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Renal carnitine transport defect(CDSP)

MedGen UID:
90999
Concept ID:
C0342788
Disease or Syndrome
Synonyms: Carnitine Deficiency, Systemic; Carnitine deficiency, systemic, due to defect in renal reabsorption of carnitine; Carnitine plasma-membrane transporter deficiency; Carnitine transporter deficiency; CARNITINE TRANSPORTER, PLASMA-MEMBRANE, DEFICIENCY OF; Carnitine uptake defect; CDSP; Primary carnitine deficiency; Systemic primary carnitine deficiency; Systemic primary carnitine deficiency disease
SNOMED CT: Renal carnitine transport defect (21764004); Systemic carnitine deficiency (21764004); Carnitine transporter deficiency (21764004); Carnitine uptake defect (21764004); Primary carnitine deficiency (21764004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SLC22A5 (5q31.1)
 
Monarch Initiative: MONDO:0008919
OMIM®: 212140
Orphanet: ORPHA158

Disease characteristics

Excerpted from the GeneReview: Systemic Primary Carnitine Deficiency
Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Childhood myopathy involving heart and skeletal muscle with onset between age two and four years. Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia. Fatigability in adulthood. Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants. [from GeneReviews]
Authors:
Ayman W El-Hattab   view full author information

Additional descriptions

From OMIM
Primary systemic carnitine deficiency is due to a defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis (Lamhonwah et al., 2002). If diagnosed early, all clinical manifestations of the disorder can be completely reversed by supplementation of carnitine. However, if left untreated, patients will develop lethal heart failure (summary by Shibbani et al., 2014). See also myopathic carnitine deficiency (212160), which is restricted to skeletal muscle.  http://www.omim.org/entry/212140
From MedlinePlus Genetics
Primary carnitine deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). Carnitine, a natural substance acquired mostly through food, is used by cells to process fats and produce energy.

Signs and symptoms of primary carnitine deficiency typically appear during infancy or early childhood and can include severe brain dysfunction (encephalopathy), a weakened and enlarged heart (cardiomyopathy), vomiting, muscle weakness, and low blood glucose (hypoglycemia). The severity of this condition varies among affected individuals. Some people with primary carnitine deficiency are asymptomatic, which means they do not have any signs or symptoms of the condition. All individuals with this disorder are at risk for sudden death.

Problems related to primary carnitine deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children who appear to be recovering from viral infections such as chickenpox or flu.   https://medlineplus.gov/genetics/condition/primary-carnitine-deficiency

Clinical features

From HPO
Dicarboxylic aciduria
MedGen UID:
343550
Concept ID:
C1856432
Finding
An increased concentration of dicarboxylic acid in the urine.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Endocardial fibroelastosis
MedGen UID:
4041
Concept ID:
C0014117
Disease or Syndrome
Diffuse thickening of the ventricular endocardium and by associated myocardial dysfunction
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Microvesicular hepatic steatosis
MedGen UID:
376784
Concept ID:
C1850415
Finding
A form of hepatic steatosis characterized by the presence of small, lipid-laden vesicles in the affected hepatocytes.
Decreased carnitine level in liver
MedGen UID:
892603
Concept ID:
C4073182
Finding
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Excessive daytime somnolence
MedGen UID:
1635612
Concept ID:
C4551761
Sign or Symptom
A state of abnormally strong desire for sleep during the daytime.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Ketosis
MedGen UID:
7206
Concept ID:
C0022638
Disease or Syndrome
Presence of elevated levels of ketone bodies in the body.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Decreased circulating carnitine concentration
MedGen UID:
222973
Concept ID:
C1142132
Finding
Concentration of carnitine in the blood circulation below the lower limit of normal.
Recurrent hypoglycemia
MedGen UID:
335382
Concept ID:
C1846288
Finding
Recurrent episodes of decreased concentration of glucose in the blood.
Impaired gluconeogenesis
MedGen UID:
480966
Concept ID:
C3279336
Finding
An impairment of gluconeogenesis.
Reduced muscle carnitine level
MedGen UID:
892651
Concept ID:
C4072902
Finding
A reduction in the level of carnitine in muscle tissue.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Professional guidelines

PubMed

Crefcoeur L, Ferdinandusse S, van der Crabben SN, Dekkers E, Fuchs SA, Huidekoper H, Janssen M, Langendonk J, Maase R, de Sain M, Rubio E, van Spronsen FJ, Vaz FM, Verschoof R, de Vries M, Wijburg F, Visser G, Langeveld M
J Med Genet 2023 Nov 27;60(12):1177-1185. doi: 10.1136/jmg-2023-109206. PMID: 37487700Free PMC Article
Huang X, Wu D, Zhu L, Wang W, Yang R, Yang J, He Q, Zhu B, You Y, Xiao R, Zhao Z
Orphanet J Rare Dis 2022 Feb 21;17(1):66. doi: 10.1186/s13023-022-02231-x. PMID: 35193651Free PMC Article
Longo N
Ann Nutr Metab 2016;68 Suppl 3:5-9. Epub 2016 Dec 9 doi: 10.1159/000448321. PMID: 27931018

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Decreased C0, Carnitine Uptake Defect (CUD; Primary Carnitine Deficiency), 2022

American College of Medical Genetics and Genomics, Algorithm, Carnitine Uptake Defect: Decreased C0 (Free Carnitine), 2022

Recent clinical studies

Etiology

Huang X, Wu D, Zhu L, Wang W, Yang R, Yang J, He Q, Zhu B, You Y, Xiao R, Zhao Z
Orphanet J Rare Dis 2022 Feb 21;17(1):66. doi: 10.1186/s13023-022-02231-x. PMID: 35193651Free PMC Article
Hanai T, Shiraki M, Imai K, Suetugu A, Takai K, Shimizu M
Nutrients 2020 Jun 29;12(7) doi: 10.3390/nu12071915. PMID: 32610446Free PMC Article
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
Longo N
Ann Nutr Metab 2016;68 Suppl 3:5-9. Epub 2016 Dec 9 doi: 10.1159/000448321. PMID: 27931018
El-Hattab AW, Scaglia F
Mol Genet Metab 2015 Nov;116(3):107-12. Epub 2015 Sep 10 doi: 10.1016/j.ymgme.2015.09.004. PMID: 26385306

Diagnosis

Huang X, Wu D, Zhu L, Wang W, Yang R, Yang J, He Q, Zhu B, You Y, Xiao R, Zhao Z
Orphanet J Rare Dis 2022 Feb 21;17(1):66. doi: 10.1186/s13023-022-02231-x. PMID: 35193651Free PMC Article
Almannai M, Alfadhel M, El-Hattab AW
Molecules 2019 Sep 6;24(18) doi: 10.3390/molecules24183251. PMID: 31500110Free PMC Article
Frigeni M, Balakrishnan B, Yin X, Calderon FRO, Mao R, Pasquali M, Longo N
Hum Mutat 2017 Dec;38(12):1684-1699. Epub 2017 Sep 14 doi: 10.1002/humu.23315. PMID: 28841266Free PMC Article
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
Longo N
Ann Nutr Metab 2016;68 Suppl 3:5-9. Epub 2016 Dec 9 doi: 10.1159/000448321. PMID: 27931018

Therapy

Hanai T, Shiraki M, Imai K, Suetugu A, Takai K, Shimizu M
Nutrients 2020 Jun 29;12(7) doi: 10.3390/nu12071915. PMID: 32610446Free PMC Article
Kamei D, Kamei Y, Tanaka N, Tsukada M, Miwa N, Hanafusa N, Mineshima M, Nitta K, Tsuchiya K
Contrib Nephrol 2019;198:73-77. Epub 2019 Apr 16 doi: 10.1159/000496524. PMID: 30991404
Higuchi T
Contrib Nephrol 2018;196:96-100. Epub 2018 Jul 24 doi: 10.1159/000485706. PMID: 30041211
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
Longo N
Ann Nutr Metab 2016;68 Suppl 3:5-9. Epub 2016 Dec 9 doi: 10.1159/000448321. PMID: 27931018

Prognosis

Crefcoeur L, Ferdinandusse S, van der Crabben SN, Dekkers E, Fuchs SA, Huidekoper H, Janssen M, Langendonk J, Maase R, de Sain M, Rubio E, van Spronsen FJ, Vaz FM, Verschoof R, de Vries M, Wijburg F, Visser G, Langeveld M
J Med Genet 2023 Nov 27;60(12):1177-1185. doi: 10.1136/jmg-2023-109206. PMID: 37487700Free PMC Article
Frigeni M, Balakrishnan B, Yin X, Calderon FRO, Mao R, Pasquali M, Longo N
Hum Mutat 2017 Dec;38(12):1684-1699. Epub 2017 Sep 14 doi: 10.1002/humu.23315. PMID: 28841266Free PMC Article
Longo N
Ann Nutr Metab 2016;68 Suppl 3:5-9. Epub 2016 Dec 9 doi: 10.1159/000448321. PMID: 27931018
Koepsell H
Mol Aspects Med 2013 Apr-Jun;34(2-3):413-35. doi: 10.1016/j.mam.2012.10.010. PMID: 23506881
Koepsell H, Endou H
Pflugers Arch 2004 Feb;447(5):666-76. Epub 2003 Jul 19 doi: 10.1007/s00424-003-1089-9. PMID: 12883891

Clinical prediction guides

Crefcoeur L, Ferdinandusse S, van der Crabben SN, Dekkers E, Fuchs SA, Huidekoper H, Janssen M, Langendonk J, Maase R, de Sain M, Rubio E, van Spronsen FJ, Vaz FM, Verschoof R, de Vries M, Wijburg F, Visser G, Langeveld M
J Med Genet 2023 Nov 27;60(12):1177-1185. doi: 10.1136/jmg-2023-109206. PMID: 37487700Free PMC Article
Savic D, Hodson L, Neubauer S, Pavlides M
Nutrients 2020 Jul 22;12(8) doi: 10.3390/nu12082178. PMID: 32708036Free PMC Article
Frigeni M, Balakrishnan B, Yin X, Calderon FRO, Mao R, Pasquali M, Longo N
Hum Mutat 2017 Dec;38(12):1684-1699. Epub 2017 Sep 14 doi: 10.1002/humu.23315. PMID: 28841266Free PMC Article
Bonafé L, Berger MM, Que YA, Mechanick JI
Curr Opin Clin Nutr Metab Care 2014 Mar;17(2):200-9. doi: 10.1097/MCO.0000000000000037. PMID: 24500444
Koepsell H
Mol Aspects Med 2013 Apr-Jun;34(2-3):413-35. doi: 10.1016/j.mam.2012.10.010. PMID: 23506881

Recent systematic reviews

Salguero Olid A, Blanco Sánchez G, Alonso Ojembarrena A
Farm Hosp 2018 Jul 1;42(4):168-173. doi: 10.7399/fh.10976. PMID: 29959842

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Decreased C0, Carnitine Uptake Defect (CUD; Primary Carnitine Deficiency), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Carnitine Uptake Defect: Decreased C0 (Free Carnitine), 2022

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