The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. PKU treatment is based on a low-Phe diet, 6R-tetrahydrobiopterin (BH4) treatment for the ...BH4-responsive PKU patients or enzyme replacement therapy. Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). The aim of this work is to study the fluctuation of Blood Phe in patients treated by BH4 from birth in comparison with patients treated by low-Phe diet. We conducted a retrospective study in a national reference center for PKU management. We compared mean phenylalanine blood concentration and its fluctuation in 10 BH4-responder patients (BH4R) and in 10 BH4 non-responder patients (BH4NR) treated from birth. The mean blood Phe concentration is similar between the two groups before 10 years of age (290 ± 135 (BH4R) vs. 329 ± 187 µmol/L, p = 0.066 (BH4NR)) while it is lower in the BH4R group after 10 years of age. (209 ± 69 vs. 579 ± 136 µmol/L, p = 0.0008). Blood Phe fluctuation is significantly lower in the BH4R group compared to the BH4NR group (70.2 ± 75.6 vs. 104.4 ± 111.6 µmol/L, p < 0.01) before 6 years of age. There are no significant differences observed on nutritional status, growth, and neuropsychological tests between the two groups. BH4 introduced in the neonatal period is associated with less blood Phe fluctuation before 6 years. Additional time and patients are required to determine if the decrease in Phe fluctuation would positively impact the long-term outcome of PKU patients.
Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in
CYP2R1,
which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial ...role in the conversion of vitamin D to 25-dihydroxyvitamin D
3
. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1–25(OH)
2
vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.
Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the ...phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.
Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.
We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.
In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of ...neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism.
The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze.
Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice.
By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.
•Defects of cobalamin metabolism lead to mislocalization of RNA binding proteins.•SRT1720 treatment rescued abnormal localization of RNA binding proteins.•SRT1720 treatment improved the cognitive defects observed in a transgenic mouse model.
Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS ...are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities.
In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments.
Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P
and P
), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2-2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency.
For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.
Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of ...metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
Background:
Multisystem inflammatory syndrome in children (MIS-C) is the most severe form associated with SARS-CoV-2 infection in children. To reduce the spread of SARS-CoV-2 at the population level, ...educational setting closure have been implemented in many countries. However, the direct benefit of school closure on the MIS-C burden remains to be explored. We aimed to assess the role of educational settings in SARS-CoV-2 transmission among children with MIS-C.
Methods:
We conducted a French national prospective surveillance of MIS-C, coordinated by Public Health France, from April 2020 to March 2021. During this period, we included all children with MIS-C fulfilling the WHO definition who were reported to Public Health France. For each child, we traced the source of SARS-CoV-2 transmission. The main outcome was the proportion of children with MIS-C, with educational setting-related SARS-CoV-2 infection, during the period of school opening.
Results:
We included 142 children fulfilling WHO criteria for MIS-C: 104 (70%) cases occurred during school opening periods. In total, 62/104 children (60%, 95%CI 50; 69) had been contaminated by a household contact and 5/104 in educational settings (5%, 95%CI 2; 11). Among children with MIS-C occurring during school closure periods, the proportion of household transmission remained similar (66%, 25/38).
Conclusion:
Children with MIS-C were mainly infected by SARS-CoV-2 within their family environment, and the educational setting played a marginal role in this transmission. This suggests that mitigating school attendance may not reduce substantially the burden of MIS-C.
Inherited disorders of cobalamin (cbl) metabolism (
cblA-J
) result in accumulation of methylmalonic acid (MMA) and/or homocystinuria (HCU). Clinical presentation includes ophthalmological ...manifestations related to retina, optic nerve and posterior visual alterations, mainly reported in cblC and sporadically in other
cbl
inborn errors.
We searched MEDLINE EMBASE and Cochrane Library, and analyzed articles reporting ocular manifestations in
cbl
inborn errors. Out of 166 studies a total of 52 studies reporting 163
cbl
and 24
mut
cases were included. Ocular manifestations were found in all
cbl
defects except for cblB and cblD-MMA;
cblC
was the most frequent disorder affecting 137 (84.0%) patients. The
c.271dupA
was the most common pathogenic variant, accounting for 70/105 (66.7%) cases. One hundred and thirty-seven out of 154 (88.9%) patients presented with early-onset disease (0–12 months). Nystagmus and strabismus were observed in all groups with the exception of MMA patients while maculopathy and peripheral retinal degeneration were almost exclusively found in MMA-HCU patients. Optic nerve damage ranging from mild temporal disc pallor to complete atrophy was prevalent in MMA-HCU.and MMA groups. Nystagmus was frequent in early-onset patients. Retinal and macular degeneration worsened despite early treatment and stabilized systemic function in these patients. The functional prognosis remains poor with final visual acuity < 20/200 in 55.6% (25/45) of cases. In conclusion, the spectrum of eye disease in Cbl patients depends on metabolic severity and age of onset. The development of visual manifestations over time despite early metabolic treatment point out the need for specific innovative therapies.
IMPORTANCE: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially ...life-threatening, but the optimal therapeutic strategy remains unknown. OBJECTIVE: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study drawn from a national surveillance system with propensity score–matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. EXPOSURES: IVIG and methylprednisolone vs IVIG alone. MAIN OUTCOMES AND MEASURES: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. RESULTS: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females 52%; median age, 8.6 years interquartile range, 4.7 to 12.1). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, −0.28 95% CI, −0.48 to −0.08; odds ratio OR, 0.25 95% CI, 0.09 to 0.70; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, −0.22 95% CI, −0.40 to −0.04; OR, 0.19 95% CI, 0.06 to 0.61; P = .004), hemodynamic support (absolute risk difference, −0.17 95% CI, −0.34 to −0.004; OR, 0.21 95% CI, 0.06 to 0.76), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, −0.18 95% CI, −0.35 to −0.01; OR, 0.20 95% CI, 0.06 to 0.66), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, −2.4 95% CI, −4.0 to −0.7). CONCLUSIONS AND RELEVANCE: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
Infection is an important cause of death during infancy worldwide and is a frequent etiology of sudden unexpected death in infancy (SUDI). Procalcitonin (PCT) is a useful marker to diagnose infection ...in patients, and several studies report the stability of PCT after death. The added value of a biological marker, such as the PCT level in the blood, remains controversial in investigating SUDI. The aim of this study was to determine if PCT can help clinicians determine whether infection caused SUDI. We conducted a retrospective, multicenter study with the French SUDI registry (Observatoire National des Morts Inattendues du Nourrisson; OMIN). We collected data from this registry on children who died between May 2015 and June 2021. The levels of PCT in the blood of 540 SUDI patients were measured. We compared PCT and other biological tests performed in terms of infection status, autopsy results, and cause of death using clinical and biological data compiled by pediatricians at the SUDI referral center. PCT levels were significantly higher in the children who died from infection than in those who did not (0.12 µg/L vs. 0.08 µg/L,
p
< 0.001). A PCT blood level exceeding 0.2 µg/L was more frequently observed when infection was present than in the absence of infection (44.3% vs. 15.4%,
p
< 0.001). The same data were obtained with a 0.5 µg/L cut-off (36.1% with infection vs. 9.2% without,
p
< 0.001).
Conclusions
: PCT is a sensitive biomarker for detecting infections postmortem; thus, additional samples may be necessary during autopsy.
What is known:
• PCT is a stable marker postmortem and increases earlier than CRP, i.e., 2–4 h after the beginning of an infection vs. 6 h.
• PCT can be measured up to 140 h after death.
What is new:
• PCT is a sensitive marker for detecting infection in SUDI patients postmortem.
• This test can reveal an infection from non-standardized samples obtained during autopsy if such an infection was not determined before death.
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