174 results on '"Carnitine palmitoyltransferase II deficiency"'
Search Results
2. Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
- Author
-
Zharmakhanova Gulmira, Head of Department of Natural Sciences disciplines (with course of Molecular Biology and Medical Genetic)
- Published
- 2023
3. Newborn Screening with (C16 + C18:1)/C2 and C14/C3 for Carnitine Palmitoyltransferase II Deficiency throughout Japan Has Revealed C12/C0 as an Index of Higher Sensitivity and Specificity
- Author
-
Go Tajima, Keiichi Hara, Miyuki Tsumura, Reiko Kagawa, Fumiaki Sakura, Hideo Sasai, Miori Yuasa, Yosuke Shigematsu, and Satoshi Okada
- Subjects
carnitine palmitoyltransferase II deficiency ,CPT2 ,newborn screening ,false-positive ,tetradecanoylcarnitine (C14) ,dodecanoylcarnitine (C12) ,Pediatrics ,RJ1-570 - Abstract
Carnitine palmitoyltransferase (CPT) II deficiency is a long-chain fatty acid oxidation disorder. It manifests as (1) a lethal neonatal form, (2) a hypoglycemic form, or (3) a myopathic form. The second form can cause sudden infant death and is more common among Japanese people than in other ethnic groups. Our study group had earlier used (C16 + C18:1)/C2 to conduct a pilot newborn screening (NBS) study, and found that the use of C14/C3 for screening yielded lower rates of false positivity; in 2018, as a result, nationwide NBS for CPT II deficiency started. In this study, we evaluated the utility of these ratios in 71 NBS-positive infants and found that the levels of both C14/C3 and (C16 + C18:1)/C2 in patients overlapped greatly with those of infants without the disease. Among the levels of acylcarnitines with various chain lengths (C18 to C2) and levels of free carnitine (C0) as well as their ratios of various patterns, C12/C0 appeared to be a promising index that could reduce false-positive results without missing true-positive cases detected by current indices. Although some cases of the myopathic form may go undetected even with C12/C0, its use will help prevent life-threatening onset of the hypoglycemic form of CPT II deficiency.
- Published
- 2023
- Full Text
- View/download PDF
4. A Rare Presentation of Carnitine Palmitoyltransferase II (CPT-2) Deficiency With Normal Acylcarnitine Profile in a 10-Year-Old Boy With Muscle Weakness and Bilateral Hearing Loss.
- Author
-
SHAHI, Mohammad VAFAEE, GHASEMI, Saeide, TAHERNIA, Leila, and RIAHI, Aina
- Subjects
CARNITINE ,SKELETAL muscle ,FEVER ,NECK pain ,HEARING disorders in children ,HYPERBILIRUBINEMIA ,GENETIC testing ,PATIENTS ,HOSPITAL admission & discharge ,VOMITING ,TRANSFERASES ,LACTATE dehydrogenase ,HEADACHE ,CREATININE ,RARE diseases ,CHILDREN - Abstract
Carnitine palmitoyltransferase II (CPT-2) deficiency is a rare and autosomal recessive disorder of long-chain fatty acids oxidation. Here, we reported a 10-year-old boy with bilateral hearing loss and a myopathic form of CPT II deficiency, which was confirmed by a molecular genetic test. He was admitted to our hospital with unexplained headaches, vomiting, and fever. Furthermore, he developed seizures, muscle weakness, neck stiffness and pain, mild respiratory distress, and an icteric appearance. The laboratory test results also showed severely elevated lactate dehydrogenase levels (LDH) and creatine phosphokinase (CPK) levels. He also had an icteric appearance with unexplained indirect hyperbilirubinemia. Further examinations revealed a normal heart and liver without any neurological disorders. Muscle pathological examination reported normal pathology without neuromuscular and mitochondrial disorders and storage diseases. Finally, molecular test analysis with next-generation sequencing (NGS) revealed CPT-II deficiency fatty acid oxidation disorder. Furthermore, we identified a homozygous pathogenic variant in the ADGRV1 gene, c.15736C>T p. (Arg5246*), which suggests the Usher syndrome type 2C and the reason for sensorineural hearing loss in this case. Our finding indicates that CPT-II can be associated with multiple symptoms and clinical features. Therefore, evaluation of CPT-II deficiency with molecular test analysis may be helpful in cases with unexplained icteric appearance, muscle weakness, and rhabdomyolysis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
5. Diagnostic Challenges in the Myopathic Variant of Carnitine Palmitoyltransferase II Deficiency: A Case Report.
- Author
-
Alabbasi L, Ben Turkia H, Nass M, and Sahin I
- Abstract
Carnitine palmitoyltransferase II deficiency is a rare metabolic disorder affecting the mitochondrial oxidation of fatty acids. We present a case of the myopathic form in a 10-year-old Bahraini male following an initial presentation of exercise-induced rhabdomyolysis and transaminitis. There was no consanguinity or findings suggestive of an underlying inborn metabolic disorder. Tandem mass spectrometry on dried blood spots showed no abnormal acyl-carnitines profile. The condition improved with hyperhydration, high glucose intake, carnitine, and alkalinization. Genetic testing revealed a compound heterozygous pathogenic variant c.338C>T ( p.Ser113Leu ) and a variant of unknown significance c.729_731del ( p.Leu244del ). The patient was kept on a high carbohydrate and low-fat diet with medium chain triglycerides supplementation and advised to avoid long fasting periods and strenuous exercise. Within the four years of follow-up, he had three further attacks. Exercise-induced myalgia or rhabdomyolysis should raise the suspicion of inherited metabolic disorders. Metabolic investigations should be taken during the acute illness, and an acylcarnitines profile should preferably be performed in the serum., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Royal Medical Services, King Hamad University Hospital issued approval 2024-778. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alabbasi et al.)
- Published
- 2024
- Full Text
- View/download PDF
6. CAUSE OF RECURRENT RHABDOMYOLYSIS, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY AND NOVEL PATHOGENIC MUTATION.
- Author
-
ÇAKAR, Nafiye Emel, GÖR, Zeynep, and YEŞIL, Gözde
- Subjects
CARNITINE palmitoyltransferase ,METABOLIC disorders ,FATTY acids ,ACUTE kidney failure ,RHABDOMYOLYSIS - Abstract
Copyright of Clinical Neuroscience / Ideggyógyászati Szemle is the property of LifeTime Media Kft. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2021
- Full Text
- View/download PDF
7. Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening
- Author
-
Ryosuke Bo, Ikuma Musha, Kenji Yamada, Hironori Kobayashi, Yuki Hasegawa, Hiroyuki Awano, Masato Arao, Toru Kikuchi, Takeshi Taketani, Akira Ohtake, Seiji Yamaguchi, and Kazumoto Iijima
- Subjects
Carnitine palmitoyltransferase II deficiency ,Metabolic decompensation ,Fatty acid oxidation disorders ,Sudden unexpected death in infancy (SUDI) ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
In Japan, carnitine palmitoyltransferase II (CPTII) deficiency has been included as one of the primary target diseases in the expanded newborn mass screening program since 2018. However, many cases of the severe infantile hepatocardiomuscular form of CPTII deficiency showed severe neurodevelopmental delay or sudden death, which indicated that management of CPTII deficiency in the acute phase remains to be studied in detail. Herein, we discuss two cases diagnosed by newborn mass screening. Patient 1 was under strict clinical management from the neonatal period, with >20 admissions in 14 months, while Patient 2 was managed using a relatively relaxed approach, with only 2 admissions in the same period. Patient 1 showed normal development; however, Patient 2 expired at the age of 1 year 2 months. To develop strategies for preventing sudden deaths in patients with CPTII deficiency, this retrospective study focused on detailed clinical management practices and biochemical findings during the acute phase. We also investigated the correlation between conventional biomarkers (such as creatine kinase) and long-chain acylcarnitines. We propose that strict monitoring and immediate medical attention, even in case of slight fever or minor abdominal symptoms, can help prevent sudden death in patients with CPTII deficiency. Considering the higher morbidity rate of such patients, strict and acute management of CPTII deficiency cannot be overemphasized.
- Published
- 2020
- Full Text
- View/download PDF
8. Recurrent Myalgia since Early Infancy—Misleading Clinical Course in a Child with Carnitine Palmitoyltransferase-II Deficiency.
- Author
-
Arélin, Maria, Zierz, Stephan, Ceglarek, Uta, Heinemann, Mitja, Beblo, Skadi, and Merkenschlager, Andreas
- Subjects
- *
MYALGIA , *CARNITINE , *GENETIC disorders , *INFANTS , *CREATINE kinase , *NEMALINE myopathy - Abstract
Metabolic myopathies are heterogeneous hereditary diseases affecting skeletal muscle energy supply. Symptoms usually comprise pain, cramps, hypotonia, weakness, and myoglobinuria. We present a boy with recurrent myalgia and weakness after some minutes of exercise or during febrile infections since early infancy. First laboratory workup at the age of 9 years showed no abnormalities, apart from a slightly elevated creatine kinase. After exclusion of common structural and metabolic myopathies, next generation sequencing panel (4 years after the initial diagnostic metabolic workup) revealed two potentially pathogenic missense mutations in the CPT2 gene (c.149C > A (p.P50H) and c.1459G > A (p.E487K)). Our case underscores the clinical variability of muscle carnitine palmitoyltransferase II (CPT II) deficiency and illustrates a pitfall of diagnostic algorithms for metabolic myopathies. Myalgia following exercise of a few minutes duration would have argued for a carbohydrate and against a fatty acid metabolic defect. However, CPT II deficiency is the most common disorder of muscle fatty acid metabolism and should be considered even in atypical scenarios. Analyses of plasma acyl carnitine profile during acute metabolic crises may help to unmask biochemical markers which are often overlooked in dried-blood analyses. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
9. SEVERE RHABDOMYOLYSIS IN HOMOZYGOTE CARNITINE PALMITOYL TRANSFERASE II DEFICIENCY.
- Author
-
Schnedl, Wolfgang J., Schenk, Michael, Enko, Dietmar, and Mangge, Harald
- Subjects
- *
CARNITINE palmitoyltransferase , *RHABDOMYOLYSIS , *FATTY acid oxidation , *SKELETAL muscle , *SYMPTOMS - Abstract
Carnitine palmitoyl transferase II (CPT II) deficiency represents an inherited defect in mitochondrial long-chain fatty acid oxidation. Rhabdomyolysis with necrosis of muscle is caused by the destruction of skeletal muscle and leads to systemic, multiorgan complications due to the release of intracellular muscle components. Severe rhabdomyolysis may be triggered by combination of a genetic predisposition, including CPT II deficiency, with additionally acting causes. Generally, patients with CPT II deficiency are rarely clinical recognized and reported. We describe a patient presenting severe rhabdomyolysis due to urosepsis, who, in genetic testing, demonstrated the homozygous CPT II deficiency (c.338C>T, p.Ser113Leu) mutation. The diagnosis of CPT II deficiency helped this patient to put the symptoms into context, and this reduced myopathy and the risk of recurring rhabdomyolysis.We report on this patient to increase awareness of diagnostic and medical management in CPT II deficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
10. When the Wind Does Not Come Back
- Author
-
Pitceathly, Robert D. S., Quinlivan, Rosaline, Manji, Hadi, editor, Turner, Chris, editor, and Evans, Matthew R. B., editor
- Published
- 2017
- Full Text
- View/download PDF
11. Effect of Bezafibrate on Muscle Metabolism in Patients With Fatty Acid Oxidation Defects (Bezafibrate)
- Author
-
Groupe Hospitalier Pitie-Salpetriere and Mette Cathrine Oerngreen, MD
- Published
- 2012
12. Unrecognized High Occurrence of Genetically Confirmed Hereditary Carnitine Palmitoyltransferase II Deficiency in an Austrian Family Points to the Ongoing Underdiagnosis of the Disease
- Author
-
Christina Zach, Karl Unterkofler, Peter Fraunberger, Heinz Drexel, and Axel Muendlein
- Subjects
carnitine palmitoyltransferase II deficiency ,family study ,mutation ,underdiagnosis ,pedigree ,Genetics ,QH426-470 - Abstract
Adult muscle carnitine palmitoyltransferase (CPT) II deficiency is a rare autosomal recessive disorder of long-chain fatty acid metabolism. It is typically associated with recurrent episodes of exercise-induced rhabdomyolysis and myoglobinuria, in most cases caused by a c.338C > T mutation in the CPT2 gene. Here we present the pedigree of one of the largest family studies of CPT II deficiency caused by the c.338C > T mutation, documented so far. The pedigree comprises 24 blood relatives of the index patient, a 32 year old female with genetically proven CPT II deficiency. In total, the mutation was detected in 20 family members, among them five homozygotes and 15 heterozygotes. Among all homozygotes, first symptoms of CPT II deficiency occurred during childhood. Additionally, two already deceased relatives of the index patient were carriers of at least one copy of the genetic variant, revealing a remarkably high prevalence of the c.338C > T mutation within the tested family. Beside the index patient, only one individual had been diagnosed with CPT II deficiency prior to this study and three cases of CPT II deficiency were newly detected by this family study, pointing to a general underdiagnosis of the disease. Therefore, this study emphasizes the need to raise awareness of CPT II deficiency for correct diagnosis and accurate management of the disease.
- Published
- 2019
- Full Text
- View/download PDF
13. Newborn Screening with (C16 + C18:1)/C2 and C14/C3 for Carnitine Palmitoyltransferase II Deficiency throughout Japan Has Revealed C12/C0 as an Index of Higher Sensitivity and Specificity.
- Author
-
Tajima G, Hara K, Tsumura M, Kagawa R, Sakura F, Sasai H, Yuasa M, Shigematsu Y, and Okada S
- Abstract
Carnitine palmitoyltransferase (CPT) II deficiency is a long-chain fatty acid oxidation disorder. It manifests as (1) a lethal neonatal form, (2) a hypoglycemic form, or (3) a myopathic form. The second form can cause sudden infant death and is more common among Japanese people than in other ethnic groups. Our study group had earlier used (C16 + C18:1)/C2 to conduct a pilot newborn screening (NBS) study, and found that the use of C14/C3 for screening yielded lower rates of false positivity; in 2018, as a result, nationwide NBS for CPT II deficiency started. In this study, we evaluated the utility of these ratios in 71 NBS-positive infants and found that the levels of both C14/C3 and (C16 + C18:1)/C2 in patients overlapped greatly with those of infants without the disease. Among the levels of acylcarnitines with various chain lengths (C18 to C2) and levels of free carnitine (C0) as well as their ratios of various patterns, C12/C0 appeared to be a promising index that could reduce false-positive results without missing true-positive cases detected by current indices. Although some cases of the myopathic form may go undetected even with C12/C0, its use will help prevent life-threatening onset of the hypoglycemic form of CPT II deficiency., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2023
- Full Text
- View/download PDF
14. Unrecognized High Occurrence of Genetically Confirmed Hereditary Carnitine Palmitoyltransferase II Deficiency in an Austrian Family Points to the Ongoing Underdiagnosis of the Disease.
- Author
-
Zach, Christina, Unterkofler, Karl, Fraunberger, Peter, Drexel, Heinz, and Muendlein, Axel
- Subjects
CARNITINE palmitoyltransferase ,FAMILIES ,FATTY acids ,DISEASE management ,GENETIC carriers - Abstract
Adult muscle carnitine palmitoyltransferase (CPT) II deficiency is a rare autosomal recessive disorder of long-chain fatty acid metabolism. It is typically associated with recurrent episodes of exercise-induced rhabdomyolysis and myoglobinuria, in most cases caused by a c.338C > T mutation in the CPT2 gene. Here we present the pedigree of one of the largest family studies of CPT II deficiency caused by the c.338C > T mutation, documented so far. The pedigree comprises 24 blood relatives of the index patient, a 32 year old female with genetically proven CPT II deficiency. In total, the mutation was detected in 20 family members, among them five homozygotes and 15 heterozygotes. Among all homozygotes, first symptoms of CPT II deficiency occurred during childhood. Additionally, two already deceased relatives of the index patient were carriers of at least one copy of the genetic variant, revealing a remarkably high prevalence of the c.338C > T mutation within the tested family. Beside the index patient, only one individual had been diagnosed with CPT II deficiency prior to this study and three cases of CPT II deficiency were newly detected by this family study, pointing to a general underdiagnosis of the disease. Therefore, this study emphasizes the need to raise awareness of CPT II deficiency for correct diagnosis and accurate management of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
15. Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: Postmortem diagnosis of fatty acid oxidation disorders
- Author
-
Takuma Yamamoto, Hiroyuki Mishima, Hajime Mizukami, Yuki Fukahori, Takahiro Umehara, Takehiko Murase, Masamune Kobayashi, Shinjiro Mori, Tomonori Nagai, Tatsushige Fukunaga, Seiji Yamaguchi, Koh-ichiro Yoshiura, and Kazuya Ikematsu
- Subjects
Sudden unexpected death in infancy ,Metabolic autopsy ,Next generation sequencing ,Fatty acid oxidation disorder ,Carnitine palmitoyltransferase II deficiency ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The recent introduction of metabolic autopsy in the field of forensic science has made it possible to detect hidden inherited metabolic diseases. Since the next generation sequencing (NGS) has recently become available for use in postmortem examinations, we used NGS to perform metabolic autopsy in 15 sudden unexpected death in infancy cases. Diagnostic results revealed a case of carnitine palmitoyltransferase II deficiency and some cases of fatty acid oxidation-related gene variants. Metabolic autopsy performed with NGS is a useful method, especially when postmortem biochemical testing is not available.
- Published
- 2015
- Full Text
- View/download PDF
16. Carnitine palmitoyltransferase-II deficiency: case presentation and review of the literature
- Author
-
Benjamin J. Mccormick and Razvan M. Chirila
- Subjects
Pediatrics ,medicine.medical_specialty ,Signs and symptoms ,Disease ,Case presentation ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Carnitine ,Myopathy ,Exercise ,Carnitine O-Palmitoyltransferase ,business.industry ,carnitine palmitoyltransferase-ii deficiency ,Middle Aged ,medicine.disease ,RC31-1245 ,rhabdomyolysis ,Treatment strategy ,Carnitine palmitoyltransferase II deficiency ,medicine.symptom ,business ,Rhabdomyolysis ,Metabolism, Inborn Errors ,030217 neurology & neurosurgery ,myopathy ,medicine.drug - Abstract
Carnitine palmitoyltransferase-II deficiency, an autosomal recessive disorder, is the most common cause of recurrent rhabdomyolysis in adults. Recognition and avoidance of triggers, such as heavy exercise and stress, is key in prevention of further episodes; however, even with preventative measures, many patients will continue to experience periodic symptoms, including rhabdomyolysis. Avoidance of renal failure, correction of electrolyte disturbances and halting further muscle breakdown are the goals of treatment. It is essential for clinicians to recognize the signs and symptoms of acute disease in CPT-II deficiency. We present a case of recurrent rhabdomyolysis requiring hospitalization in a patient with CPT-II deficiency and review the literature for common clinical manifestations, diagnostics, and treatment strategies.
- Published
- 2021
17. Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases
- Author
-
Yasemin Topçu, Erhan Bayram, Pakize Karaoglu, Uluç Yis, and Semra Hiz Kurul
- Subjects
Carnitine palmitoyltransferase II deficiency ,recurrent rhabdomyolysis ,acylcarnitine profile ,very long-chain acyl-CoA dehydrogenase deficiency ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16-year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies.
- Published
- 2014
- Full Text
- View/download PDF
18. Normal FGF-21-Serum Levels in Patients with Carnitine Palmitoyltransferase II (CPT II) Deficiency
- Author
-
Leila Motlagh Scholle, Diana Lehmann, Pushpa Raj Joshi, and Stephan Zierz
- Subjects
FGF-21 ,mitochondrial diseases ,carnitine palmitoyltransferase II deficiency ,biomarker ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.
- Published
- 2019
- Full Text
- View/download PDF
19. Carnitine Palmitoyltransferase II Deficiency
- Author
-
Deschauer, Marcus, Zierz, Stephan, and Lang, Florian, editor
- Published
- 2009
- Full Text
- View/download PDF
20. Severe rhabdomyolysis in homozygote carnitine palmitoyltransferase II deficiency
- Author
-
Schnedl, Wolfgang J., Schenk, Michael, Enko, Dietmar, and Mangge, Harald
- Subjects
myalgia ,endocrine system diseases ,Carnitine palmitoyltransferase II deficiency ,rhabdomyolysis ,heterocyclic compounds ,Case Report ,neoplasms ,urosepsis ,digestive system diseases - Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency represents an inherited defect in mitochondrial long-chain fatty acid oxidation. Rhabdomyolysis with necrosis of muscle is caused by the destruction of skeletal muscle and leads to systemic, multiorgan complications due to the release of intracellular muscle components. Severe rhabdomyolysis may be triggered by combination of a genetic predisposition, including CPT II deficiency, with additionally acting causes. Generally, patients with CPT II deficiency are rarely clinical recognized and reported. We describe a patient presenting severe rhabdomyolysis due to urosepsis, who, in genetic testing, demonstrated the homozygous CPT II deficiency (c.338C>T, p.Ser113Leu) mutation. The diagnosis of CPT II deficiency helped this patient to put the symptoms into context, and this reduced myopathy and the risk of recurring rhabdomyolysis. We report on this patient to increase awareness of diagnostic and medical management in CPT II deficiency., EXCLI Journal;Vol. 19 2020
- Published
- 2020
21. Tratamiento de la hipercolesterolemia en un paciente con hipercolesterolemia familiar y una miopatía por déficit de carnitina palmitoiltransferasa II con inhibidores de PCSK9
- Author
-
P. Luque Linero, I. Rojas Marcos Rodriguez, M.A. Rico Corral, and Luis Castilla-Guerra
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,medicine ,Neurology (clinical) ,Carnitine palmitoyltransferase II deficiency ,medicine.symptom ,PCSK9 Inhibitors ,Myopathy ,business ,medicine.disease - Published
- 2022
22. Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening: Should CPT II Deficiency Be a Primary Disease Target?
- Author
-
Rachel Mador-House, Zaiping Liu, and Sarah Dyack
- Subjects
Pediatrics ,medicine.medical_specialty ,transferase ,Case Report ,Disease ,Primary disease ,CPT II deficiency ,RJ1-570 ,Immunology and Microbiology (miscellaneous) ,newborn ,medicine ,Carnitine ,Early onset ,Newborn screening ,treatment ,business.industry ,screening ,carnitine ,Obstetrics and Gynecology ,medicine.disease ,CPT II Deficiency ,Treatment intervention ,Pediatrics, Perinatology and Child Health ,Carnitine palmitoyltransferase II deficiency ,business ,medicine.drug - Abstract
Early-onset carnitine palmitoyltransferase II deficiency (CPT II deficiency) (OMIM 600650) can result in severe outcomes, which are often fatal in the neonatal to infantile period. CPT II deficiency is a primary target in the Maritime Newborn Screening Program. We report a case of neonatal-onset CPT II deficiency identified through expanded newborn screening with tandem mass spectrometry. Identification through newborn screening led to early treatment interventions, avoidance of metabolic decompensation, and a better clinical outcome. Newborn screening for CPT II deficiency is highly sensitive and specific with no false positives identified. The only screen positive case detected identified a true positive case. This experience illustrates the importance of newborn screening for CPT II deficiency and demonstrates why reconsideration should be taken to add this disease as a primary newborn screening target.
- Published
- 2021
23. Carnitine palmitoyltransferase II deficiency and post-COVID vaccination rhabdomyolysis
- Author
-
Karolina M. Stepien, Alicia Tan, and Shashi Thej Koppa Narayana
- Subjects
medicine.medical_specialty ,Population ,Case Report ,Rhabdomyolysis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Carnitine palmitoyltransferase II ,Humans ,030212 general & internal medicine ,Carnitine O-palmitoyltransferase ,Myopathy ,education ,Beta oxidation ,education.field_of_study ,medicine.diagnostic_test ,Carnitine O-Palmitoyltransferase ,business.industry ,SARS-CoV-2 ,Vaccination ,COVID-19 ,General Medicine ,medicine.disease ,Endocrinology ,Carnitine palmitoyltransferase II deficiency ,medicine.symptom ,Liver function tests ,business ,AcademicSubjects/MED00010 ,Metabolism, Inborn Errors - Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder affecting fatty acid oxidation. The myopathic form of the condition is the most common among adults and manifests itself with a high serum creatine kinase (CK) concentration. Triggers of very high CK concentrations include periods of fasting, infection, exercise, stress, and exposure to extreme temperatures. A 27-year-old man known to have CPT II deficiency presented feeling generally unwell after his COVID-19 vaccine. His CK concentration of 105,000 U/L and deranged liver function tests (ALT 300 U/L and AST 1496 U/L) were in keeping with rhabdomyolysis. His biochemical parameters and myopathy resolved with continuous intravenous dextrose 10% and a high carbohydrate diet. Caution should be exercised when administering vaccinations (including the COVID-19 vaccination) to this population. Clinicians should be wary for signs and symptoms of CPT II deficiency exacerbations and be vigilant in monitoring serum CK.
- Published
- 2021
24. Statin use in carnitine palmitoyltransferase II deficiency
- Author
-
Trevor D. Hadley, Christie M. Ballantyne, Xiaoming Jia, and Anum Saeed
- Subjects
Male ,Heterozygote ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Pharmacotherapy ,Lisinopril ,Polymorphism (computer science) ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Creatine Kinase ,Aged ,Polymorphism, Genetic ,Nutrition and Dietetics ,Carnitine O-Palmitoyltransferase ,business.industry ,Heterozygote advantage ,Statin treatment ,medicine.disease ,Lipids ,Endocrinology ,Cardiovascular Diseases ,Drug Therapy, Combination ,Amlodipine ,Carnitine palmitoyltransferase II deficiency ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,Metabolism, Inborn Errors ,Metoprolol - Published
- 2019
25. Carnitine palmitoyltransferase II deficiency with a focus on newborn screening
- Author
-
Go Tajima, Miori Yuasa, and Keiichi Hara
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Disease ,030105 genetics & heredity ,Gastroenterology ,Mitochondrial fatty acid ,03 medical and health sciences ,Neonatal Screening ,Internal medicine ,Genetics ,medicine ,Humans ,Carnitine ,Genetics (clinical) ,Newborn screening ,Carnitine O-Palmitoyltransferase ,business.industry ,Infant, Newborn ,food and beverages ,Variant allele ,Prognosis ,medicine.disease ,CPT II Deficiency ,030104 developmental biology ,Fatal disease ,lipids (amino acids, peptides, and proteins) ,Carnitine palmitoyltransferase II deficiency ,business ,Metabolism, Inborn Errors ,medicine.drug - Abstract
Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder. Its clinical phenotypes are classified into the muscle, severe infantile, and lethal neonatal forms. Among Caucasians, the muscle form predominates, and the c.338C > T (p.S113L) variant is detected in most cases, whereas among the Japanese, c.1148T > A (p.F383Y) is the variant allele occurring with the highest frequency and can apparently cause symptoms of the severe infantile form. Newborn screening (NBS) for this potentially fatal disease has not been established. We encountered an infantile case of CPT II deficiency not detected in NBS using C16 and C18:1 concentrations as indices, and therefore we adopted the (C16 + C18:1)/C2 ratio as an alternative primary index. As a result, the disease was diagnosed in nine of 31 NBS-positive subjects. The values for (C16 + C18:1)/C2 in the affected newborns partly overlapped with those in unaffected ones. Among several other indices proposed previously, C14/C3 has emerged as a more promising index. Based on these findings, nationwide NBS for CPT II deficiency using both (C16 + C18:1)/C2 and C14/C3 as indices was officially approved and started in April 2018. We diagnosed the disease in four young children presenting with symptoms of the muscle form, whose values for the new indices were not elevated. Although it is still difficult to detect all cases of the muscle form of CPT II deficiency in NBS, our system is expected to save many affected children in Japan with the severe infantile form predominating.
- Published
- 2018
26. Cause of recurrent rhabdomyolysis, carnitine palmitoyltransferase II deficiency and novel pathogenic mutation
- Author
-
Gozde Yesil, Zeynep Gör, and Nafiye Emel Çakar
- Subjects
myalgia ,Starvation ,medicine.medical_specialty ,business.industry ,Pathogenic mutation ,Metabolic disorder ,Disease ,medicine.disease ,Gastroenterology ,Neurology ,Internal medicine ,medicine ,Carnitine palmitoyltransferase II ,Neurology (clinical) ,Carnitine palmitoyltransferase II deficiency ,medicine.symptom ,business ,Rhabdomyolysis - Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal inherited metabolic disorder in which the β-oxidation of the long chain fatty acids is defective. The clinical presentation may be in various forms; it presents itself in the severe form during neonatal and infantile periods and as the less severe myopathic form in the school age and adolescence. While the severity of the rhabdomyolysis attacks varies, occasionally the clinical course may be complicated with acute renal failure. Acylcarnitine analysis may help in the diagnosis of CPT II, but its normality does not indicate the absence of the disease. If there is strong suspicion, genetic analysis should be performed on the cases. In this article, we present a 15-year-old male patient who had two rhabdomyolysis attacks triggered by infection and starvation. Acylcarnitine analysis of the case was normal, CPT II deficiency was considered when the history was evaluated, and CPT II gene c.137A>G (p.Gln46Arg) homozygous novel pathogenic mutation was detected. CPT II deficiency is one of the most common causes of metabolic rhabdomyolysis in patients with recurrent episodes of rhabdomyolysis.
- Published
- 2021
27. Case Report. Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases.
- Author
-
Topçu, Yasemin, Bayram, Erhan, Karaoğlu, Pakize, Yiş, Uluç, and Kurul, Semra Hız
- Subjects
- *
METABOLIC disorder diagnosis , *CARNITINE , *METABOLIC disorders , *MYALGIA , *RHABDOMYOLYSIS , *URINE , *GENETIC testing , *MUSCLE weakness , *DISEASE complications - Abstract
Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16-year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
28. Schizophrenic Psychosis Symptoms in a Background of Mild-to-Moderate Carnitine Palmitoyltransferase II Deficiency: A Case Report
- Author
-
Rochelle N. Wickramasekara, Annemarie Shibata, Holly A.F. Stessman, Pashayar P. Lookian, and Jeannie Ngo
- Subjects
0301 basic medicine ,Proband ,lcsh:Medical physics. Medical radiology. Nuclear medicine ,medicine.medical_specialty ,Psychosis ,lcsh:R895-920 ,03 medical and health sciences ,Fraternal twin ,0302 clinical medicine ,Internal medicine ,Genetic variation ,Medicine ,Carnitine palmitoyltransferase II ,psychosis ,Electrical and Electronic Engineering ,lcsh:R5-920 ,business.industry ,Metabolic disorder ,whole-exome sequencing (WES) ,dopamine-β-hydroxylase ,medicine.disease ,Atomic and Molecular Physics, and Optics ,schizophrenia ,030104 developmental biology ,Endocrinology ,carnitine palmitoyltransferase II (CPT II) ,Schizophrenia ,Carnitine palmitoyltransferase II deficiency ,business ,lcsh:Medicine (General) ,metabolic deficiency ,030217 neurology & neurosurgery - Abstract
Schizophrenia is a multifaceted mental illness characterized by cognitive and neurobehavioral abnormalities. Carnitine palmitoyltransferase II (CPT II) deficiency is a metabolic disorder resulting in impaired transport of long-chain fatty acids from the cytosol to the mitochondrial inner membrane, where fatty acid β-oxidation takes place. Here, we present an interesting clinical case of an adolescent male that presented with psychosis and a history of mild-to-moderate CPT II deficiency. To identify germline genetic variation that may contribute to the phenotypes observed, we performed whole-exome sequencing on DNA from the proband, unaffected fraternal twin, and biological parents. The proband was identified to be homozygous for the p.Val368Ile and heterozygous for the p.Met647Val variant in CPT2. Each of these variants are benign on their own; however, their combined effect is unclear. Further, variation was identified in the dopamine β-hydroxylase (DBH) gene (c.339+2T>C), which may contribute to decreased activity of DBH; however, based on the patient’s presentation, severe DBH deficiency is unlikely. In conclusion, the variants identified in this study do not clearly explain the observed patient phenotypes, indicating that the complex phenotypes are likely caused by an interplay of genetic and environmental factors that warrant further investigation.
- Published
- 2020
29. Echogenic Kidneys as an Antenatal Clue to the Metabolic Etiology: A Case Report
- Author
-
Yadav, Sakshi, Kabra, Madhulika, and Gupta, Neerja
- Published
- 2019
- Full Text
- View/download PDF
30. An ignored cause of red urine in children: rhabdomyolysis due to carnitine palmitoyltransferase II (CPT-II) deficiency.
- Author
-
Melek, Engin, Bulut, Fatma Derya, Atmış, Bahriye, Yılmaz, Berna Şeker, Bayazıt, Aysun Karabay, and Mungan, Neslihan Önenli
- Abstract
Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessively inherited disorder involving the β-oxidation of long-chain fatty acids, which leads to rhabdomyolysis and subsequent acute renal failure. The clinical phenotype varies from a severe infantile form to a milder muscle form. Here, we report a 9-year-old boy referred to our hospital for the investigation of hematuria with a 2-day history of dark urine and malaise. As no erythrocytes in the microscopic examination of the urine and hemoglobinuria were present, myoglobinuria due to rhabdomyolysis was the most probable cause of dark urine. After excluding the other causes of rhabdomyolysis, with the help of metabolic investigations, the patient was suspected to have CPT-II deficiency, the most common cause of metabolic rhabdomyolysis. Our aim in presenting this case is to emphasize considering rhabdomyolysis in the differential diagnosis of dark urine in order to prevent recurrent rhabdomyolysis and renal injury. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
31. Functional analysis of iPSC-derived myocytes from a patient with carnitine palmitoyltransferase II deficiency.
- Author
-
Yasuno, Tetsuhiko, Osafune, Kenji, Sakurai, Hidetoshi, Asaka, Isao, Tanaka, Akihito, Yamaguchi, Seiji, Yamada, Kenji, Hitomi, Hirofumi, Arai, Sayaka, Kurose, Yuko, Higaki, Yasuki, Sudo, Mizuki, Ando, Soichi, Nakashima, Hitoshi, Saito, Takao, and Kaneoka, Hidetoshi
- Subjects
- *
PLURIPOTENT stem cells , *MUSCLE cells , *CARNITINE palmitoyltransferase , *ENZYME deficiency , *METABOLIC disorders , *CELL differentiation , *PATIENTS - Abstract
Highlights: [•] We derived disease-specific iPSCs from a patient with CPT II deficiency. [•] We differentiated iPSCs into mature myocytes. [•] Our hiPSC-derived myocytes mimicked the metabolic characteristics of the disease. [•] The bezafibrate reduced long-chain ACs effectively in myocytes from patient. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
32. Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening
- Author
-
Akira Ohtake, Hironori Kobayashi, Masato Arao, Kenji Yamada, Toru Kikuchi, Hiroyuki Awano, Takeshi Taketani, Ikuma Musha, Ryosuke Bo, Seiji Yamaguchi, Yuki Hasegawa, and Kazumoto Iijima
- Subjects
Pediatrics ,medicine.medical_specialty ,Metabolic decompensation ,Case Report ,Sudden death ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Carnitine palmitoyltransferase II deficiency ,Fatty acid oxidation disorders ,Sudden unexpected death in infancy (SUDI) ,Genetics ,Medicine ,Carnitine palmitoyltransferase II ,Molecular Biology ,lcsh:QH301-705.5 ,Mass screening ,0303 health sciences ,Newborn screening ,lcsh:R5-920 ,biology ,business.industry ,Mortality rate ,030305 genetics & heredity ,Retrospective cohort study ,medicine.disease ,lcsh:Biology (General) ,biology.protein ,Creatine kinase ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery - Abstract
In Japan, carnitine palmitoyltransferase II (CPTII) deficiency has been included as one of the primary target diseases in the expanded newborn mass screening program since 2018. However, many cases of the severe infantile hepatocardiomuscular form of CPTII deficiency showed severe neurodevelopmental delay or sudden death, which indicated that management of CPTII deficiency in the acute phase remains to be studied in detail. Herein, we discuss two cases diagnosed by newborn mass screening. Patient 1 was under strict clinical management from the neonatal period, with >20 admissions in 14 months, while Patient 2 was managed using a relatively relaxed approach, with only 2 admissions in the same period. Patient 1 showed normal development; however, Patient 2 expired at the age of 1 year 2 months. To develop strategies for preventing sudden deaths in patients with CPTII deficiency, this retrospective study focused on detailed clinical management practices and biochemical findings during the acute phase. We also investigated the correlation between conventional biomarkers (such as creatine kinase) and long-chain acylcarnitines. We propose that strict monitoring and immediate medical attention, even in case of slight fever or minor abdominal symptoms, can help prevent sudden death in patients with CPTII deficiency. Considering the higher morbidity rate of such patients, strict and acute management of CPTII deficiency cannot be overemphasized.
- Published
- 2020
33. A rare presentation of Carnitine palmitoyltransferase II (CPT-2) deficiency with normal acylcarnitine profile in a 10-year-old boy with muscle weakness and bilateral hearing loss; a case report.
- Author
-
Vafaee Shahi M, Ghasemi S, Tahernia L, and Riahi A
- Abstract
Carnitine palmitoyltransferase II (CPT-2) deficiency is a rare and autosomal recessive disorder of long-chain fatty acids oxidation. Here, we reported a 10-year-old boy with bilateral hearing loss and a myopathic form of CPT II deficiency, which was confirmed by a molecular genetic test. He was admitted to our hospital with unexplained headaches, vomiting, and fever. Furthermore, he developed seizures, muscle weakness, neck stiffness and pain, mild respiratory distress, and an icteric appearance. The laboratory test results also showed severely elevated lactate dehydrogenase levels (LDH) and creatine phosphokinase (CPK) levels. He also had an icteric appearance with unexplained indirect hyperbilirubinemia. Further examinations revealed a normal heart and liver without any neurological disorders. Muscle pathological examination reported normal pathology without neuromuscular and mitochondrial disorders and storage diseases. Finally, molecular test analysis with next-generation sequencing (NGS) revealed CPT-II deficiency fatty acid oxidation disorder. Furthermore, we identified a homozygous pathogenic variant in the ADGRV1 gene, c.15736C>T p. (Arg5246*), which suggests the Usher syndrome type 2C and the reason for sensorineural hearing loss in this case. Our finding indicates that CPT-II can be associated with multiple symptoms and clinical features. Therefore, evaluation of CPT-II deficiency with molecular test analysis may be helpful in cases with unexplained icteric appearance, muscle weakness, and rhabdomyolysis., Competing Interests: The authors declare no conflict of interest in preparing this case presentation. This case presentation received no specific grant from any funding agency in the public, institutions, or not-for-profit sectors, (© 2022 The Authors.)
- Published
- 2022
- Full Text
- View/download PDF
34. Echogenic Kidneys as an Antenatal Clue to the Metabolic Etiology: A Case Report
- Author
-
Sakshi Yadav, Madhulika Kabra, and Neerja Gupta
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,030219 obstetrics & reproductive medicine ,business.industry ,Reproductive medicine ,Prenatal diagnosis ,030105 genetics & heredity ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Inborn error of metabolism ,Modeling and Simulation ,Polycystic kidney disease ,Etiology ,Medicine ,Echogenic kidneys ,Carnitine palmitoyltransferase II deficiency ,Subsequent pregnancy ,business - Abstract
Antenatally diagnosed echogenic kidneys have several underlying etiologies such as aneuploidies, monogenic isolated or syndromic polycystic kidney disease, infections and rarely with inborn error of metabolism. Even a careful evaluation for additional abnormalities may not be able to provide a specific diagnosis. However with next generation sequencing, the diagnostic odyssey can be ended successfully. We report one such case of carnitine palmitoyltransferase II deficiency (CPT2) deficiency that manifested as isolated echogenic kidneys with early neonatal demise where successful early prenatal diagnosis was possible in the subsequent pregnancy.
- Published
- 2019
35. Rhabdomyolysis with different etiologies in childhood
- Author
-
Belde Kasap, Demet Alaygut, Meral Torun Bayram, Mehmet Türkmen, Alper Soylu, and Salih Kavukçu
- Subjects
Pediatrics ,medicine.medical_specialty ,Etiology ,Physical examination ,Rhabdomyolysis ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Retrospective Study ,030225 pediatrics ,medicine ,030212 general & internal medicine ,Family history ,Children ,medicine.diagnostic_test ,business.industry ,Acute kidney injury ,medicine.disease ,Treatment ,Pneumonia ,Hemodialysis ,Pediatrics, Perinatology and Child Health ,Carnitine palmitoyltransferase II deficiency ,business - Abstract
Aim To investigate different etiologies and management of the rhabdomyolysis in children. Methods Eight pediatric rhabdomyolysis cases who applied to the Dokuz Eylul University Faculty of Medicine Department of Pediatric Nephrology with different etiologies between January 2004 and January 2012 were evaluated in terms of age, gender, admission symptoms, physical examination findings, factors provoking rhabdomyolysis, number of rhabdomyolysis attacks, laboratory results, family history and the final diagnosis received after the treatment. Results Average diagnosis ages of eight cases were 129 (24-192) ± 75.5 mo and five of them were girls. All of them had applied with the complaint of muscle pain, calf pain, and dark color urination. Infection (pneumonia) and excessive physical activity were the most important provocative factors and excessive licorice consumption was observed in one case. In 5 cases, acute kidney injury was determined and two cases needed hemodialysis. As a result of the further examinations; the cases had received diagnoses of rhabdomyolysis associated with mycoplasma pneumoniae, sepsis associated rhabdomyolysis, licorice-induced hypokalemic rhabdomyolysis, carnitine palmitoyltransferase II deficiency, very long-chain acyl-CoA dehydrogenase deficiency, congenital muscular dystrophy and idiopathic paroxysmal rhabdomyolysis (Meyer-Betz syndrome). Conclusion It is important to distinguish the sporadic and recurrent rhabdomyolysis cases from each other. Recurrent rhabdomyolysis cases should follow up more regardful and attentive.
- Published
- 2017
36. A Case of Carnitine Palmitoyltransferase II Deficiency in Bahrain With a Novel Mutation.
- Author
-
Alsahlawi Z, Fadhul Z, Mahmood A, Mohamed A, Khalil M, and Aljishi E
- Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency is a rare genetic metabolic disorder. Three forms of the disease have been described: the lethal neonatal form, the severe infantile hepatocardiomuscular form, and the myopathic form. We report a case of the infantile form of CPT II deficiency with a novel mutation. Our patient is a seven-year-old Bahraini male who was investigated by the pediatric metabolic team following the sudden death of his twin sister in infancy. A fatty acid metabolic disorder was suspected based on his echocardiogram and tandem mass spectrometry (TMS) findings. Genetic analysis was initially inconclusive. Nonetheless, he was started on a fat-free diet, L-carnitine, and medium-chain triglycerides (MCT). At nearly two years of age, the patient had a metabolic crisis precipitated by a viral illness. TMS during this time was consistent with CPT II deficiency. Sanger sequencing then identified the presence of the variant c.161T>G (p.ille54Ser) in a homozygous state, confirming the diagnosis. Although this mutation has not been reported before in previous literature concerning CPT II deficiency, it is extremely likely that this mutation is pathogenic. Although the initial work-up of the patient was inconclusive, our clinical judgment was paramount in managing the patient., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Alsahlawi et al.)
- Published
- 2022
- Full Text
- View/download PDF
37. Retrospective review of Japanese sudden unexpected death in infancy: The importance of metabolic autopsy and expanded newborn screening
- Author
-
Yamamoto, Takuma, Tanaka, Hidekazu, Kobayashi, Hironori, Okamura, Ko, Tanaka, Tatsuya, Emoto, Yuko, Sugimoto, Kana, Nakatome, Masato, Sakai, Norio, Kuroki, Hisanaga, Yamaguchi, Seiji, and Matoba, Ryoji
- Subjects
- *
SUDDEN infant death syndrome , *JAPANESE people , *RETROSPECTIVE studies , *AUTOPSY , *MEDICAL screening , *METABOLIC disorders , *GENETIC mutation , *DEHYDROGENASES , *DISEASES - Abstract
Abstract: Sudden unexpected death in infancy is defined as sudden unexpected death occurring before 12months of age. The common causes of sudden unexpected death in infancy are infection, cardiovascular anomaly, child abuse, and metabolic disorders. However, the many potential inherited metabolic disorders are difficult to diagnose at autopsy and may therefore be underdiagnosed as a cause of sudden unexpected death in infancy. In the present study we retrospectively reviewed 30 Japanese sudden unexpected death in infancy cases encountered between 2006 and 2009 at our institute. With postmortem blood acylcarnitine analysis and histological examination of the liver, we found two cases of long-chain fatty acid oxidation defects. Molecular analysis revealed that the one patient had a compound heterozygote for a novel mutation (p.L644S) and a disease-causing mutation (p.F383Y) in the carnitine palmitoyltransferase 2 gene. Furthermore, retrospective acylcarnitine analysis of the newborn screening card of this patient was consistent with carnitine palmitoyltransferase II deficiency. Metabolic autopsy and expanded newborn screening would be helpful for forensic scientists and pediatricians to diagnose fatty acid oxidation disorders and prevent sudden unexpected death in infancy. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
38. Neonatal Arrhythmias Due to Deficiency of Carnitine Palmitoyltransferase II.
- Author
-
Casadei, Annachiara, Biasini, Augusto, Cuna, Chiara Dalla, Mancini, Luciano, and Sensi, Alberto
- Subjects
- *
CARDIAC hypertrophy , *ARRHYTHMIA in children , *HEART disease case studies , *CARNITINE palmitoyltransferase , *CARNITINE deficiency , *HYPERKALEMIA - Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency is a rare disorder of mitochondrial fatty acid oxidation characterized by a multisystemic course and early death during the neonatal period. Early recognition and diagnosis are important because a prompt treatment at birth may prolong survival. In this case report, we detected and corrected hypoglycemia and severe hyperkalemia in a collapsed neonate who manifested early heart rate anomalies and myocardial hypertrophy on cardiac ultrasound rapidly followed by death. Multiorgan degeneration, mostly in the heart and liver, was revealed by autopsy. The tandem mass and molecular genetic testing confirmed the diagnosis of CPT II deficiency. Our data document and confirm the severity of the disease. Laboratories alterations such as hyperkalemia and hypoglycemia in a term neonate with myocardial hypertrophy must always alert the physician to investigate and treat the metabolic disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
39. No carnitine palmitoyltransferase deficiency in skeletal muscle in 18 malignant hyperthermia susceptible individuals
- Author
-
Wieser, Thomas, Kraft, Birgit, and Kress, Hans Georg
- Subjects
- *
MALIGNANT hyperthermia , *PATIENTS , *CARNITINE , *MITOCHONDRIA - Abstract
Abstract: Malignant hyperthermia is a rare, potentially life threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. The clinical picture comprises rhabdomyolysis, metabolic and respiratory acidosis, and hyperthermia. Carnitine palmitoyltransferase II deficiency is a metabolic myopathy affecting the transport of fatty acids into the mitochondria, leading to impaired energy supply under stressful conditions resulting in muscle weakness and rhabdomyolysis. It was postulated in a previous study that some patients with the MH phenotype have a carnitine palmitoyltransferase deficiency. To investigate a potential association, we tested 18 individuals with proven MH susceptibility for impairment of carnitine palmitoyltransferase enzyme activity in muscle. Enzyme activity was normal in all individuals tested indicating no impairment of the CPT system in this sample of malignant hyperthermia susceptible individuals. Thus our data do not support the hypothesis that susceptibility to malignant hyperthermia has an effect on the carnitine palmitoyltransferase enzyme system. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
40. Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency.
- Author
-
Yasuno, T., Kaneoka, H., Tokuyasu, T., Aoki, J., Yoshida, S., Takayanagi, M., Ohtake, A., Kanazawa, M., Ogawa, A., Tojo, K., and Saito, T.
- Subjects
- *
CARNITINE , *VITAMIN B complex , *ACETYLCARNITINE , *POLYMERASE chain reaction , *CELL culture , *GENETIC polymorphisms , *CELL lines - Abstract
Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving β-oxidation of long-chain fatty acids. CPT II deficiency is a wide-spectrum disorder that includes a lethal neonatal form, an infantile form, and an adult-onset form. However, the ethnic characteristics and the relationship between genotype and clinical manifestation are not well understood. We investigated three non-consanguineous Japanese patients with CPT II deficiency and examined cell lines from 4 unrelated patients and 50 healthy donors. The CPT 2 gene was typed by direct DNA sequencing of polymerase chain reaction-amplified gene products. Case 1 (infantile form) was heterozygous for a phenylalanine to tyrosine substitution at position 383 (p.F383Y) and a novel valine to leucine substitution at 605 (p.V605L). Cases 2, 4, and 5 (infantile form) and case 3 (adult-onset form) were heterozygous for a single mutation at F383Y. Case 6 (adult-onset form) was compound heterozygous at the CPT 2 locus, with deletion of cytosine and thymine at residue 408, resulting in a stop signal at 420 (p.Y408fsX420), and an arginine to cysteine substitution at position 631 (p.R631C). Case 7 (adult-onset form) was homozygous for the p.F383Y mutation. In conclusion, we identified p.F383Y mutations in six of seven patients with CPT II deficiency and two novel variants of the coding gene: p.Y408fsX420 and p.V605L. These mutations differ from those in Caucasian patients, who commonly harbor p.S113L, p.P50H, and p.Q413fsX449 mutations; therefore, our data and those of other Japanese groups suggest that the p.F383Y mutation is significant in Japanese patients with CPT II deficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
41. Recurrent Rhabdomyolysis in a Collegiate Athlete: A Case Report.
- Author
-
Krivickas, Lisa S.
- Subjects
- *
RHABDOMYOLYSIS , *STRIATED muscle necrosis , *ATHLETES , *METABOLIC disorders , *DISEASES , *CARNITINE , *VITAMIN B complex , *PHOSPHORYLASES , *GLYCOSYLTRANSFERASES - Abstract
Purpose: Hereditary metabolic disorders can cause rhabdomyolysis in athletes. Team physicians should be aware of the presentation, workup, and management of the most common of these disorders, carnitine palmitoyltransferase (CPT) II deficiency and muscle phosphorylase deficiency. Methods: The case of a collegiate athlete with recurrent bouts of rhabdomyolysis is presented, and the diagnostic workup is discussed. Results: The patient described in this case has CPT II deficiency. The diagnosis and management of CPT II deficiency and muscle phosphorylase deficiency (McArdle's disease) are discussed. Conclusion: Athletes with rhabdomyolysis, in the absence of an obvious cause such as drug toxicity, severe trauma, or excessive exercise, should be evaluated for the presence of a metabolic myopathy. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
42. A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency
- Author
-
Deschauer, Marcus, Chrzanowska-Lightowlers, Zofia M.A., Biekmann, Eckhard, Pourfarzam, Morteza, Taylor, Robert W., Turnbull, Douglass M., and Zierz, Stephan
- Subjects
- *
GENETIC mutation , *MYALGIA - Abstract
We report the first splice junction mutation to be described in the carnitine palmitoyltransferase (CPT) 2 gene in a patient with the muscle form of CPT II deficiency. The patient, a 25-year-old man, suffered from attacks of myalgia and muscle weakness in early adult life. There was biochemical evidence of CPT II deficiency. Molecular genetic analysis revealed the common S113L mutation on one allele whilst a novel mutation at the splice donor junction in intron 3 was identified on the other allele. Sequencing of reverse transcription polymerase chain reaction (RT-PCR) products clearly demonstrated that this mutation causes the skipping of exon 3, thus establishing its pathogenic role. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
43. Carnitine palmitoyltransferase II deficiency in a prenatal case with polycystic kidney disease‐like phenotype
- Author
-
Dong‐Zhi Li and Yi He
- Subjects
Male ,Polycystic Kidney Diseases ,Embryology ,Carnitine O-Palmitoyltransferase ,business.industry ,Fatty Acids ,General Medicine ,Bioinformatics ,medicine.disease ,Phenotype ,Pregnancy ,Prenatal Diagnosis ,Pediatrics, Perinatology and Child Health ,Polycystic kidney disease ,medicine ,Humans ,Female ,Lipid Peroxidation ,Carnitine palmitoyltransferase II deficiency ,business ,Metabolism, Inborn Errors ,Developmental Biology - Published
- 2019
44. Carnitine Palmitoyltransferase II Deficiency (CPT II) Followed By Rhabdomyolysis and Acute Kidney Injury
- Author
-
Gjulsen Selim, Liljana Tozija, Aleksandar Sikole, Zvezdana Petronijevic, Pavlina Dzekova-Vidimliski, Nikola Gjorgjievski, and Petar Dejanov
- Subjects
0301 basic medicine ,myalgia ,medicine.medical_specialty ,medicine.medical_treatment ,Carnitine palmitoyltransferase II deficiency ,Rhabdomyolysis ,Metabolic disorder ,Creatine kinase ,Myoglobin ,Acute kidney injury ,Hemodialysis ,lcsh:Medicine ,Case Report ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,biology ,business.industry ,lcsh:R ,Myoglobinuria ,General Medicine ,medicine.disease ,030104 developmental biology ,Nephrology ,biology.protein ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
BACKGROUND: Carnitine palmitoyltransferase II deficiency (CPT II) is an autosomal recessive disorder and the most common inherited disorder of mitochondrial long-chain fatty acid oxidation, characterised by attacks of myalgia and myoglobinuria. The most common “classic” myopathic form occurs in young adults and is characterised by recurrent episodes of rhabdomyolysis triggered by prolonged exercise, fasting or febrile illness.CASE PRESENTATION: We present a case of a 22-year-old Caucasian male admitted to our hospital with fever, dyspnea, fatigue, myalgia and dark urine (brown-coloured). The symptoms appeared after viral infection followed by fever. Acute kidney injury (AKI) developed as a complication, and there was a need for treatment with hemodialysis. At the clinical presentation, the patient had plasma creatine kinase (pCK) level of 130.383 U/L and plasma myoglobin level over 5000 µg/L. Genetic testing (molecular analysis) confirmed the diagnosis of inherited rhabdomyolysis, a metabolic disorder of carnitine palmitoyltransferase II deficiency. A previous episode with the same symptoms, the patient had four years ago but did not ask for medical treatment. The patient was discontinued from hemodialysis because of the resolution of acute kidney injury. The patient was discharged from the hospital in good condition, with a recommendation about his future lifestyle in order to prevent similar episodes.CONCLUSION: Every patient presenting with myalgia, dark urine (brown-coloured), high level of pCK and development of AKI requiring hemodialysis, should be explored for inherited rhabdomyolysis induced by CPT II deficiency.
- Published
- 2018
45. Recurrent Myalgia since Early Infancy-Misleading Clinical Course in a Child with Carnitine Palmitoyltransferase-II Deficiency
- Author
-
Andreas Merkenschlager, Uta Ceglarek, Maria Arelin, Mitja L. Heinemann, Skadi Beblo, and Stephan Zierz
- Subjects
0301 basic medicine ,myalgia ,Male ,Weakness ,Mutation, Missense ,Physiology ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Medicine ,Carnitine palmitoyltransferase II ,Humans ,Carnitine ,Child ,Carnitine O-Palmitoyltransferase ,business.industry ,Myoglobinuria ,Skeletal muscle ,General Medicine ,Myalgia ,medicine.disease ,Hypotonia ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Carnitine palmitoyltransferase II deficiency ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Metabolism, Inborn Errors ,medicine.drug - Abstract
Metabolic myopathies are heterogeneous hereditary diseases affecting skeletal muscle energy supply. Symptoms usually comprise pain, cramps, hypotonia, weakness, and myoglobinuria.We present a boy with recurrent myalgia and weakness after some minutes of exercise or during febrile infections since early infancy. First laboratory workup at the age of 9 years showed no abnormalities, apart from a slightly elevated creatine kinase. After exclusion of common structural and metabolic myopathies, next generation sequencing panel (4 years after the initial diagnostic metabolic workup) revealed two potentially pathogenic missense mutations in the CPT2 gene (c.149C > A (p.P50H) and c.1459G > A (p.E487K)).Our case underscores the clinical variability of muscle carnitine palmitoyltransferase II (CPT II) deficiency and illustrates a pitfall of diagnostic algorithms for metabolic myopathies. Myalgia following exercise of a few minutes duration would have argued for a carbohydrate and against a fatty acid metabolic defect. However, CPT II deficiency is the most common disorder of muscle fatty acid metabolism and should be considered even in atypical scenarios. Analyses of plasma acyl carnitine profile during acute metabolic crises may help to unmask biochemical markers which are often overlooked in dried-blood analyses.
- Published
- 2019
46. Normal FGF-21-Serum Levels in Patients with Carnitine Palmitoyltransferase II (CPT II) Deficiency
- Author
-
Scholle, Leila Motlagh, Lehmann, Diana, Joshi, Pushpa Raj, and Zierz, Stephan
- Subjects
Adult ,Male ,endocrine system ,endocrine system diseases ,Enzyme-Linked Immunosorbent Assay ,Citrate (si)-Synthase ,Article ,lcsh:Chemistry ,Mice ,Animals ,Humans ,heterocyclic compounds ,lcsh:QH301-705.5 ,neoplasms ,Mice, Knockout ,mitochondrial diseases ,FGF-21 ,Carnitine O-Palmitoyltransferase ,Middle Aged ,digestive system diseases ,Fibroblast Growth Factors ,Malonyl Coenzyme A ,lcsh:Biology (General) ,lcsh:QD1-999 ,carnitine palmitoyltransferase II deficiency ,biomarker ,Female ,Biomarkers ,Metabolism, Inborn Errors - Abstract
Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.
- Published
- 2019
47. Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: Postmortem diagnosis of fatty acid oxidation disorders
- Author
-
Takahiro Umehara, Yuki Fukahori, Hajime Mizukami, Koh-ichiro Yoshiura, Masamune Kobayashi, Tomonori Nagai, Shinjiro Mori, Tatsushige Fukunaga, Takehiko Murase, Takuma Yamamoto, Hiroyuki Mishima, Kazuya Ikematsu, and Seiji Yamaguchi
- Subjects
Pathology ,medicine.medical_specialty ,Autopsy ,Biology ,Unexpected death ,DNA sequencing ,Fatty acid oxidation disorder ,Endocrinology ,Next generation sequencing ,Genetics ,medicine ,Biochemical testing ,Molecular Biology ,Beta oxidation ,lcsh:QH301-705.5 ,Postmortem Diagnosis ,lcsh:R5-920 ,Carnitine palmitoyltransferase II deficiency ,medicine.disease ,lcsh:Biology (General) ,Sudden unexpected death in infancy ,Metabolic autopsy ,lcsh:Medicine (General) ,Research Paper - Abstract
The recent introduction of metabolic autopsy in the field of forensic science has made it possible to detect hidden inherited metabolic diseases. Since the next generation sequencing (NGS) has recently become available for use in postmortem examinations, we used NGS to perform metabolic autopsy in 15 sudden unexpected death in infancy cases. Diagnostic results revealed a case of carnitine palmitoyltransferase II deficiency and some cases of fatty acid oxidation-related gene variants. Metabolic autopsy performed with NGS is a useful method, especially when postmortem biochemical testing is not available., Highlights • This is the first metabolic autopsy performed with next generation sequencing (NGS). • We detected one case of CPT II deficiency and three cases of FAOD-related rare variants. • Some of them had no specific abnormality except for genetic variants. • These cases would be undetected without NGS. • We advocate metabolic autopsy performed with NGS.
- Published
- 2015
48. A newborn case with carnitine palmitoyltransferase II deficiency initially judged as unaffected by acylcarnitine analysis soon after birth
- Author
-
Mako Ago, Takeshi Taketani, Kenji Yamada, Hironori Kobayashi, Ryosuke Bo, Seiji Yamaguchi, Yuki Hasegawa, and Seiji Fukuda
- Subjects
0301 basic medicine ,Newborn screening ,medicine.medical_specialty ,False negative ,Tandem mass spectrometry ,Carnitine palmitoyltransferase deficiency ,Case Report ,Biology ,03 medical and health sciences ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Carnitine palmitoyltransferase II ,lcsh:QH301-705.5 ,Molecular Biology ,Beta oxidation ,Genetic testing ,lcsh:R5-920 ,medicine.diagnostic_test ,Catabolism ,Vaginal delivery ,medicine.disease ,030104 developmental biology ,lcsh:Biology (General) ,Gestation ,Carnitine palmitoyltransferase II deficiency ,Serum acylcarnitine ,lcsh:Medicine (General) - Abstract
Carnitine palmitoyltransferase II (CPT-2) deficiency, an autosomal recessive disorder of fatty acid oxidation, can be detected by newborn screening using tandem mass spectrometry (TMS). Our case was a boy born at 38 weeks and 6 days of gestation via normal vaginal delivery; his elder sister was affected with CPT-2 deficiency. Acylcarnitine (AC) was analyzed in both dried blood spots (DBS) and serum 2 h after birth to determine whether the boy was also affected. His C16 and C18:1 AC levels in DBS were in the normal range, while his serum long-chain AC levels were marginally increased but lower than those of his sister. After the samples were taken, he was treated with glucose infusion to prevent any catabolism for 2 days. On day 4, the long-chain AC levels in both DBS and serum obtained were higher than those on day 0 and were equivalent to those of his sister. Genetic testing confirmed the presence of the same mutation found in his sister, a homozygous F383Y mutation in the CPT2 gene, thus leading to the diagnosis of CPT-2 deficiency. The sample for TMS should be taken between days 1 and 7. If the sample is not obtained at an appropriate time, correct diagnosis may not be made, as in our case. Although early diagnosis is required, samples taken within 24 h after birth should not be used for TMS.
- Published
- 2017
49. A surviving 24-month-old patient with neonatal-onset carnitine palmitoyltransferase II deficiency
- Author
-
Kosuke Yanagimoto, Shinsuke Maruyama, Yasuhiro Okamoto, Yasuyuki Kakihana, Naohiro Ikeda, Go Tajima, Ryo Imakiire, Shunji Seki, Yumiko Ninomiya, Yoshifumi Kawano, Kanna Nakano, and Keiichi Hara
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Short Communication ,Neonatal onset ,CPT II deficiency ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Genetics ,medicine ,Hyperammonemia ,In patient ,Carnitine ,Intensive care medicine ,lcsh:QH301-705.5 ,Molecular Biology ,lcsh:R5-920 ,business.industry ,Intensive treatment ,Continuous hemodialysis ,medicine.disease ,CPT II Deficiency ,030104 developmental biology ,lcsh:Biology (General) ,Neonatal-onset ,Prolonged survival ,Carnitine palmitoyltransferase II deficiency ,lcsh:Medicine (General) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The early-onset form of carnitine palmitoyltransferase (CPT) II deficiency has severe outcomes; patients typically die during the newborn period. We report a case of neonatal-onset CPT II deficiency with prolonged survival, exceeding 24 months. The patient was successfully treated by continuous hemodialysis (CHD), which enabled her to overcome repeated crises. We suggest that early intensive treatment, including CHD, is a key for prolonged survival in patients with neonatal-onset CPT II deficiency.
- Published
- 2017
50. Exome-Based Rare-Variant Analyses in CKD
- Author
-
Jan Fleckner, Bengt Fellström, Dimitrios Vitsios, Ruth March, Sophia R. Cameron-Christie, Simone Sanna-Cherchi, Slavé Petrovski, Ali G. Gharavi, Sitharthan Kamalakaran, Charles J. Wolock, Gundula Povysil, Krzysztof Kiryluk, Adam Platt, Andrew S. Allen, Emily E. Groopman, Yifu Li, David Goldstein, Mengqi Zhang, Sahar Gelfman, Carolina Haefliger, and Maddalena Marasa
- Subjects
0301 basic medicine ,Collagen Type IV ,Male ,medicine.medical_specialty ,Candidate gene ,TRPP Cation Channels ,030232 urology & nephrology ,Biology ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,Clinical Research ,Molecular genetics ,Exome Sequencing ,medicine ,Humans ,Renal Insufficiency, Chronic ,Exome ,Exome sequencing ,Genetics ,Case-control study ,Genetic Variation ,General Medicine ,medicine.disease ,Prognosis ,Human genetics ,030104 developmental biology ,Nephrology ,Case-Control Studies ,Medical genetics ,Female ,Carnitine palmitoyltransferase II deficiency ,Protein Kinases ,Protein Kinase D2 - Abstract
Background Studies have identified many common genetic associations that influence renal function and all-cause CKD, but these explain only a small fraction of variance in these traits. The contribution of rare variants has not been systematically examined. Methods We performed exome sequencing of 3150 individuals, who collectively encompassed diverse CKD subtypes, and 9563 controls. To detect causal genes and evaluate the contribution of rare variants we used collapsing analysis, in which we compared the proportion of cases and controls carrying rare variants per gene. Results The analyses captured five established monogenic causes of CKD: variants in PKD1 , PKD2 , and COL4A5 achieved study-wide significance, and we observed suggestive case enrichment for COL4A4 and COL4A3 . Beyond known disease-associated genes, collapsing analyses incorporating regional variant intolerance identified suggestive dominant signals in CPT2 and several other candidate genes. Biallelic mutations in CPT2 cause carnitine palmitoyltransferase II deficiency, sometimes associated with rhabdomyolysis and acute renal injury. Genetic modifier analysis among cases with APOL1 risk genotypes identified a suggestive signal in AHDC1 , implicated in Xia–Gibbs syndrome, which involves intellectual disability and other features. On the basis of the observed distribution of rare variants, we estimate that a two- to three-fold larger cohort would provide 80% power to implicate new genes for all-cause CKD. Conclusions This study demonstrates that rare-variant collapsing analyses can validate known genes and identify candidate genes and modifiers for kidney disease. In so doing, these findings provide a motivation for larger-scale investigation of rare-variant risk contributions across major clinical CKD categories.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.