Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure

Pérez-Torras, Sandra; Mata-Ventosa, Aida; Drögemöller, Britt I.; Tarailo‐Graovac, Maja; Meijer, Judith; Meinsma, Rutger; Cruchten, Arno G. van; Kulik, Wim; Viel-Oliva, A.; Bidon‐Chanal, Axel; Ross, Colin J.D.; Wassermann, Wyeth W.; Pastor‐Anglada, Marçal; Kuilenburg, André B. P.

doi:10.1016/j.bbadis.2019.01.013

Cited by 8 publications

(12 citation statements)

References 31 publications

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“…Disorders of lipid metabolism such as glutaric aciduria type IIC and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency ( 13 ) or disorders of organic acid metabolism such as lysinuric protein intolerance (LPI) ( 19 , 20 , 35 ), methylmalonic acidemia ( 17 ), propionic acidemia ( 17 , 18 ) may be complicated by HLH. There are many other rare IEMs complicated by HLH that are also reported such as biotinidase deficiency ( 12 ), hepatolenticular degeneration ( 33 ), mevalonate kinase deficiency ( 30 , 31 ), pyrimidine deficiency ( 32 ), disorder of glycogen metabolism ( 14 , 15 ), prolidase deficiency ( 16 ) and cobalamin C disease ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…Some patients may develop metabolic encephalopathy ( 17 , 18 , 30 ), and some patients may have severe gastrointestinal symptoms ( 20 , 26 , 27 ). Metabolic acidosis is also a relatively common clinical manifestation in IEM complicated by HLH ( 17 , 32 ). Treatments may be variable and may include IVIG, etoposide, cyclosporine, plasma exchange and hematopoietic cell transplantation (table 2).…”

Section: Discussionmentioning

confidence: 99%

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Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

Huang

Zhu

et al. 2022

Front. Immunol.

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Hemophagocytic lymphocytosis (HLH) is a rare disease caused by inborn errors of immunity (IEI), secondary to infection, lymphoma or autoimmune disorders, but we often overlook the fact that HLH can be secondary to inborn errors of metabolism (IEM). Here, we describe a patient who was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. The diagnosis of glutaric aciduria type IIC, a IEM, was confirmed by whole exome sequencing. The patient was treated with coenzyme Q10 and riboflavin which effectively improved her liver function. During treatment, the patient developed severe anemia and thrombocytopenia. Persistent fever, splenomegaly, cytopenias, increased ferritin, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis in the bone marrow pointed to the diagnosis of HLH; however, the patient eventually died of gastrointestinal bleeding. After other potential causes were ruled out, the patient was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. When cytopenias occurs in IEM patients, HLH is a possible complication that cannot be ignored. This case suggests a possible relationship between IEM and risk for immune dysregulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

Huang

Zhu

et al. 2022

Front. Immunol.

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“…The mixed phenotype of the two coexisting single gene defects might have been the main reason for the rapid deterioration of the condition in the patient, leading to multiple organ failure and early death. 11 …”

Section: Literature Reviewmentioning

confidence: 99%

RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review

Shi¹,

Qiao²,

Bi³

et al. 2021

PGPM

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Objective Gene mutation analysis was performed on a family with familial hemophagocytic lymphohistiocytosis (FHL) so as to provide an accurate etiological diagnosis, leading to genetic counseling for the family members. Methods The clinical data of two probands (siblings) with FHL in one family were analyzed, and eight genes related to the onset of the primary hemophagocytic lymphohistiocytosis (pHLH) ( PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4/XIAP, Rab27a, LYST ) were detected and analyzed in the probands and their parents with whole exome sequencing. Results Proband 1 was a two-year-old male with the clinical manifestations of fever, hepatosplenomegaly, and a decreased peripheral blood cell count, sCD25: 12504pg/mL. The results of genetic testing showed that there was a c.1349C>T heterozygous missense mutation and a c.853_855del heterozygous mutation in the PRF1 in proband 1. Proband 2 was an eight-year-old female with the clinical manifestations of convulsions and disturbance of consciousness with fever. The genetic test results were the same as those of proband 1. There was a single heterozygous mutation in the parents of the probands, and both probands had compound heterozygous mutations. Conclusion According to the clinical manifestations, laboratory tests, and results of the family molecular genetic testing, the probands could be clinically diagnosed as FHL2. The results of gene sequencing revealed that this was an autosomal recessive family with familial hemophagocytic syndrome. A rare pathogenic mutation (c.853_855del) in the PRF1 was discovered in the two patients with HLH.

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“…With the advent of HTS, it had been recognized that phenotypic variability or atypical presentation of a disease may be due to two or more genetic conditions with overlapping (blended) or discrete (composite) manifestations [25,26,27]. Newly discovered genetic conditions may also co-occur with another genetic condition(s) [28,29] (e.g., NPL and GJB2 composite effects in a patient with sialuria, exercise intolerance/muscle wasting, cardiac symptoms, and deafness) [28]. Thus, considering multiple diagnoses in a patient is important in presumed monogenic disorders, especially the ones with atypical ‘ultra’ rare phenotypes [30] and/or substantial phenotypic variability [31] before a conclusion on expanded clinical presentation of a monogenic disease is made.…”

Section: Complexity Of Rare Diseasesmentioning

confidence: 99%

Uncovering Missing Heritability in Rare Diseases

Maroilley

Tarailo‐Graovac

2019

Genes

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The problem of ‘missing heritability’ affects both common and rare diseases hindering: discovery, diagnosis, and patient care. The ‘missing heritability’ concept has been mainly associated with common and complex diseases where promising modern technological advances, like genome-wide association studies (GWAS), were unable to uncover the complete genetic mechanism of the disease/trait. Although rare diseases (RDs) have low prevalence individually, collectively they are common. Furthermore, multi-level genetic and phenotypic complexity when combined with the individual rarity of these conditions poses an important challenge in the quest to identify causative genetic changes in RD patients. In recent years, high throughput sequencing has accelerated discovery and diagnosis in RDs. However, despite the several-fold increase (from ~10% using traditional to ~40% using genome-wide genetic testing) in finding genetic causes of these diseases in RD patients, as is the case in common diseases—the majority of RDs are also facing the ‘missing heritability’ problem. This review outlines the key role of high throughput sequencing in uncovering genetics behind RDs, with a particular focus on genome sequencing. We review current advances and challenges of sequencing technologies, bioinformatics approaches, and resources.

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Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure

Cited by 8 publications

References 31 publications

Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review

Uncovering Missing Heritability in Rare Diseases

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