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Inherited metabolic diseases

The inherited metabolic diseases (IMD) section publishes original research (clinical, biochemical, and genetic), well-phenotyped case series, clinical trial outcome reports, and comprehensive reviews of rare inherited disorders of metabolism.

Submissions that increase our understanding or make new observations regarding IMD are particularly welcome. Detailed natural history studies of well-phenotyped case series, and publication of consensus statements on investigation and management of IMD, including collaborations between centres, are encouraged.

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  1. Phenylalanine-free infant formula is an essential source of safe protein in a phenylalanine restricted diet, but its efficacy is rarely studied. We report a multicentre, open, longitudinal, prospective interve...

    Authors: Ozlem Yilmaz, Barbara Cochrane, Jo Wildgoose, Alex Pinto, Sharon Evans, Anne Daly, Catherine Ashmore and Anita MacDonald
    Citation: Orphanet Journal of Rare Diseases 2023 18:16
  2. Cerebrotendinous xanthomatosis (CTX) is a rare recessive genetic disease characterized by disruption of bile acid synthesis due to inactivation of the CYP27A1 gene. Treatment is available in the form of bile acid...

    Authors: Tiziano Pramparo, Robert D. Steiner, Steve Rodems and Celia Jenkinson
    Citation: Orphanet Journal of Rare Diseases 2023 18:13
  3. Alkaptonuria is a rare inherited disorder for which there was no disease-modifying treatment. In order to develop a successful approved therapy of AKU multiple barriers had to be overcome. These included activ...

    Authors: L. R. Ranganath and Nick Sireau
    Citation: Orphanet Journal of Rare Diseases 2023 18:1
  4. Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction sin...

    Authors: Filippo Manti, Stefania Caviglia, Chiara Cazzorla, Annamaria Dicintio, Andrea Pilotto and Alessandro P. Burlina
    Citation: Orphanet Journal of Rare Diseases 2022 17:443
  5. Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one...

    Authors: Gorka Fernández-Eulate, Gilles C. Martin, Pascal Dureau, Claude Speeg-Spatz, Anais Brassier, Perrine Gillard, Dominique Bremond-Gignac, Dominique Thouvenin, Cecile Pagan, Foudil Lamari and Yann Nadjar
    Citation: Orphanet Journal of Rare Diseases 2022 17:434
  6. Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by pathogenic variants in the tyrosine aminotransfer...

    Authors: Zahra Beyzaei, Sara Nabavizadeh, Sara Karimzadeh and Bita Geramizadeh
    Citation: Orphanet Journal of Rare Diseases 2022 17:424
  7. Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may...

    Authors: Emily Shelkowitz, Russell P. Saneto, Walla Al-Hertani, Charlotte M. A. Lubout, Nicholas V. Stence, Mark S. Brown, Patrick Long, Diana Walleigh, Julie A. Nelson, Francisco E. Perez, Dennis W. W. Shaw, Emma J. Michl and Johan L. K. Van Hove
    Citation: Orphanet Journal of Rare Diseases 2022 17:423
  8. ENPP1 Deficiency—caused by biallelic variants in ENPP1—leads to widespread arterial calcification in early life (Generalized Arterial Calcification of Infancy, GACI) or hypophosphatemic rickets in later life (Aut...

    Authors: Lauren M. Chunn, Jeffrey Bissonnette, Stefanie V. Heinrich, Stephanie A. Mercurio, Mark J. Kiel, Frank Rutsch and Carlos R. Ferreira
    Citation: Orphanet Journal of Rare Diseases 2022 17:421
  9. Betaine is an “alternate” methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for m...

    Authors: Apolline Imbard, Artemis Toumazi, Sophie Magréault, Nuria Garcia-Segarra, Dimitri Schlemmer, Florentia Kaguelidou, Isabelle Perronneau, Jérémie Haignere, Hélène Ogier de Baulny, Alice Kuster, François Feillet, Corinne Alberti, Sophie Guilmin-Crépon, Jean-François Benoist and Manuel Schiff
    Citation: Orphanet Journal of Rare Diseases 2022 17:417
  10. Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limitin...

    Authors: C. Pascoal, I. Ferreira, C. Teixeira, E. Almeida, A. Slade, S. Brasil, R. Francisco, A. N. Ligezka, E. Morava, H. Plotkin, J. Jaeken, P. A. Videira, L. Barros and V. dos Reis Ferreira
    Citation: Orphanet Journal of Rare Diseases 2022 17:398
  11. In children with phenylketonuria (PKU), transitioning protein substitutes at the appropriate developmental age is essential to help with their long-term acceptance and ease of administration. We assessed the p...

    Authors: Ozlem Yilmaz, Alex Pinto, Anne Daly, Catherine Ashmore, Sharon Evans, Nurcan Yabanci Ayhan and Anita MacDonald
    Citation: Orphanet Journal of Rare Diseases 2022 17:395
  12. Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARS...

    Authors: F. Eichler, Caroline Sevin, M. Barth, F. Pang, K. Howie, M. Walz, A. Wilds, C. Calcagni, C. Chanson and L. Campbell
    Citation: Orphanet Journal of Rare Diseases 2022 17:370
  13. Galactose epimerase (GALE) deficiency is a rare hereditary disorder of galactose metabolism with only a few cases described in the literature. This study aims to present the data of patients with GALE deficien...

    Authors: Britt Derks, Didem Demirbas, Rodrigo R. Arantes, Samantha Banford, Alberto B. Burlina, Analía Cabrera, Ana Chiesa, M. Luz Couce, Carlo Dionisi-Vici, Matthias Gautschi, Stephanie Grünewald, Eva Morava, Dorothea Möslinger, Sabine Scholl-Bürgi, Anastasia Skouma, Karolina M. Stepien…
    Citation: Orphanet Journal of Rare Diseases 2022 17:331
  14. cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investig...

    Authors: Zhehui Chen, Hui Dong, Yupeng Liu, Ruxuan He, Jinqing Song, Ying Jin, Mengqiu Li, Yi Liu, Xueqin Liu, Hui Yan, Jianguang Qi, Fang Wang, Huijie Xiao, Hong Zheng, Lulu Kang, Dongxiao Li…
    Citation: Orphanet Journal of Rare Diseases 2022 17:330
  15. Parents of children with a rare progressive life-limiting illness are at risk for parental posttraumatic stress disorder (PTSD). Studies on the treatment of parental PTSD with eye movement and desensitization ...

    Authors: T. Conijn, C. De Roos, H. J. I. Vreugdenhil, E. M. Van Dijk-Lokkart, F. A. Wijburg and L. Haverman
    Citation: Orphanet Journal of Rare Diseases 2022 17:328
  16. Hereditary fructose intolerance (HFI) caused by aldolase B reduction or deficiency that results in fructose metabolism disorder. The disease prevalence in the Chinese population is unknown, which impedes the f...

    Authors: Meiling Tang, Xiang Chen, Qi Ni, Yulan Lu, Bingbing Wu, Huijun Wang, Zhaoqing Yin, Wenhao Zhou and Xinran Dong
    Citation: Orphanet Journal of Rare Diseases 2022 17:326
  17. Congenital disorders of glycosylation (CDG) are a large family of rare genetic diseases for which therapies are virtually nonexistent. However, CDG therapeutic research has been expanding, thanks to the contin...

    Authors: Maria Monticelli, Rita Francisco, Sandra Brasil, Dorinda Marques-da-Silva, Tatiana Rijoff, Carlota Pascoal, Jaak Jaeken, Paula A. Videira and Vanessa dos Reis Ferreira
    Citation: Orphanet Journal of Rare Diseases 2022 17:303
  18. Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. If untreated, the complications of PKU lead to significant neucognitive and neuropsychiatr...

    Authors: A. L. S. Pessoa, A. M. Martins, E. M. Ribeiro, N. Specola, A. Chiesa, D. Vilela, E. Jurecki, D. Mesojedovas and I. V. D. Schwartz
    Citation: Orphanet Journal of Rare Diseases 2022 17:302
  19. Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, heari...

    Authors: Julia B. Hennermann, Eva M. Raebel, Francesca Donà, Marie-Line Jacquemont, Graziella Cefalo, Andrea Ballabeni and Dag Malm
    Citation: Orphanet Journal of Rare Diseases 2022 17:287
  20. Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients w...

    Authors: Francesco Tagliaferri, Miriam Massese, Luisa Russo, Anna Commone, Serena Gasperini, Roberta Pretese, Carlo Dionisi-Vici and Arianna Maiorana
    Citation: Orphanet Journal of Rare Diseases 2022 17:285
  21. The clinical signs and symptoms of hypophosphatasia (HPP) can manifest during any stage of life. The age at which a patient’s symptoms are reported can impact access to targeted treatment with enzyme replaceme...

    Authors: Kathryn M. Dahir, Lothar Seefried, Priya S. Kishnani, Anna Petryk, Wolfgang Högler, Agnès Linglart, Gabriel Ángel Martos-Moreno, Keiichi Ozono, Shona Fang and Cheryl Rockman-Greenberg
    Citation: Orphanet Journal of Rare Diseases 2022 17:277
  22. Dietary management is the most important and effective treatment for citrin deficiency, as well as a decisive factor in the clinical outcome of patients. However, the dietary management ability of caregivers o...

    Authors: Shuxian Zhang, Yun Du, Lingli Cai, Meixue Chen, Yuanzong Song, Lilan He, Ni Gong and Qingran Lin
    Citation: Orphanet Journal of Rare Diseases 2022 17:256
  23. Pain of musculoskeletal origin is very common in young patients affected by Mucopolysaccharidoses. This scoping review evaluates the evidence for assessment, pharmacological treatment and rehabilitation manage...

    Authors: R. Gnasso, B. Corrado, I. Iommazzo, F. Migliore, G. Magliulo, B. Giardulli and C. Ruosi
    Citation: Orphanet Journal of Rare Diseases 2022 17:255
  24. Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients w...

    Authors: Sinziana Stanescu, Irene Bravo-Alonso, Amaya Belanger-Quintana, Belen Pérez, Montserrat Medina-Diaz, Pedro Ruiz-Sala, Nathaly Paola Flores, Raquel Buenache, Francisco Arrieta and Pilar Rodríguez-Pombo
    Citation: Orphanet Journal of Rare Diseases 2022 17:243
  25. Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but mus...

    Authors: Miriam Massese, Francesco Tagliaferri, Carlo Dionisi-Vici and Arianna Maiorana
    Citation: Orphanet Journal of Rare Diseases 2022 17:241
  26. Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is sti...

    Authors: Wei Zhang, Yanmeng Li, Anjian Xu, Qin Ouyang, Liyan Wu, Donghu Zhou, Lina Wu, Bei Zhang, Xinyan Zhao, Yu Wang, Xiaoming Wang, Weijia Duan, Qianyi Wang, Hong You, Jian Huang, Xiaojuan Ou…
    Citation: Orphanet Journal of Rare Diseases 2022 17:216
  27. Patients with maple syrup urine disease (MSUD) experiencing metabolic decompensations have traditionally been treated with branched-chain amino acid (BCAA)-free mixture via oral or nasogastric administration r...

    Authors: Jean-Meidi Alili, Marie-Pierre Berleur, Marie-Caroline Husson, Karine Mention, Manuel Schiff, Jean-Baptiste Arnoux, Anaïs Brassier, Anne-Sophie Guemman, Coraline Grisel, Sandrine Dubois, Marie-Thérèse Abi-Wardé, Christine Broissand, Aude Servais, Myriam Dao and Pascale de Lonlay
    Citation: Orphanet Journal of Rare Diseases 2022 17:202
  28. Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently b...

    Authors: Rebecca K. Halligan, R. Neil Dalton, Charles Turner, Katherine A. Lewis and Helen R. Mundy
    Citation: Orphanet Journal of Rare Diseases 2022 17:195
  29. Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeleta...

    Authors: Martin Magner, Zsuzsanna Almássy, Zoran Gucev, Beata Kieć-Wilk, Vasilica Plaiasu, Anna Tylki-Szymańska, Dimitrios Zafeiriou, Ioannis Zaganas and Christina Lampe
    Citation: Orphanet Journal of Rare Diseases 2022 17:190
  30. Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an inborn error of metabolism causing ectopic soft tissue calcification due to low plasma pyrophosphate concentration. We aimed to assess the prevalence of PXE i...

    Authors: Saku Pelttari, Suvi Väärämäki, Olivier Vanakker, Shana Verschuere, Hannu Uusitalo, Heini Huhtala, Tero Hinkka, Ilkka Pörsti and Pasi I. Nevalainen
    Citation: Orphanet Journal of Rare Diseases 2022 17:185
  31. Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threaten...

    Authors: Matteo Marcacci, Andrea Ricci, Chiara Cuoghi, Stefano Marchini, Antonello Pietrangelo and Paolo Ventura
    Citation: Orphanet Journal of Rare Diseases 2022 17:160
  32. Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, conve...

    Authors: Jason A. Randall, Carolyn Sutter, Stella Wang, Evan Bailey, Lydia Raither, Riccardo Perfetti, Shoshana Shendelman and Claire Burbridge
    Citation: Orphanet Journal of Rare Diseases 2022 17:138
  33. Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes ...

    Authors: Anna Tylki-Szymańska, Zsuzsanna Almássy, Violetta Christophidou-Anastasiadou, Daniela Avdjieva-Tzavella, Ingeborg Barisic, Rimante Cerkauskiene, Goran Cuturilo, Maja Djiordjevic, Zoran Gucev, Anna Hlavata, Beata Kieć-Wilk, Martin Magner, Ivan Pecin, Vasilica Plaiasu, Mira Samardzic, Dimitrios Zafeiriou…
    Citation: Orphanet Journal of Rare Diseases 2022 17:136
  34. Propionic acidemia is a severe inherited metabolic disorder, caused by the deficiency of propionyl-CoA carboxylase which encoded by the PCCA and PCCB genes. The aim of the study was to investigate the clinical fe...

    Authors: Yi Liu, Zhehui Chen, Hui Dong, Yuan Ding, Ruxuan He, Lulu Kang, Dongxiao Li, Ming Shen, Ying Jin, Yao Zhang, Jinqing Song, Yaping Tian, Yongtong Cao, Desheng Liang and Yanling Yang
    Citation: Orphanet Journal of Rare Diseases 2022 17:135
  35. Congenital Disorders of Glycosylation (CDG) are a complex family of rare metabolic diseases. Robust clinical data collection faces many hurdles, preventing full CDG biological and clinical comprehension. Web-b...

    Authors: Rita Francisco, Sandra Brasil, Carlota Pascoal, Jaak Jaeken, Merell Liddle, Paula A. Videira and Vanessa dos Reis Ferreira
    Citation: Orphanet Journal of Rare Diseases 2022 17:134
  36. Glycogen storage diseases (GSDs) are inherited glycogen metabolic disorders which have various subtypes. GSDs of type I, III, IV, VI, and IX show liver involvement and are considered as hepatic types of GSDs. ...

    Authors: Zahra Beyzaei, Alireza Shamsaeefar, Kurosh Kazemi, Saman Nikeghbalian, Ali Bahador, Masoud Dehghani, Seyed-Ali Malekhosseini and Bita Geramizadeh
    Citation: Orphanet Journal of Rare Diseases 2022 17:127
  37. Mucopolysaccharidoses are a group of lysosomal storage disorders caused by deficiency of enzymes involved in glycosaminoglycans degradation. Relationship between mucopolysaccharidoses and related enzymes has b...

    Authors: Weijing Kong, Cheng Lu, Yingxue Ding and Yan Meng
    Citation: Orphanet Journal of Rare Diseases 2022 17:112
  38. Since the beginning of the COVID-19 pandemic, MetabERN has been monitoring the SARS-CoV-2 infection rates within its metabolic community. To gather data on the total number of cases and the severity of symptom...

    Authors: Laura Paneghetti, Cinzia Maria Bellettato, Annalisa Sechi, Karolina M. Stepien and Maurizio Scarpa
    Citation: Orphanet Journal of Rare Diseases 2022 17:109
  39. Porphyria cutanea tarda (PCT) is a skin disorder caused by a defect in the liver enzyme uroporphyrinogen decarboxylase and is associated with hepatitis C virus infection, high alcohol intake, smoking and iron ...

    Authors: Carl Michael Baravelli, Aasne Karine Aarsand, Sverre Sandberg and Mette Christophersen Tollånes
    Citation: Orphanet Journal of Rare Diseases 2022 17:72

    The Correction to this article has been published in Orphanet Journal of Rare Diseases 2022 17:180

  40. Current world experience regarding living donor liver transplantation (LDLT) in the treatment of propionic acidemia (PA) is limited, especially in terms of using obligate heterozygous carriers as donors. This ...

    Authors: Zhi-Gui Zeng, Guang-Peng Zhou, Lin Wei, Wei Qu, Ying Liu, Yu-Le Tan, Jun Wang, Li-Ying Sun and Zhi-Jun Zhu
    Citation: Orphanet Journal of Rare Diseases 2022 17:62
  41. Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children, and carries a considerable risk of neurological damage and developmental delays if diagnosis and tr...

    Authors: Indraneel Banerjee, Julie Raskin, Jean-Baptiste Arnoux, Diva D. De Leon, Stuart A. Weinzimer, Mette Hammer, David M. Kendall and Paul S. Thornton
    Citation: Orphanet Journal of Rare Diseases 2022 17:61

    The Correction to this article has been published in Orphanet Journal of Rare Diseases 2022 17:205

  42. Reproductive planning is an emerging concern for women with inherited metabolic disease (IMD). Anticipatory guidance on contraception is necessary to prevent unintended pregnancies in this population. Few reso...

    Authors: Jessica I. Gold, Nina B. Gold, Diva D. DeLeon and Rebecca Ganetzky
    Citation: Orphanet Journal of Rare Diseases 2022 17:41
  43. Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomoc...

    Authors: Silvia Kalantari, Brigida Brezzi, Valeria Bracciamà, Antonella Barreca, Paolo Nozza, Tiziana Vaisitti, Antonio Amoroso, Silvia Deaglio, Marco Manganaro, Francesco Porta and Marco Spada
    Citation: Orphanet Journal of Rare Diseases 2022 17:33
  44. In recent years, much progress has been made in understanding the mechanisms of bone growth and development over a lifespan, including the crosstalk between muscle and bone, to achieve optimal structure and fu...

    Authors: Francis H. Glorieux, Lynda F. Bonewald, Nicholas C. Harvey and Marjolein C. H. van der Meulen
    Citation: Orphanet Journal of Rare Diseases 2022 17:30
  45. Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capaci...

    Authors: Philip J. Hennis, Elaine Murphy, Rick I. Meijer, Robin H. Lachmann, Radha Ramachandran, Claire Bordoli, Gurinder Rayat and David J. Tomlinson
    Citation: Orphanet Journal of Rare Diseases 2022 17:28
  46. Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria (PKU) and their treatment have a major impact on the life of affected chil...

    Authors: Florin Bösch, Nina A. Zeltner, Matthias R. Baumgartner, Martina Huemer and Markus A. Landolt
    Citation: Orphanet Journal of Rare Diseases 2022 17:26
  47. Cerliponase alfa, an enzyme replacement therapy for neuronal ceroid lipofuscinosis type 2 (CLN2), is currently available in England through a managed access agreement (MAA). It is administered every 2 weeks vi...

    Authors: Amanda Mortensen, Eva M. Raebel and Samantha Wiseman
    Citation: Orphanet Journal of Rare Diseases 2022 17:19
  48. Fabry disease (FD) is a treatable X-linked condition leading to progressive cardiac disease, arrhythmia and premature death. We aimed to increase awareness of the arrhythmogenicity of Fabry cardiomyopathy, by ...

    Authors: Ravi Vijapurapu, William Bradlow, Francisco Leyva, James C. Moon, Abbasin Zegard, Nigel Lewis, D. Kotecha, Ana Jovanovic, Derralynn A. Hughes, Peter Woolfson, Richard P. Steeds and Tarekegn Geberhiwot
    Citation: Orphanet Journal of Rare Diseases 2022 17:6
  49. Recently published European Society for Phenylketonuria (ESPKU) guidelines have recommended a lifelong diet with phenylalanine (Phe) control ≤ 600 μmol/L for phenylketonuria (PKU) patients. This study aimed to...

    Authors: George Altman, Kamran Hussain, Diane Green, Boyd J. G. Strauss and Gisela Wilcox
    Citation: Orphanet Journal of Rare Diseases 2021 16:520
  50. Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited...

    Authors: Yiming Lin, Bangbang Lin, Yanru Chen, Zhenzhu Zheng, Qingliu Fu, Weihua Lin and Weifeng Zhang
    Citation: Orphanet Journal of Rare Diseases 2021 16:503

    The Correction to this article has been published in Orphanet Journal of Rare Diseases 2022 17:21