Journal of Inherited Metabolic Disease最新文献

{"title":"Impact of theta transcranial alternating current stimulation on language production in adult classic galactosemia patients","authors":"Britt Derks,&nbsp;Varsha Shashi Kumar,&nbsp;Sai Yadnik,&nbsp;Bianca Panis,&nbsp;Annet M. Bosch,&nbsp;David Cassiman,&nbsp;Mirian C. H. Janssen,&nbsp;Teresa Schuhmann,&nbsp;M. Estela Rubio-Gozalbo,&nbsp;Bernadette M. Jansma","doi":"10.1002/jimd.12742","DOIUrl":"10.1002/jimd.12742","url":null,"abstract":"<p>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.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12742","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140664950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy","authors":"Melanie B. Gillingham,&nbsp;Dongseok Choi,&nbsp;Ashley Gregor,&nbsp;Nida Wongchaisuwat,&nbsp;Danielle Black,&nbsp;Hannah L. Scanga,&nbsp;Ken K. Nischal,&nbsp;Jose-Alain Sahel,&nbsp;Georgianne Arnold,&nbsp;Jerry Vockley,&nbsp;Cary O. Harding,&nbsp;Mark E. Pennesi","doi":"10.1002/jimd.12738","DOIUrl":"10.1002/jimd.12738","url":null,"abstract":"<p>Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies","authors":"Bernd C. Schwahn,&nbsp;Francjan van Spronsen,&nbsp;Albert Misko,&nbsp;Julija Pavaine,&nbsp;Victoria Holmes,&nbsp;Ronen Spiegel,&nbsp;Guenter Schwarz,&nbsp;Flora Wong,&nbsp;Alistair Horman,&nbsp;James Pitt,&nbsp;Jörn Oliver Sass,&nbsp;Charlotte Lubout","doi":"10.1002/jimd.12730","DOIUrl":"10.1002/jimd.12730","url":null,"abstract":"<p>Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140609817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass cytometry reveals atypical immune profile notably impaired maturation of memory CD4 T with Gb3-related CD27 expression in CD4 T cells in Fabry disease","authors":"Wladimir Mauhin,&nbsp;Gaelle Dzangue-Tchoupou,&nbsp;Damien Amelin,&nbsp;Aurélien Corneau,&nbsp;Foudil Lamari,&nbsp;Yves Allenbach,&nbsp;Bertrand Dussol,&nbsp;Vanessa Leguy-Seguin,&nbsp;Pauline D'Halluin,&nbsp;Marie Matignon,&nbsp;François Maillot,&nbsp;Kim-Heang Ly,&nbsp;Gérard Besson,&nbsp;Marjolaine Willems,&nbsp;Fabien Labombarda,&nbsp;Agathe Masseau,&nbsp;Christian Lavigne,&nbsp;Didier Lacombe,&nbsp;Hélène Maillard,&nbsp;Olivier Lidove,&nbsp;Olivier Benveniste","doi":"10.1002/jimd.12727","DOIUrl":"10.1002/jimd.12727","url":null,"abstract":"<p>Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45- and CD45 + CCR7-CD4 T cells (respectively <i>p</i> &lt; 0.014 and <i>p</i> &lt; 0.02). Percentage of CD45RA-CCR7-CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (<i>r</i> = 0.60; <i>p</i> = 0.0036) and phenotype (<i>p</i> &lt; 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (<i>r</i> = 0.33; <i>p</i> = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term personalized high-protein, high-fat diet in pediatric patients with glycogen storage disease type IIIa: Evaluation of myopathy, metabolic control, physical activity, growth, and dietary compliance","authors":"Sema Kalkan Uçar,&nbsp;Yasemin Atik Altınok,&nbsp;Yelda Mansuroglu,&nbsp;Ebru Canda,&nbsp;Havva Yazıcı,&nbsp;Merve Yoldaş Çelik,&nbsp;Fehime Erdem,&nbsp;Ayşe Yüksel Yanbolu,&nbsp;Zülal Ülger,&nbsp;Mahmut Çoker","doi":"10.1002/jimd.12741","DOIUrl":"10.1002/jimd.12741","url":null,"abstract":"<p>Dietary lipid manipulation has recently been proposed for managing glycogen storage disease (GSD) type IIIa. This study aimed to evaluate the myopathic, cardiac, and metabolic status, physical activity, growth, and dietary compliance of a personalized diet high in protein and fat for 24 months. Of 31 patients with type IIIa GSD, 12 met the inclusion criteria. Of these, 10 patients (mean age 11.2 ± 7.4 years) completed the study. Patients were prescribed a personalized high-protein, high-fat diet, comprising 3.0–3.5 g/kg/day of protein and 3.0–4.5 g/kg/day of fat, constituting 18.5%–28% and 70.5%–75.7% of daily energy, respectively. Dietary compliance was ensured and assessed via the regular administration of questionnaires. Our results revealed consistent and significant decreases of 22%, 54%, and 30% in the creatinine kinase, creatine kinase–myocardial band, and lactate dehydrogenase levels, respectively. Echocardiography revealed improvements in the Z-scores of the left ventricular mass and interventricular septum thickness. A significant increase in body muscle mass was observed, and a higher score was achieved using the Daily Activity Questionnaire. Growth monitoring revealed an arrest in the height-SDS at the 6th and 12th months, followed by subsequent improvement at the end of the second year. A gradual and persistent decline in the periods of hypo- and hyperglycemia has been reported. Biotinidase activity decreased, whereas hepatosteatosis increased and then decreased by the end of the study. Implementing a high-protein, high-fat diet and monitoring key parameters in patients with type IIIa GSD can lead to myopathic and cardiac improvements and increased physical activity.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variants of unknown significance in alpha-galactosidase A: Cellular delineation from Fabry disease","authors":"Alexandra Klein,&nbsp;Katharina Klug,&nbsp;Maximilian Breyer,&nbsp;Julia Grüner,&nbsp;Vijay Krishna Medala,&nbsp;Peter Nordbeck,&nbsp;Christoph Wanner,&nbsp;Eva Klopocki,&nbsp;Nurcan Üçeyler","doi":"10.1002/jimd.12743","DOIUrl":"10.1002/jimd.12743","url":null,"abstract":"<p>Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (<i>GLA</i>). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 <i>GLA</i> variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (<i>p</i> &lt; 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (<i>p</i> &lt; 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in <i>GLA</i>.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12743","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered neural oscillations in classical galactosaemia during sentence production","authors":"Sara Mazzini,&nbsp;Sai Yadnik,&nbsp;Inge Timmers,&nbsp;Estela Rubio-Gozalbo,&nbsp;Bernadette M. Jansma","doi":"10.1002/jimd.12740","DOIUrl":"10.1002/jimd.12740","url":null,"abstract":"<p>Classical galactosaemia (CG) is a hereditary disease in galactose metabolism that despite dietary treatment is characterized by a wide range of cognitive deficits, among which is language production. CG brain functioning has been studied with several neuroimaging techniques, which revealed both structural and functional atypicalities. In the present study, for the first time, we compared the oscillatory dynamics, especially the power spectrum and time–frequency representations (TFR), in the electroencephalography (EEG) of CG patients and healthy controls while they were performing a language production task. Twenty-one CG patients and 19 healthy controls described animated scenes, either in full sentences or in words, indicating two levels of complexity in syntactic planning. Based on previous work on the P300 event related potential (ERP) and its relation with theta frequency, we hypothesized that the oscillatory activity of patients and controls would differ in theta power and TFR. With regard to behavior, reaction times showed that patients are slower, reflecting the language deficit. In the power spectrum, we observed significant higher power in patients in delta (1–3 Hz), theta (4–7 Hz), beta (15–30 Hz) and gamma (30–70 Hz) frequencies, but not in alpha (8–12 Hz), suggesting an atypical oscillatory profile. The time-frequency analysis revealed significantly weaker event-related theta synchronization (ERS) and alpha desynchronization (ERD) in patients in the sentence condition. The data support the hypothesis that CG language difficulties relate to theta–alpha brain oscillations.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12740","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG","authors":"Earnest J. P. Daniel,&nbsp;Andrew C. Edmondson,&nbsp;Yair Argon,&nbsp;Hind Alsharhan,&nbsp;Christina Lam,&nbsp;Hudson H. Freeze,&nbsp;Miao He","doi":"10.1002/jimd.12739","DOIUrl":"10.1002/jimd.12739","url":null,"abstract":"<p>ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man₅GlcNAc₂ (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway. In addition, we show that N-linked Man3-4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non-hepatic origin. We found that like other CDGs such as ALG1- or PMM2-CDG, in transferrin, the assembling intermediate Man5 in ALG3-CDG, are likely further processed into a distinct glycan, NeuAc₁Gal₁GlcNAc₁Man₃GlcNAc₂, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3-CDG which will have important implications in the pathogenesis of CDG.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure","authors":"J. J. Wedman,&nbsp;O. C. M. Sibon,&nbsp;E. Mastantuono,&nbsp;A. Iuso","doi":"10.1002/jimd.12737","DOIUrl":"10.1002/jimd.12737","url":null,"abstract":"<p>Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4′-phosphopantetheine.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12737","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning","authors":"J. J. A. van den Dorpel,&nbsp;M. J. Mackenbach,&nbsp;M. H. G. Dremmen,&nbsp;W. M. C. van der Vlugt,&nbsp;D. Rizopoulos,&nbsp;P. A. van Doorn,&nbsp;A. T. van der Ploeg,&nbsp;R. Muetzel,&nbsp;N. A. M. E. van der Beek,&nbsp;J. M. P. van den Hout","doi":"10.1002/jimd.12736","DOIUrl":"10.1002/jimd.12736","url":null,"abstract":"<p>The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5–22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (<i>p</i> &lt; 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (<i>p</i> = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1–6.0 points) in all the IQ index scores (<i>p</i> &lt; 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood–brain barrier in order to treat this CNS phenotype.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12736","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}