Primary Carnitine Deficiency

Synonyms: Carnitine Deficiency, Carnitine Transport Defect (CTD), Carnitine Uptake Defect (CUD), Systemic Primary Carnitine Deficiency

El-Hattab AW, Almannai M.

Publication Details

Estimated reading time: 27 minutes

Summary

Clinical characteristics.

Primary carnitine deficiency (PCD) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. If untreated, it encompasses a broad clinical spectrum including: (1) 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; (2) childhood myopathy involving heart and skeletal muscle with onset between age two and four years; (3) pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia; (4) fatigability in adulthood; and (5) absence of symptoms. The latter two categories often include mothers diagnosed with PCD after newborn screening has identified low carnitine levels in their infants.

Diagnosis/testing.

The diagnosis of PCD is established in a proband with consistent biochemical analyte findings and/or suggestive clinical and laboratory features by identification of biallelic pathogenic variants in SLC22A5 on molecular genetic testing. In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available.

Management.

Targeted therapy: Metabolic decompensation and skeletal and cardiac muscle function improve with 100-200 mg/kg/day oral levocarnitine if it is started before irreversible organ damage occurs.

Supportive care: Routine treatment includes preventing hypoglycemia with frequent feeding and avoidance of prolonged fasting; notifying designated metabolic center in advance of scheduled surgical or medical procedures; hospitalization for intravenous glucose administration for individuals who are required to fast for a procedure or who cannot tolerate oral intake due to illness such as gastroenteritis; implementing transitional care plan prior to adulthood. Emergency outpatient treatment includes levocarnitine and carbohydrate supplementation, antipyretics for fever, and antiemetics for occasional vomiting. Acute inpatient treatment includes high-calorie fluids, insulin as needed, intravenous or oral levocarnitine (100-200 mg/kg/day), evaluation of muscle and liver involvement by measuring serum creatine kinase concentration and liver transaminases, and evaluation by cardiologist with EKG and echocardiogram for cardiomyopathy.

Surveillance: Monitor plasma carnitine concentration frequently until levels reach normal range; once levels reach normal range, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults. Assess growth and development at each visit throughout childhood. Neuropsychological testing and quality of life assessment as needed. EKG and echocardiogram annually during childhood and less frequently in adulthood.

Agents/circumstances to avoid: Fasting longer than age-appropriate periods; catabolic illness; inadequate calorie provision during other stressors.

Evaluation of relatives at risk: Evaluation of all sibs of any age by molecular genetic testing if the SLC22A5 pathogenic variants in the family are known or measurement of plasma-free carnitine concentration to identify as early as possible those who would benefit from institution of treatment and preventive measures.

Pregnancy management: Pregnant women with PCD require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain plasma carnitine levels in the normal range.

Genetic counseling.

PCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC22A5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC22A5 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

A diagnosis of primary carnitine deficiency (PCD) may be suspected due to an abnormal newborn screening result prior to onset of suggestive findings (see Scenario 1) or may be considered because of symptoms of PCD (see Scenario 2).

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for PCD is primarily based on use of dried blood spots collected between 24 hours and 72 hours after birth to quantify free carnitine (C0) concentration by tandem mass spectrometry. (For information on NBS by state in the United States, see www.newbornscreening.hrsa.gov.) Low concentration of free carnitine can identify (1) an infant with PCD, (2) a mother with PCD, or (3) both. NBS can identify a mother with PCD because transfer of carnitine across the placenta from an affected mother to her fetus results in a low plasma carnitine concentration in her newborn. Thus, an infant who does not have PCD but is born to a mother who has PCD can have low plasma carnitine concentrations shortly after birth, resulting in a false positive NBS result [Onuki et al 2023, van den Heuvel et al 2023].

Note: (1) NBS for PCD has low positive predictive value (e.g., 4.7% in California [Gallant et al 2017]). There are many factors that may affect NBS for PCD, including maternal carnitine deficiency, prematurity, pivalic acid-containing antibiotics, and some other inborn errors of metabolism. At least one country (New Zealand) has discontinued NBS for this disorder because of its very low sensitivity and positive predictive value [Wilson et al 2019]. (2) In the US, most NBS laboratories determine their own cutoff levels for test results that are considered to be out of range and require further laboratory testing because out-of-range NBS results individually are not entirely specific to PCD.

Positive NBS results (i.e., low blood concentrations of free carnitine) require evaluation of the newborn and mother as soon as possible and no later than three days after birth.

  • See Table 1 and Establishing the Diagnosis on how to make an analyte diagnosis or confirm a diagnosis molecularly.
  • For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
  • If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see Management) to prevent metabolic decompensation.
Table Icon

Table 1.

Primary Carnitine Deficiency: Testing Recommended at the Time of Diagnosis of Low Carnitine Blood Levels via NBS

Scenario 2: Symptomatic Individual

A symptomatic individual can have either (1) typical findings associated with later-onset PCD or (2) untreated infantile-onset PCD resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PCD should be considered in probands with the following clinical and laboratory findings and family history.

Clinical and supportive laboratory findings

  • Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
  • Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
  • Cardiomyopathy in children
  • Unexplained fatigability in adults
  • Decreased plasma carnitine concentrations without an identified cause in individuals of any age

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Analyte Diagnosis

The biochemical diagnosis (in limited instances) is established in a proband by identification of extremely reduced plasma free, acylated, and total (i.e., the sum of free and acylated) carnitine concentrations (i.e., <10% of controls).

Molecular Genetic Diagnosis

The molecular genetic diagnosis of PCD is established in a proband with consistent analyte findings and/or suggestive clinical and laboratory features by identification of biallelic pathogenic (or likely pathogenic) variants in SLC22A5 on molecular genetic testing (see Table 2).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SLC22A5 variants of uncertain significance (or of one known SLC22A5 pathogenic variant and one SLC22A5 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When NBS results and other laboratory findings suggest the diagnosis of PCD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel testing.

  • Single-gene testing. Sequence analysis of SLC22A5 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; at least one large deletion has been identified [Li et al 2010].
    In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [Crefcoeur et al 2023].
  • An inborn errors of metabolism or metabolic myopathy multigene panel that includes SLC22A5 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2

Exome or genome sequencing can be used. Ordering a rapid turnaround time exome or genome sequencing is necessary when newborns or infants are critically ill. To date, the majority of SLC22A5 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing [Frigeni et al 2017, Chen et al 2021, Lin et al 2021, Koleske et al 2022].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table Icon

Table 2.

Molecular Genetic Testing Used in Primary Carnitine Deficiency

Clinical Characteristics

Clinical Description

The clinical manifestations of primary carnitine deficiency (PCD) can vary widely with respect to age of onset, organ involvement, and severity. The broad clinical spectrum ranges from metabolic decompensation in infancy to cardiomyopathy in childhood, fatigability in adulthood, and absence of clinical manifestations. PCD has typically been associated with an infantile metabolic presentation that usually presents before age two years in about half of untreated affected individuals. The remaining half have a childhood myopathic presentation that typically presents between ages two and four years with dilated cardiomyopathy, hypotonia, muscle weakness, and elevated creatine kinase (CK). However, adults with PCD and mild or no manifestations are likely underdiagnosed, making it difficult to determine the relative proportion of these presentations [El-Hattab & Scaglia 2015, Longo et al 2016].

Table Icon

Table 3.

Primary Carnitine Deficiency: Select Features

Infantile Early Diagnosis and Treatment

Infants diagnosed with newborn screening (NBS) and treated early are usually asymptomatic, as manifestations can be prevented by maintaining normal plasma carnitine levels.

Infantile Metabolic (Hepatic) Presentation

Metabolic decompensation. Affected children can present between age three months and two years with episodes of metabolic decompensation triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. These episodes are characterized clinically by poor feeding, irritability, lethargy, and hepatomegaly. Laboratory evaluations usually reveal hypoketotic hypoglycemia (hypoglycemia with minimal or no ketones in urine), hyperammonemia, and elevated liver transaminases. If affected children are not treated with intravenous dextrose infusion during episodes of metabolic decompensation (see Management), they may develop coma and die [Longo et al 2006, El-Hattab & Scaglia 2015].

Myopathic manifestations. Older children with the infantile presentation may also develop myopathic manifestations including elevated CK, cardiomyopathy, and skeletal muscle weakness [Longo et al 2006, El-Hattab & Scaglia 2015].

Neurologic manifestations. Muscular hypotonia, irritability, rigors, dystonia, and reduced consciousness secondary to metabolic decompensation are possible complications of PCD. Long-term clinical effects are related to the number and severity of metabolic decompensation episodes.

Growth. Growth (linear growth, head circumference, and weight) can be negatively impacted if untreated.

Childhood Myopathic (Cardiac) Presentation

Skeletal myopathy. Myopathic manifestations include hypotonia, skeletal muscle weakness, and elevated serum CK.

Cardiomyopathy. Dilated cardiomyopathy is often present. PCD is associated with shortening of the QT interval and can result in arrhythmia [Lodewyckx et al 2023]. Death from cardiac failure can occur before the diagnosis is established, indicating that this presentation can be fatal if not treated.

Metabolic decompensations also occur in childhood-onset PCD, with hypotonia, weakness, hypoketotic hypoglycemia, hyperammonemia, increased liver transaminases, and increased CK.

Growth. Growth (linear growth, head circumference, and weight) can be negatively impacted if untreated.

Adulthood Presentation

Adults can present with life-threatening symptoms after being asymptomatic [Crefcoeur et al 2022]. Cardiac arrythmias and sudden death can occur. Cardiomyopathy in individuals with PCD responds poorly to standard therapy, and without accurate diagnosis and carnitine supplementation, it can be fatal. PCD can result in shortening of the QT interval, inducing severe arrhythmia [Lodewyckx et al 2023].

One study from the Faroe Islands estimated an odds ratio (OR) of 54.3 for the association between sudden death and untreated PCD [Rasmussen et al 2014]. This indicates the importance of screening at-risk individuals and adherence to treatment with levocarnitine supplementation to prevent the possibility of decompensation during intercurrent illness or stress or even sudden death.

Several women have been diagnosed with PCD after NBS identified low carnitine levels in their infants. About half of those women reported fatigability, whereas the other half were asymptomatic. One woman had dilated cardiomyopathy, and another had arrhythmias [Schimmenti et al 2007, El-Hattab et al 2010, Lee et al 2010].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nonsense and frameshift variants in SLC22A5 are more prevalent in symptomatic individuals. Missense variants are more prevalent in asymptomatic individuals [Rose et al 2012, Ji et al 2023].

Prevalence

PCD is very common in the Faroe Islands, where the reported prevalence is 1:300 [Rasmussen et al 2014]. The most prevalent pathogenic founder variant in this population is c.95A>G (p.Asn32Ser) (see Table 11).

NBS data estimated the incidence of PCD to be 1:348,333 in Australia and New Zealand, 1:121,609 in North America, 1:127,912 in Europe (excluding Denmark, Greenland, and the Faroe Islands) and 1:50,386 in Asia [Lefèvre et al 2023]. Some studies have suggested a higher prevalence in the Chinese population of 1:17,456 [Ji et al 2023].

Differential Diagnosis

Primary carnitine deficiency (PCD) needs to be differentiated from secondary carnitine deficiency associated with other inherited metabolic disorders, including organic acidemias and fatty acid oxidation defects (see Table 4), and acquired conditions [Longo et al 2016].

Genetic disorders. Free and total carnitines, a plasma acylcarnitine profile, and urine organic acid analysis can be useful in differentiating fatty acid oxidation disorders and organic acidemias from PCD.

Table Icon

Table 4.

Selected Autosomal Recessive Disorders Associated with Secondary Carnitine Deficiency in the Differential Diagnosis of Primary Carnitine Deficiency

Acquired conditions

  • Pharmacologic therapy (e.g., valproate, cyclosporine, pivampicillin)
  • Malnutrition
  • Hemodialysis and renal tubular dysfunction (e.g., renal Fanconi syndrome)
  • Prematurity. Premature neonates may have mild reduction in plasma carnitine concentrations due to a lack of carnitine placental transfer in the third trimester and decreased tissue stores. Moreover, immature renal tubular function in premature neonates could lead to increased renal carnitine elimination [Li et al 2010, Clark et al 2014].

Management

No clinical practice guidelines for primary carnitine deficiency (PCD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PCD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table Icon

Table 5.

Primary Carnitine Deficiency: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Targeted therapy for PCD involves oral carnitine supplementation to prevent carnitine deficiency (see Table 6).

Table Icon

Table 6.

Primary Carnitine Deficiency: Targeted Therapy

Oral levocarnitine supplementation in infants with PCD identified through newborn screening (NBS) results in slow normalization of the plasma carnitine concentration.

Metabolic decompensation and skeletal and cardiac muscle function improve with levocarnitine supplementation. Individuals with PCD respond well if oral levocarnitine supplementation is started before irreversible organ damage occurs.

Supportive Care

One of the most important components of preventing carnitine deficiency is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see Table 7 and Table 8). Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary.

Table Icon

Table 7.

Primary Carnitine Deficiency: Routine Outpatient Treatment of Manifestations

Emergency outpatient treatment. Parents or local hospitals should immediately inform the specialized metabolic center when the following occurs:

  • Fever
  • Vomiting/diarrhea or other manifestations of intercurrent illness
  • New neurologic findings
Table Icon

Table 8.

Primary Carnitine Deficiency: Emergency Outpatient Treatment

Table Icon

Table 9.

Primary Carnitine Deficiency: Acute Inpatient Treatment

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 10 are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Table Icon

Table 10.

Primary Carnitine Deficiency: Recommended Surveillance

Agents/Circumstances to Avoid

Avoid the following:

  • Prolonged fasting beyond age-appropriate periods
  • Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)
  • Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

Evaluation of Relatives at Risk

Testing of all sibs of any age at increased risk of PCD is warranted to identify as early as possible those who would benefit from institution of treatment and preventive measures.

  • If the SLC22A5 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, measure plasma free carnitine concentrations. If the free carnitine concentrations are low, further evaluation for PCD is available using carnitine uptake studies in cultured skin fibroblasts [Crefcoeur et al 2023].

For at-risk newborn sibs when prenatal testing was not performed. In parallel with NBS, perform either molecular genetic testing for the familial SLC22A5 pathogenic variants or plasma carnitines (free and total).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is a metabolically challenging state for women with PCD because energy consumption significantly increases. In addition, plasma carnitine concentrations are physiologically lower in women with PCD during pregnancy than those of non-pregnant controls. Women with PCD can have decreased stamina or worsening of cardiac arrhythmia during pregnancy, suggesting that PCD may manifest or exacerbate during pregnancy [Schimmenti et al 2007, El-Hattab et al 2010]. Therefore, it is recommended that all pregnant women with PCD, including those who are asymptomatic, have close monitoring of plasma carnitine concentrations, followed by increased carnitine supplementation as needed to maintain normal plasma carnitine concentrations.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Primary carnitine deficiency (PCD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are presumed to be heterozygous for an SLC22A5 pathogenic variant.
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to determine the genetic status of the parents and allow reliable recurrence risk assessment.
  • Occasionally an asymptomatic parent is found to have biallelic SLC22A5 pathogenic variants. In this event, the asymptomatic parent should be referred to a specialist center with experience in management of inherited metabolic diseases for initiation of treatment and surveillance (see Management).
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
    • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an SLC22A5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with PCD are obligate heterozygotes (carriers) for an SLC22A5 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC22A5 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the SLC22A5 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PCD, particularly if both partners are of the same ancestry. A founder variant has been identified in the Faroe Islander population (see Table 11).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC22A5 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table Icon

Table A.

Primary Carnitine Deficiency: Genes and Databases

Table Icon

Table B.

OMIM Entries for Primary Carnitine Deficiency (View All in OMIM)

Molecular Pathogenesis

Carnitine, required for the intracellular transfer of long-chain fatty acids from the cytoplasm to the mitochondrial matrix for beta-oxidation, is transported into cells by OCTN2 (encoded by SLC22A5), the organic cation transporter present in the kidney, heart, and muscle and many other tissues. During periods of fasting, fatty acids are the predominant substrate for energy production via oxidation in the liver, cardiac muscle, and skeletal muscle. When OCTN2 is not working properly, carnitine is improperly transferred across the cell membrane, resulting in urinary carnitine wasting, low plasma carnitine concentration, and decreased intracellular carnitine accumulation. As the main function of carnitine is to transfer long-chain fatty acids from the cytoplasm into the mitochondria for beta-oxidation, carnitine deficiency results in defective fatty acid oxidation. When fat cannot be utilized glucose is consumed without regeneration via gluconeogenesis, resulting in hypoglycemia. In addition, fats released from adipose tissue accumulate in the liver, skeletal muscle, and heart result in hepatic steatosis and myopathy [Longo et al 2006, El-Hattab & Scaglia 2015].

Mechanism of disease causation. Loss of function

SLC22A5-specific laboratory technical considerations. In one cohort of 236 individuals, a variant in the 5' untranslated region (UTR) (c.‐149G>A) was identified in 57 individuals in whom only one or no SLC22A5 pathogenic variant in the coding region was identified [Ferdinandusse et al 2019].

Table Icon

Table 11.

SLC22A5 Pathogenic Variants Referenced in This GeneReview

Chapter Notes

Revision History

  • 5 December 2024 (gf) Comprehensive update posted live
  • 3 November 2016 (sw) Comprehensive update posted live
  • 26 June 2014 (me) Comprehensive update posted live
  • 15 March 2012 (me) Review posted live
  • 5 December 2011 (aeh) Original submission

References

Literature Cited

  • Chen Y, Lin Q, Zeng Y, Qiu X, Liu G, Zhu W. Gene spectrum and clinical traits of 10 patients with primary carnitine deficiency. Mol Genet Genomic Med. 2021;9:e1583. [PMC free article: PMC8077093] [PubMed: 33560599]

  • Clark RH, Kelleher AS, Chace DH, Spitzer AR. Gestational age and age at sampling influence metabolic profiles in premature infants. Pediatrics. 2014;134:e37-46. [PubMed: 24913786]

  • Crefcoeur LL, Visser G, Ferdinandusse S, Wijburg FA, Langeveld M, Sjouke B. Clinical characteristics of primary carnitine deficiency: a structured review using a case-by-case approach. J Inherit Metab Dis. 2022;45:386-405. [PMC free article: PMC9305179] [PubMed: 34997761]

  • 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. Newborn screening for primary carnitine deficiency: who will benefit? - a retrospective cohort study. J Med Genet. 2023;60:1177-85. [PMC free article: PMC10715524] [PubMed: 37487700]

  • El-Hattab AW, Li FY, Shen J, Powell BR, Bawle EV, Adams DJ, Wahl E, Kobori JA, Graham B, Scaglia F, Wong LJ. Maternal primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med. 2010;12:19-24. [PubMed: 20027113]

  • El-Hattab AW, Scaglia F. Disorders of carnitine biosynthesis and transport. Mol Genet Metab. 2015;116:107-12. [PubMed: 26385306]

  • Ferdinandusse S, Te Brinke H, Ruiter JPN, Haasjes J, Oostheim W, van Lenthe H, IJlst L, Ebberink MS, Wanders RJA, Vaz FM, Waterham HR. A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency. Hum Mutat. 2019;40:1899-904. [PMC free article: PMC6790604] [PubMed: 31187905]

  • Frigeni M, Balakrishnan B, Yin X, Calderon FRO, Mao R, Pasquali M, Longo N. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017;38:1684-99. [PMC free article: PMC5665702] [PubMed: 28841266]

  • Gallant NM, Leydiker K, Wilnai Y, Lee C, Lorey F, Feuchtbaum L, Tang H, Carter J, Enns GM, Packman S, Lin HJ, Wilcox WR, Cederbaum SD, Abdenur JE. Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California. Mol Genet Metab. 2017;122:76-84. [PubMed: 28711408]

  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]

  • Ji X, Ge Y, Ni Q, Xu S, Xiong Z, Yang L, Hu L, Cao Y, Lu Y, Wei Q, Kang W, Zhuang D, Zhou W, Dong X. Primary carnitine deficiency: estimation of prevalence in Chinese population and insights into newborn screening. Front Genet. 2023;14:1304458. [PMC free article: PMC10730660] [PubMed: 38125748]

  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]

  • Koleske ML, McInnes G, Brown JEH, Thomas N, Hutchinson K, Chin MY, Koehl A, Arkin MR, Schlessinger A, Gallagher RC, Song YS, Altman RB, Giacomini KM. Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for carnitine transporter deficiency. Proc Natl Acad Sci U S A. 2022;119:e2210247119. [PMC free article: PMC9674959] [PubMed: 36343260]

  • Lee NC, Tang NL, Chien YH, Chen CA, Lin SJ, Chiu PC, Huang AC, Hwu WL. Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. Mol Genet Metab. 2010;100:46-50. [PubMed: 20074989]

  • Lefèvre CR, Labarthe F, Dufour D, Moreau C, Faoucher M, Rollier P, Arnoux JB, Tardieu M, Damaj L, Bendavid C, Dessein AF, Acquaviva-Bourdain C, Cheillan D. Newborn screening of primary carnitine deficiency: an overview of worldwide practices and pitfalls to define an algorithm before expansion of newborn screening in France. Int J Neonatal Screen. 2023;9:6. [PMC free article: PMC9944086] [PubMed: 36810318]

  • Li FY, El-Hattab AW, Bawle EV, Boles RG, Schmitt ES, Scaglia F, Wong LJ. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010;31:E1632-51. [PubMed: 20574985]

  • Lin Y, Lin B, Chen Y, Zheng Z, Fu Q, Lin W, Zhang W. Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening. Orphanet J Rare Dis. 2021;16:503. [PMC free article: PMC8642906] [PubMed: 34863234]

  • Lodewyckx P, Issa J, Gaschignard M, Lamireau D, De Lonlay P, Servais A, Barth M, Courapied S, Morin G, Benbrik N, Maillot F, Babuty D, Labarthe F, Lefort B. Systemic primary carnitine deficiency induces severe arrhythmia due to shortening of QT interval. Mol Genet Metab. 2023;140:107733. [PubMed: 37979236]

  • Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;142C:77-85. [PMC free article: PMC2557099] [PubMed: 16602102]

  • Longo N, Frigeni M, Pasquali M. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. 2016;1863:2422-35. [PMC free article: PMC4967041] [PubMed: 26828774]

  • Onuki T, Hiroshima S, Sawano K, Shibata N, Ogawa Y, Nagasaki K, Nyuzuki H. A study of maternal patients diagnosed with inborn errors of metabolism due to positive newborn mass screening in their newborns. Children (Basel). 2023;10:1341. [PMC free article: PMC10452974] [PubMed: 37628339]

  • Rose EC, di San Filippo CA, Ndukwe Erlingsson UC, Ardon O, Pasquali M, Longo N. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012;33:118-23. [PMC free article: PMC3240685] [PubMed: 21922592]

  • Rasmussen J, Nielsen OW, Janzen N, Duno M, Gislason H, Køber L, Steuerwald U, Lund AM. Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands. J Inherit Metab Dis. 2014;37:215-22. [PubMed: 23653224]

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

  • Schimmenti LA, Crombez EA, Schwahn BC, Heese BA, Wood TC, Schroer RJ, Bentler K, Cederbaum S, Sarafoglou K, McCann M, Rinaldo P, Matern D, di San Filippo CA, Pasquali M, Berry SA, Longo N. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007;90:441-5. [PubMed: 17126586]

  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]

  • van den Heuvel LM, Kater-Kuipers A, van Dijk T, Crefcoeur LL, Visser G, Langeveld M, Henneman L. A qualitative study on the perspectives of mothers who had been diagnosed with primary carnitine deficiency through newborn screening of their child. Orphanet J Rare Dis. 2023;18:134. [PMC free article: PMC10236393] [PubMed: 37268964]

  • Wilson C, Knoll D, de Hora M, Kyle C, Glamuzina E, Webster D. The decision to discontinue screening for carnitine uptake disorder in New Zealand. J Inherit Metab Dis. 2019;42:86-92. [PubMed: 30740730]