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We report on the largest single dataset of patients with PMM2‐CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease‐associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2‐CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration:NCT03173300. [ABSTRACT FROM AUTHOR]

Patients with classic galactosemia (CG), an inborn error of galactose metabolism, suffer from impairments in cognition, including language processing. Potential causes are atypical brain oscillations. Recent electroencephalogram (EEG) showed differences in the P300 event‐related‐potential (ERP) and alterations in the alpha/theta‐range during speech planning. This study investigated whether transcranial alternating current stimulation (tACS) at theta‐frequency compared to sham can cause a normalization of the ERP post stimulation and improves language performance. Eleven CG patients and fourteen healthy controls participated in two tACS‐sessions (theta 6.5 Hz/sham). They were engaged in an active language task, describing animated scenes at three moments, that is, pre/during/post stimulation. Pre and post stimulation, behavior (naming accuracy, voice‐onset‐times; VOT) and mean‐amplitudes of ERP were compared, by means of a P300 time‐window analysis and cluster‐based‐permutation testing during speech planning. The results showed that theta stimulation, not sham, significantly reduced naming error‐percentage in patients, not in controls. Theta did not systematically speed up naming beyond a general learning effect, which was larger for the patients. The EEG analysis revealed a significant pre‐post stimulation effect (P300/late positivity), in patients and during theta stimulation only. In conclusion, theta‐tACS improved accuracy in language performance in CG patients compared to controls and altered the P300 and late positive ERP‐amplitude, suggesting a lasting effect on neural oscillation and behavior. [ABSTRACT FROM AUTHOR]

Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end‐stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long‐term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. None of the siblings treated from neonatal age (n = 9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n = 9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared with their index counterparts, reached ESKD at a significant older age (13 ± 3 vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs. Synopsis: In infantile nephropathic cystinosis, presymptomatic treatment with cysteamine improves the renal outcome which justifies the inclusion of cystinosis into newborn screening programs. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive disease leading to end‐stage renal disease within the second or third decade of life. Since the era of specific treatment with cysteamine, prognosis has substantially improved and pregnancy becomes an increasing concern. Pregnancy data in patients with cystinosis were collected through an anonymized survey. We collected data for 19 pregnancies in 12 women. Seventeen patients were transplanted, 1 was on hemodialysis and 1 had chronic kidney disease (CKD) stage 4. These 19 pregnancies resulted in 13 live births (68.4%): 3 spontaneous early miscarriages, 1 ectopic pregnancy, 1 early pre‐eclampsia (at 21 weeks), and 1 preterm birth with neonatal death at 24 weeks were reported. After exclusion of early miscarriage or termination, pregnancy success rate was 86.7%. In successful pregnancies, median gestational age at delivery was 34 weeks (24–37). Preeclampsia occurred in seven pregnancies (7/15, 46.7%). A cesarean section was performed in all pregnancies. Median baby weight at delivery was 2175 g (620–3374 g). After pregnancy, one patient reached end‐stage renal disease, but she already had advanced CKD before pregnancy (creatinine 239 μmol/L, eGFR 23 ml/min/1.73 m2). In three other patients, there was a decrease of eGFR of 8, 20, and 53 ml/min/1.73 m2, respectively. The majority of pregnancies were successful, but severe antenatal and post‐natal complications may occur, in particular preeclampsia that was noticed in nearly half of patients and fetal loss in one‐third of them. These results may help pre‐pregnancy counseling and pregnancy management. [ABSTRACT FROM AUTHOR]