Journal of Inherited Metabolic Disease最新文献

{"title":"Reshaping the Treatment Landscape of a Galactose Metabolism Disorder","authors":"M. Estela Rubio-Gozalbo,&nbsp;E. Naomi Vos,&nbsp;Isabel Rivera,&nbsp;Kent Lai,&nbsp;Gerard T. Berry","doi":"10.1002/jimd.70013","DOIUrl":"https://doi.org/10.1002/jimd.70013","url":null,"abstract":"<p>The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the <i>GALT</i> gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423971","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":"C1GALT1C1-Associated Mosaic Disorder of Glycosylation in a Female","authors":"Rajindra P. Aryal,&nbsp;Aditya Ramanujan,&nbsp;Camille Bucci,&nbsp;Christian Neckelmann,&nbsp;Jamie Heimburg-Molinaro,&nbsp;Sandra F. Cummings,&nbsp;Florian Erger,&nbsp;Bodo B. Beck,&nbsp;Laurie H. Seaver,&nbsp;Richard D. Cummings","doi":"10.1002/jimd.70006","DOIUrl":"https://doi.org/10.1002/jimd.70006","url":null,"abstract":"<p>Cosmc, encoded by the X-linked <i>C1GALT1C1</i>, is a molecular chaperone in the endoplasmic reticulum and a master regulator of O-glycosylation of mammalian glycoproteins. Recently, we described a germline mutation in <i>C1GALT1C1</i> in two male patients, giving rise to a congenital disorder of glycosylation—<i>COSMC</i>-CDG. Here, we have identified a female patient with a <i>de novo</i> mosaic variant in <i>C1GALT1C1</i> (c.202C&gt;T, p.Arg68*), which results in a truncated and nonfunctional form of Cosmc (Cosmc-R68). The patient is mosaic, as ~27% of her buccal cells carry the mutation. The patient is now a 5-year old who presented with nonimmune hydrops fetalis. As Cosmc is essential for the generation of normal O-glycans through regulating T-synthase activity, thereby enabling the formation of the universal Core 1 O-glycan Galβ1-3GalNAcα1-Ser/Thr (T-antigen), the loss of Cosmc leads to the expression of the unusual precursor O-glycan termed Tn-antigen (CD175) (GalNAcα1-Ser/Thr). Owing to the mutational mosaicism, only a significant minority of cells would exhibit abnormal O-glycosylation. Analysis of red blood cells (RBCs), leukocytes, and serum from this patient indicated reduced expression of Cosmc and T-synthase proteins and lower T-synthase activity. Consistent with these findings, we observed reduced normal O-glycans in serum glycoproteins and RBCs from the patient, along with elevated expression of the Tn-antigen in serum glycoproteins compared to controls. This case represents the first description of a true mosaic loss-of-function variant in <i>C1GALT1C1</i>, that is, one that occurred postzygotically during embryogenesis, and raises interesting questions about the role of O-glycosylation during fetal development and its consequences on the clinical presentation.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404536","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":"Human Milk Feeding in Inherited Metabolic Disorders: A Systematic Review of Growth, Metabolic Control, and Neurodevelopment Outcomes","authors":"Fatma Ilgaz,&nbsp;Alexander Höller,&nbsp;Cyril Marsaux,&nbsp;Sandra Banta-Wright,&nbsp;Turgay Coşkun,&nbsp;Kelly A. Dingess,&nbsp;Monika Jörg-Streller,&nbsp;Camille Newby,&nbsp;Rani Singh,&nbsp;Bernd Stahl,&nbsp;Clare Szwec,&nbsp;Annemiek van Wegberg,&nbsp;Willie Woestenenk,&nbsp;Anita MacDonald,&nbsp;Daniela Karall","doi":"10.1002/jimd.70001","DOIUrl":"https://doi.org/10.1002/jimd.70001","url":null,"abstract":"<p>Human milk (HM) is the optimal source of nutrition for infants. Yet the suitability of HM macronutrient composition, paired with the challenge of regulating HM intake, may deserve some consideration for infants with inherited metabolic disorders (IMDs) requiring restrictive and controlled dietary management. Except for classic galactosemia, HM feeding is expected to be feasible, allowing infants to maintain metabolic stability, while growing and developing optimally. However, information about HM feeding in nonphenylketonuria (PKU) literature is scarce. In this systematic review, 52 studies were included, representing 861 infants (86% PKU) receiving HM after IMD diagnosis (mean duration 4–10 months depending on the IMD). For non-PKU IMDs (e.g., other amino acidopathies, urea cycle disorders, organic acidemias, fatty acid oxidation disorders), outcomes of HM feeding were available for few infants, except for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (<i>n</i> = 48). In PKU, HM feeding combined with phenylalanine-free formula, led to adequate metabolic control (25 studies), growth (15 studies), and neurodevelopment (10 studies). For other IMDs, more evidence is required, but the limited data suggest that HM feeding is possible, with attentive monitoring and disease-specific formula supplementation where applicable. In MCAD deficiency, ensuring adequate HM intake is essential, as symptoms were more frequently reported in exclusively breastfed infants. No IMD-specific articles were found on the relationship between HM feeding and many other outcomes of interest (e.g., immune status or comorbidity risk later in life). With the exception of galactosemia, HM feeding is expected to benefit infants with IMD. More data should be published for IMDs other than PKU.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248883","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":"The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: 10 Years Later, Another Report From the SSIEM Adult Metabolic Physicians Group","authors":"Michel Tchan,&nbsp;Anna Lehman,&nbsp;Laura van Dussen,&nbsp;Janneke G. Langendonk,&nbsp;Mirian C. H. Janssen,&nbsp;Mirjam Langeveld,&nbsp;Elaine Murphy,&nbsp;Bryony Ryder,&nbsp;Emma Glamuzina,&nbsp;Martin Merkel,&nbsp;Annalisa Sechi,&nbsp;Jean-Baptiste Arnoux,&nbsp;Fanny Mochel,&nbsp;Gonnie Alkemade,&nbsp;Francois Maillot,&nbsp;Elsa Kaphan,&nbsp;Karin Mazodier,&nbsp;Quentin Thomas,&nbsp;Vanessa Leguy-Seguin,&nbsp;Cecilia Marelli","doi":"10.1002/jimd.70005","DOIUrl":"https://doi.org/10.1002/jimd.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>There are still few centres, which specialise in the care of adults with inborn errors of metabolism (IEM). All physicians who participated in the SSIEM adult metabolic physicians group paper in 2014 were contacted to provide updated data on their IEM patients. Fifteen adult centres responded to our survey with information on their patients. Nine thousand, six hundred fifty-one patients were included in the final cohort, compared with 6 182 in the previous analysis. There were 394 separate diagnoses. The most common diseases were phenylketonuria (19.6%), mitochondrial disorders (12.3%) and lysosomal storage disorders such as Fabry disease (20.1% of LSD's), Pompe disease (3.1%), and Gaucher disease (2.8%). Among the disorders that can present with acute metabolic decompensation, the urea cycle disorders (4.0%), were most common (ornithine transcarbamylase deficiency 2.6%), followed by maple syrup urine disease (1.1%) and glycogen storage disease type I (0.7%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. Many patients are only diagnosed in adulthood (&gt; 40%) and the cohort is increasing substantially with 9 651 patients included in the final analysis (34% increase compared to our original paper). Thus reinforcing the need for adult specialists to be trained in this area.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248884","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":"Contribution of Brain Intrinsic Branched-Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease","authors":"Amanda C. Kuhs,&nbsp;Laura Ohl,&nbsp;Tegan Thurston,&nbsp;Jeet Singh,&nbsp;Sangeetha Bhuyan,&nbsp;Sarah Grandinette,&nbsp;Jing Xu,&nbsp;Sophie A. Siemsgluess,&nbsp;Youseff Jakher,&nbsp;Rebecca C. Ahrens-Nicklas","doi":"10.1002/jimd.70003","DOIUrl":"https://doi.org/10.1002/jimd.70003","url":null,"abstract":"<div>\u0000 \u0000 <p>Maple syrup urine disease (MSUD) results from loss of branched-chain ketoacid dehydrogenase (BCKDH) activity, the committed, rate-limiting step of branched-chain amino acid (BCAA) oxidation. Current treatments, including a low protein diet and liver transplantation, improve peripheral biochemistry and limit episodes of metabolic decompensation but do not fully prevent chronic neuropsychiatric symptoms. The mechanisms underlying chronic neurologic phenotypes remain poorly understood. Currently available MSUD mouse models do not survive long enough to evaluate chronic central nervous system (CNS) pathology. To investigate if loss of brain-intrinsic BCAA metabolism contributes to chronic neurologic disease, we developed a new brain-specific knockout mouse model of MSUD. First, we generated a mouse harboring a floxed <i>Dbt</i> allele (<i>Dbt</i>^flox/flox). Then we crossed this line with Cre recombinase driver lines to induce loss of <i>Dbt</i> expression in (1) all developing CNS cell populations (2) neurons alone or (3) astrocytes alone. We found that brain-specific KO mice have elevations in BCAA levels in cortex that are exacerbated by a high protein diet. They also have secondary changes in amino acids in brain that are important for neuronal function, including glutamine and glycine. These metabolic differences result in subtle functional deficits as measured by electroencephalogram and behavioral testing. Astrocyte and neuron-specific KO mice each also demonstrate mild biochemical features of MSUD in the cortex, suggesting that both cell populations may contribute to disease pathology. Collectively, these data suggest that therapies targeting the CNS directly, in addition to the periphery, may improve outcomes in MSUD.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111629","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":"Assessment of Long-Term Safety and Efficacy of Purple Sweet Potato Color (PSPC) and Myo-Inositol (MI) Treatment for Motor Related and Behavioral Phenotypes in a Mouse Model of Classic Galactosemia","authors":"Olivia Bellagamba,&nbsp;Aaron j Guo,&nbsp;Sandhya Senthilkumar,&nbsp;Synneva Hagen Lillevik,&nbsp;Davide De Biase,&nbsp;Kent Lai,&nbsp;Bijina Balakrishnan","doi":"10.1002/jimd.70002","DOIUrl":"10.1002/jimd.70002","url":null,"abstract":"<p>Classic galactosemia (CG) is a rare inherited metabolic disease caused by mutations in the <i>GALT</i> gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. The condition develops as a potentially fatal illness during the newborn period, but its acute clinical manifestations can be alleviated through a galactose restricted diet. Nonetheless, such dietary intervention is inadequate in preventing significant long-term consequences, including neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. At present, no effective therapy exists to stop the progression of these complications, highlighting the urgent need for new treatment approaches to be developed. Supplements have been used in the treatment of other inborn errors of metabolism; however, they are not typically included in the clinical therapeutic regimen for CG. Recently, our research team has demonstrated that two generally recognized as safe supplements (purple weet potato color, PSPC and <i>myo</i>-inositol, MI) have been effective in partially restoring functions in the ovaries of our <i>GalT</i>-KO mouse model. However, the toxicological profile of both PSPC and MI has not been determined. In this study, we investigated the acute (30 days) and chronic (180 days) oral toxicities of PSPC and MI both in WT control and <i>GalT</i>-KO mice. Furthermore, our study aims to evaluate the effectiveness of oral feeding of PSPC and MI in correcting motor-related and behavioral phenotypes in <i>GalT</i>-KO mice. The long-term treatment of MI at a lower dose demonstrated promising improvements in motor deficit and anxiety driven hyperactivity in the mutant mice.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080255","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":"Obituary for Professor Ishwar Chander Verma","authors":"Sunita Bijarnia-Mahay,&nbsp;Ratna Dua Puri,&nbsp;Madhulika Kabra","doi":"10.1002/jimd.12825","DOIUrl":"10.1002/jimd.12825","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12825","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033248","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":"Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders","authors":"Yaiza Díaz-Osorio,&nbsp;Helena Gimeno-Agud,&nbsp;Rosanna Mari-Vico,&nbsp;Sofía Illescas,&nbsp;Jose Miguel Ramos,&nbsp;Alejandra Darling,&nbsp;Àngels García-Cazorla,&nbsp;Alfonso Oyarzábal","doi":"10.1002/jimd.12841","DOIUrl":"10.1002/jimd.12841","url":null,"abstract":"<p>Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in <i>SYNJ1</i> and <i>NBAS</i> genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age-matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n-of-1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006782","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":"Unifying biology of neurodegeneration in lysosomal storage diseases","authors":"Anna M. Ludlaim,&nbsp;Simon N. Waddington,&nbsp;Tristan R. McKay","doi":"10.1002/jimd.12833","DOIUrl":"10.1002/jimd.12833","url":null,"abstract":"<p>There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006784","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":"Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease","authors":"Lottie D. Morison,&nbsp;Ineka T. Whiteman,&nbsp;Adam P. Vogel,&nbsp;Lisa Tilbrook,&nbsp;Michael C. Fahey,&nbsp;Ruth Braden,&nbsp;Joanna Bredebusch,&nbsp;Michael S. Hildebrand,&nbsp;Ingrid E. Scheffer,&nbsp;Angela T. Morgan","doi":"10.1002/jimd.12838","DOIUrl":"10.1002/jimd.12838","url":null,"abstract":"<p>CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3–28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis. At the time of study all participants, bar one, had language impairments. The remaining participant with typical language was tested at age 3 years, following pre-symptomatic enzyme replacement therapy (ERT) from age 9 months. CLN2 and CLN3 disease had different profiles. For CLN2 disease, all affected individuals showed language impairment with dysarthria; older individuals with classical disease progressively became non-verbal. For CLN3 disease, the presentation was more heterogeneous. Speech impairment was evident early in the disease course, with dysarthria (13/15, 87%), often manifesting as neurogenic stuttering (5/15, 33%). Participants with CLN2 disease had comparable expressive and receptive language skills (<i>p</i> &gt; 0.99), yet participants with CLN3 disease had stronger expressive language than receptive language skills (<i>p</i> = 0.004). Speech, cognitive and language impairment and adaptive behaviour showed progressive decline in both diseases. Individuals with pre-symptomatic ERT or atypical CLN2 disease were less impaired. Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006780","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}