospital admissions and the accelerated development of ESRD thereafter in our two patients, we recommend proactively involving Nephrology early in the care of these patients.