Purpose
Several weeks after COVID-19 infection, some children report the persistence or recurrence of functional complaints. This clinical presentation has been referred as “long COVID” in the adult ...population, and an
18
F-FDG brain PET hypometabolic pattern has recently been suggested as a biomarker. Herein, we present a retrospective analysis of 7 paediatric patients with suspected long COVID who were explored by
18
F-FDG brain PET exam. Metabolic brain findings were confronted to those obtained in adult patients with long COVID, in comparison to their respective age-matched control groups.
Methods
Review of clinical examination and whole-brain voxel-based analysis of
18
F-FDG PET metabolism of the 7 children in comparison to 21 paediatric controls, 35 adult patients with long COVID and 44 healthy adult subjects.
Results
Despite lower initial severity at the acute stage of the infection, paediatric patients demonstrated on average 5 months later a similar brain hypometabolic pattern as that found in adult long COVID patients, involving bilateral medial temporal lobes, brainstem and cerebellum (p-voxel < 0.001, p-cluster < 0.05 FWE-corrected), and also the right olfactory gyrus after small volume correction (p-voxel = 0.010 FWE-corrected), with partial PET recovery in two children at follow-up.
Conclusion
These results provide arguments in favour of possible long COVID in children, with a similar functional brain involvement to those found in adults, regardless of age and initial severity.
The risk of neuropsychological disorders appears to be high in hyperphenylalaninemia (HPA). The hypothesis of executive function impairment is prominent in accounting for the neuropsychological ...phenotype in phenylketonuria (PKU) and is suspected in moderate hyperphenylalaninemia (MHP). However, the issue of early onset of executive disorders remains. The aim of this study was to explore the hypothesis of early executive dysfunction in HPA patients and the possible links with certain metabolic variables according to the new international classifications for patients with PKU and MHP. A group of 23 HPA children (12 PKU, 11 MHP) aged 3 to 5 years was included and compared to 50 control children. The two groups were comparable in terms of socio-demographics (age, sex, parental education level). Executive functions were assessed using performance-based tests and daily life questionnaires (parents and teachers).
Preschool HPA patients have comparable executive scores to control subjects. In contrast, PKU patients score significantly worse than MHP patients on 3 executive tests (verbal working memory, visual working memory and cognitive inhibition. There is no executive complaints in daily life (parents and teachers) for the 2 groups of patients. In addition, 3 correlations were identified between executive scores and Phe levels at inclusion, mean Phe level and variability of Phe levels throughout life.
Thus, there appears to be evidence of early executive dysfunction in PKU preschool-children, but not in MHP children. Occasionally, certain metabolic indicators can predict executive difficulties in young children with PKU.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public ...healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination-Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.
Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity ...mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.
Objective
Wolfram syndrome (WS) is a rare neurodegenerative disorder characterized by juvenile‐onset diabetes mellitus and optic atrophy. Our aim was to describe the nature and the frequency of the ...neurologic manifestations, which had been poorly studied until now.
Methods
We performed a detailed clinical study with genotype‐phenotype correlation in a series of 59 patients with WS.
Results
The onset of neurologic symptoms, with a median age of 15 years, was much earlier than previously reported. Cognitive impairment, which was not frequent in previous reports, was observed in 32% of patients with neurologic signs. Like epilepsy, it was mainly found in patients who developed neurologic signs before 15 years of age. In contrast to previous series, we also found malformations of cortical development on magnetic resonance imaging in epileptic children and white matter involvement, including diffuse leukoencephalopathy, in adult patients. We identified 109 mutated alleles corresponding to 56 different mutations of the WFS1 gene, among which 10 were novel. Homozygosity or compound heterozygosity for missense mutation does not seem to influence the age of onset and the occurrence of neurologic complications. However, an interesting point concerns a possible correlation between the location of the mutations and the development of the neurologic manifestations.
Interpretation
This series concerns the largest cohort of WS patients reported to date. It illustrates the wide variety of neurologic signs in this syndrome and the necessity of rapid therapeutic coverage to improve the prognosis. Ann Neurol 2010.
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize ...neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients.
Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded.
Ten patients were included in the treated group (year of birth: 2006-2012), and 16 patients in the untreated group born 1987-2005 (n = 15), 2012 (n = 1). The median age at neurological onset was 9 months (5-18) in the treated group, and 12 months (3-18) in the untreated group (p = 0.22). Miglustat therapy was started at a median age of 24.5 months (9-29) and median duration was 30 months (11-56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p = 0.11).
Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C.
Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase ...alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.
This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.
As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.
To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.
Collagen type VI-related dystrophies (COL6-RD) are rare diseases with a wide phenotypic spectrum ranging from severe Ullrich's congenital muscular dystrophy Ullrich congenital muscular dystrophy to ...much milder Bethlem myopathy Both dominant and recessive forms of COL6-RD are caused by pathogenic variants in three collagen VI genes (
,
and
). The prognosis of these diseases is variable and difficult to predict during early disease stages, especially since the genotype-phenotype correlation is not always clear. For this reason, studies with long-term follow-up of patients with genetically confirmed COL6-RD are still needed. In this study, we present phenotypic and genetic data from 25 patients (22 families) diagnosed with COL6-RD and followed at a single French center, in both adult and pediatric neurology departments. We describe three novel pathogenic variants and identify
:c.1970-9G>A as the most frequent variant in our series (29%). We also observe an accelerated progression of the disease in a subgroup of patients. This large series of rare disease patients provides essential information on phenotypic variability of COL6-RD patients as well as on frequency of pathogenic
gene variants in Southern France, thus contributing to the phenotypic and genetic description of Collagen type VI-related dystrophies.
Transition from childhood to adulthood (TCA) is usually difficult in rare, progressive and multisystemic diseases. New treatments and modalities of care for many lysosomal diseases (LD) can increase ...life expectancy, and a successful TCA can help patient who reach adulthood to avoid disruption to health care. In France, some TCA initiatives have been taken by referral centers but in view of the problems encountered by Vaincre les Maladies Lysosomales (VML), the LD patient association, they seem to be insufficient. The aim of this study is to determine the current state of the TCA process and to identify actions to improve it through interviews with patient families and physicians in LD referral centers. The study is based upon an observational, non-interventional, cross-sectional, national survey which used two anonymous questionnaires. These questionnaires, developed by a scientific committee including representatives from VML and medical specialists in LD, were sent to patients who were receiving care in pediatric departments at age 15 years or older. Questionnaires were also sent to their referral pediatricians.
Fifty-four patients were included. Forty-two questionnaires were completed by patients and their corresponding physicians and 12 were completed by physicians only. The majority of the patients (80%) were informed that transfer to adult healthcare would occur, but 52% were informed after their eighteenth birthday. Forty-eight percent indicated that they were informed that a TCA coordinator would be appointed; for 39% the time frame for the transfer was communicated, and 31% were informed of the composition of the adult medical team. Among the actions that patients rated as "important/very important", and considered to be a priority in their comments, the most frequently cited were the provision of explanatory documents on the TCA (94%), the transmission of the medical file from the pediatric sector to the adult sector (94%) and a joint consultation with both pediatrician and adult unit physician (91%). Physicians were in agreement concerning the primary importance of the last two actions.
This study provides a basis for the deployment, on the national level, of transition programs which include specific actions that patients view as priorities.
Background and aim
To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation.
Methods
Datasets of ...567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA,
n
= 164), propionic (PA,
n
= 144) and isovaleric aciduria (IVA,
n
= 83), and glutaric aciduria type 1 (GA1,
n
= 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO).
Results
Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days,
p
< 0.001, but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl
−
) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl
−
: 10 % versus 39 %,
p
= 0.002; GA1: 26 % versus 73 %,
p
< 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl
−
to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used.
Conclusions
NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl
−
. Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.
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