Disorder of carnitine cycle and carnitine transport
-Rare genetic disease
Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Muscular lipidosis
-Rare genetic disease
-Rare neurologic disease
Comment:
The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms. The most common presentations are in infancy and early childhood with either metabolic decompensation or cardiac and myopathic manifestations, respectively (PMID:22989098). Single cases with somnolence (PMID:7432384), anemia (PMID:17926086) or vomiting (PMID:9634512) are also described.
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 ... 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). See also myopathic carnitine deficiency (212160), which is restricted to skeletal muscle.
Schimmenti et al. (2007) diagnosed primary carnitine deficiency in 6 unrelated women whose unaffected infants were identified with low free carnitine levels by newborn screening using tandem mass spectrometry. The authors concluded that given a lifetime risk of ... Schimmenti et al. (2007) diagnosed primary carnitine deficiency in 6 unrelated women whose unaffected infants were identified with low free carnitine levels by newborn screening using tandem mass spectrometry. The authors concluded that given a lifetime risk of morbidity or sudden death, identification of adult patients with primary carnitine deficiency is an added benefit of expanded newborn screening programs.
Karpati et al. (1975) reported systemic carnitine deficiency in an 11-year-old boy who had had recurrent episodes of hepatic and cerebral dysfunction and underdeveloped muscles. Overt weakness developed at age 10. Lipid excess, especially in type I fibers, ... Karpati et al. (1975) reported systemic carnitine deficiency in an 11-year-old boy who had had recurrent episodes of hepatic and cerebral dysfunction and underdeveloped muscles. Overt weakness developed at age 10. Lipid excess, especially in type I fibers, was found in muscle. There was marked carnitine deficiency in skeletal muscle, plasma, and liver. Oral replacement therapy resulted in clinical improvement and restored carnitine levels to normal in plasma, but not in liver or muscle. Chapoy et al. (1980) reported a 3.5-year-old boy who presented at age 3 months with an acute episode of lethargy, somnolence, hypoglycemia, hepatomegaly, and cardiomegaly. He had hypoketotic hypoglycemia associated with decreased carnitine in plasma, muscle, and liver (all less than 5% of normal values). Prolonged treatment with oral carnitine over a 6-month period resulted in increased muscle strength, a dramatic reduction in cardiac size, relief of cardiomyopathy, partial repletion of carnitine levels in plasma and muscle, and complete repletion in the liver. Tripp et al. (1981) reported systemic carnitine deficiency in a patient with cardiomyopathy. Waber et al. (1982) described a 3.5-year-old boy with cardiomegaly, congestive heart failure, and skeletal muscle weakness. A brother had died of heart failure. In the proband, muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Treatment with carnitine resolved the cardiac disease and muscle weakness. Plasma carnitine concentrations increased with treatment, but urinary carnitine excretion also increased 30-fold of normal, indicating a defect in renal carnitine reabsorption. Matsuishi et al. (1985) described 2 Japanese brothers with a lipid storage myopathy and hypertrophic cardiomyopathy. Their developmental milestones were normal until 3 years of age when mild weakness of the lower limbs became evident. Carnitine was decreased in skeletal muscle and serum. Treatment with L-carnitine resulted in marked clinical improvement. Treem et al. (1988) described a female infant with hypoketotic hypoglycemia who had a serious defect of carnitine transport in kidney, muscle, and cultured fibroblasts. Urinary carnitine content was increased, but plasma content was low. Carnitine concentrations are normally kept 20 to 40 times higher in tissue than in plasma by a carrier-mediated transport process that is driven by the large sodium gradient across the plasma membrane. Carnitine transport systems have been identified that may be involved in the renal conservation of carnitine. Although carnitine deficiency in the liver of this patient could be corrected when plasma carnitine levels were raised to normal, carnitine deficiency in muscle was not corrected, suggesting that a transport defect was present in muscle but not in liver. The same defect may have been present in the patient of Waber et al. (1982), although the presenting problem in that case was progressive cardiomyopathy and chronic muscle weakness that began at 2 years of age, was not accompanied by episodes of hypoglycemia, and was reversed by carnitine treatment. Eriksson et al. (1988) reported very low levels of carnitine in fibroblasts from a girl with carnitine deficiency and myopathy who may have had the same defect as in the patient of Treem et al. (1988). Stanley et al. (1991) examined the presenting features of 15 infants and children with defects in carnitine uptake. Progressive cardiomyopathy, with or without chronic muscle weakness, was the most common presentation; the median age of onset was 3 years. Other patients presented with episodes of fasting hypoglycemia during the first 2 years of life before cardiomyopathy became apparent. A defect in carnitine uptake was demonstrable in fibroblasts and leukocytes; the defect appeared to be expressed also in muscle and kidney. In parents, the concentrations of plasma carnitine and the rates of carnitine uptake were intermediate between those of affected patients and normal controls, consistent with autosomal recessive inheritance. Stanley et al. (1991) emphasized that early recognition and treatment with high doses of oral carnitine can be life-saving. Shoji et al. (1998) reported a Japanese girl with carnitine deficiency who began to complain intermittently of easy fatigue, vomiting, and abdominal pain at the age of 7 years and was first admitted to hospital at 8 years of age. She had unexplained fever, weakness, irregular respiration, and bradycardia, and had lapsed into unconsciousness. She was found to have hepatomegaly and muscle weakness. Echocardiogram showed left ventricular hypertrophy with normal left ventricular systolic function. The symptoms gradually abated with intravenous glucose infusion and disappeared within a few days. However, hyperammonemia and extremely low carnitine concentrations in the serum were not alleviated by the treatment. Carnitine uptake was assessed in vitro by use of cultured skin fibroblasts from the proband and her parents. This was the proband's first episode of a Reye-like syndrome. There was no family history of sudden infant death syndrome, Reye syndrome, or unexplained neuralgic, cardiac, or muscle disease. Marques (1998) reported a 6-year-old Chinese girl, born of nonconsanguineous parents, who presented with acute heart failure due to dilated cardiomyopathy. A defect in the plasma membrane carnitine transporter was confirmed by carnitine uptake assay on fibroblast cultures. She had an excellent response to carnitine therapy. Nezu et al. (1999) reported a 5-year-old boy with systemic carnitine deficiency. He had recurrent episodes of Reye syndrome, including encephalopathy, hyperammonemia, elevated liver enzymes, and hepatic steatosis. He had had episodes of hypoglycemia in the first 2 years of life. Oral carnitine prevented further episodes. Lamhonwah et al. (2004) reported a 3-year-old Saudi Arabian girl, born of consanguineous parents, who presented at 6 months with recurrent respiratory infections. She had dilated cardiomyopathy, was hypotonic, and showed mildly delayed gross motor development. Laboratory studies showed impaired fatty acid oxidation and decreased carnitine uptake in skin fibroblasts (less than 1% of control values). Treatment with oral carnitine resulted in improved muscle tone and exercise tolerance as well as improved cardiac function. Intellectual and motor development were normal at age 3 years. Molecular analysis identified a homozygous mutation in the SLC22A5 gene (R254X; 603377.0019). El-Hattab et al. (2010) identified systemic primary carnitine deficiency in asymptomatic mothers of children with low carnitine detected by newborn screening.
After demonstration of a mutation in the Slc22a5 gene in the jvs mouse model of primary systemic carnitine deficiency, Nezu et al. (1999) analyzed the human SLC22A5 gene and identified mutations in 3 SCD pedigrees (603377.0001-603377.0004). Affected individuals ... After demonstration of a mutation in the Slc22a5 gene in the jvs mouse model of primary systemic carnitine deficiency, Nezu et al. (1999) analyzed the human SLC22A5 gene and identified mutations in 3 SCD pedigrees (603377.0001-603377.0004). Affected individuals in 2 families were homozygous and the affected individual in the third pedigree was a compound heterozygote. Two families had previously been reported by Matsuishi et al. (1985) and Shoji et al. (1998). Lamhonwah and Tein (1998), who referred to this disorder as carnitine uptake defect (CUD), identified compound heterozygosity for mutations in the gene encoding the OCTN2 transporter (603377.0005-603377.0007) in 2 patients in whom they had previously documented CUD (Tein et al., 1990). Wang et al. (2001) reported 4 novel mutations responsible for primary carnitine deficiency. Two patients within the same family who were homozygous for the same mutation (603377.0016) had completely different clinical presentations. The first sib presented at 2 years of age in coma during an episode of gastroenteritis, while her older sister had weakness of the proximal limb girdle musculature requiring physical therapy, and developmental delays involving language skills, concentration, and attention span. Starting her on carnitine resulted in marked improvement of muscle tone, general mood, alertness, activity, and concentration span. Di San Filippo et al. (2006) found by confocal microscopy that several OCTN2 missense mutants in primary carnitine deficiency matured normally to the plasma membrane. By contrast, other mutations caused significant retention of the mutant OCTN2 transporter in the cytoplasm. Failed maturation to the plasma membrane is a common mechanism in disorders affecting membrane transporters/ion channels, including cystic fibrosis. To correct this defect, di San Filippo et al. (2006) tested whether drugs reducing the efficiency of protein degradation in the endoplasmic reticulum (phenylbutyrate, curcumin) or capable of binding the OCTN2 carnitine transporter (verapamil, quinidine) could improve carnitine transport. Prolonged incubation with phenylbutyrate, quinidine, and verapamil partially stimulated carnitine transport, while curcumin was ineffective. The authors concluded that pharmacologic therapy can be effective in partially restoring activity of mutant transporters. El-Hattab et al. (2010) reported 5 families in which low free carnitine levels in the infants' newborn screen led to the diagnosis of maternal systemic primary carnitine deficiency. Affected mothers were compound heterozygotes or homozygotes for missense mutations. All infants were asymptomatic at the time of diagnosis and 1 was found to have systemic primary carnitine deficiency. Three mothers were asymptomatic, one had decreased stamina during pregnancy, and the fifth had mild fatigability and developed preeclampsia. El-Hattab et al. (2010) concluded that these findings provided further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from metabolic decomposition in infancy to an asymptomatic adult.
Koizumi et al. (1999) determined serum free-carnitine levels in 973 unrelated white collar workers in Akita, Japan. In 14 of these participants, serum free-carnitine levels were consistently below the 5th percentile. They sequenced the OCTN2 gene in these ... Koizumi et al. (1999) determined serum free-carnitine levels in 973 unrelated white collar workers in Akita, Japan. In 14 of these participants, serum free-carnitine levels were consistently below the 5th percentile. They sequenced the OCTN2 gene in these 14 subjects, as well as in 22 subjects whose carnitine levels were below the 5th percentile in the first screening but were normal in the second measurement, and in 69 individuals with normal carnitine levels for 2 separate measurements. Polymorphic sequences defined 3 major haplotypes with equal frequencies. Mutations were identified in 9 subjects with low carnitine levels. The 2 seemingly frequent mutations were associated with specific haplotypes, suggesting a founder effect. They arrived at a conservative estimate of 1.01% representing the overall prevalence of heterozygotes in the Akita prefecture of Japan, giving an estimated incidence of primary systemic carnitine deficiency as 1 in 40,000 births. Echocardiographic studies of the families of patients with primary carnitine deficiency revealed that the heterozygotes for OCTN2 mutations were predisposed to late-onset benign cardiac hypertrophy (odds ratio 15.1, 95% CI 1.39-164) compared with the wildtypes. Sequencing of DNA isolated from 3 deceased sibs in 2 families retrospectively confirmed that all 3 were homozygous for the OCTN2 mutations.
Systemic primary carnitine deficiency (CDSP) should be considered in the following clinical situations:...
DiagnosisClinical Diagnosis Systemic primary carnitine deficiency (CDSP) should be considered in the following clinical situations:Infants with hypoketotic hypoglycemic episodes that may be associated with hepatomegaly, elevated transaminases, and hyperammonemia Children with skeletal myopathy and/or elevated serum concentration of creatine kinase (CK).Children with cardiomyopathyAdults with unexplained fatigabilitySudden deathTestingPlasma carnitine levels. Plasma free, acylated, and total (the sum of free and acylated) carnitine levels in affected individuals are extremely reduced (i.e., <10% of controls) [Scaglia et al 1999, Longo et al 2006]. Urine organic acid analysis. Nonspecific dicarboxylic aciduria has been reported in some affected individuals [Scaglia et al 1998]. Fibroblast carnitine transport (uptake). Carnitine transport in skin fibroblasts from affected individuals is typically reduced below 10% of control rates [Roe & Ding 2001, Longo et al 2006].Newborn screening. Newborn screening using tandem mass spectrometry (MS/MS) detects low levels of free carnitine (C0) [Wilcken et al 2001] and can identify: Infants with CDSPMothers with CDSP. Because carnitine is transferred from the placenta to the fetus during pregnancy, an infant’s carnitine levels during the neonatal period can reflect those of the mother [Scaglia & Longo 1999]. Thus, unaffected infants born to affected mothers can have low carnitine levels shortly after birth [Vijay et al 2006, Schimmenti et al 2007, El-Hattab et al 2010, Lee et al 2010]. Heterozygous carriers. Heterozygous carriers usually have about 50% carnitine transport activity in fibroblasts and can have borderline low plasma carnitine levels [Scaglia et al 1998]. However, normal plasma carnitine levels have been reported in some heterozygous carriers. Because the diet, which provides about 75% of the daily requirement of carnitine, may play a role modulating carnitine levels, plasma carnitine levels are not a reliable indicator for heterozygous carrier status; thus, either molecular testing or fibroblast carnitine transport assay is needed to determine carrier status [El-Hattab et al 2010]. Molecular Genetic Testing Gene. SLC22A5 is the only gene in which mutations are known to cause systemic primary carnitine deficiency. Clinical testingSequence analysis. In one study, SLC22A5 sequencing performed in 70 infants with low carnitine levels detected by newborn screening identified two mutations in 23 infants and one mutation in 25 infants; no mutations were detected in 22 infants [Li et al 2010]. Table 1. Summary of Molecular Genetic Testing Used in Systemic Primary Carnitine DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC22A5Sequence analysisSequence variants 2~70% 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Sequence analysis of the coding regions and the flanking intronic sequences of SLC22A5 can detect at least one mutation in approximately 70% of affected individuals [Li et al 2010].4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. The frequency of large deletions or duplications is unknown, but appears to be low. One out of 26 affected individuals tested by oligonucleotide array CGH was found to have a large deletion encompassing all of SLC22A5 [Li et al 2010].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. After the finding of low plasma carnitine levels on a newborn screening assay, in a symptomatic individual, or in an asymptomatic at-risk relative, the diagnosis of CDSP can be confirmed by:SLC22A5 molecular genetic testing: Sequence analysis. If homozygous or compound heterozygous mutations are identified, the diagnosis is confirmed. If one or no mutations are detected, deletion/duplication analysis is recommended. Note: If two pathogenic SLC22A5 alleles are identified, the diagnosis of CDSP is confirmed. If molecular genetic testing fails to demonstrate two pathogenic SLC22A5 alleles, a skin biopsy can be considered to assess carnitine transport in cultured fibroblasts. The plasma carnitine levels should be measured in all mothers of infants found to have low free carnitine levels on newborn screening in order to determine if the mother, not the infant, has CDSP [Vijay et al 2006, Schimmenti et al 2007, El-Hattab et al 2010, Lee et al 2010]. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Heterozygotes usually have about 50% carnitine transport activity in fibroblasts [Scaglia et al 1998]. (3) Normal or borderline low plasma carnitine levels can be seen in heterozygous carriers. Therefore, plasma carnitine analysis alone is not sufficient to determine an individual’s carrier status and fibroblast carnitine transport assay or molecular genetic testing is needed to confirm the carrier status [El-Hattab et al 2010].Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in SLC22A5.
The systemic primary carnitine deficiency (CDSP) phenotype encompasses a broad clinical spectrum including metabolic decompensation in infancy, cardiomyopathy in childhood, fatigability in adulthood, or lack of symptoms. CDSP has been typically associated with infantile metabolic presentation in about half of affected individuals and childhood myopathic presentation in the other half [Roe & Ding 2001, Longo et al 2006]. However, adults with CDSP have been reported with mild or no symptoms. Such milder phenotypes are expected to be underdiagnosed; therefore, it is difficult to determine the relative prevalence of different phenotypes associated with CDSP. ...
Natural History The systemic primary carnitine deficiency (CDSP) phenotype encompasses a broad clinical spectrum including metabolic decompensation in infancy, cardiomyopathy in childhood, fatigability in adulthood, or lack of symptoms. CDSP has been typically associated with infantile metabolic presentation in about half of affected individuals and childhood myopathic presentation in the other half [Roe & Ding 2001, Longo et al 2006]. However, adults with CDSP have been reported with mild or no symptoms. Such milder phenotypes are expected to be underdiagnosed; therefore, it is difficult to determine the relative prevalence of different phenotypes associated with CDSP. Infantile metabolic (hepatic) presentation. 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 [Roe & Ding 2001, Stanley 2004, Longo et al 2006]. Childhood myopathic (cardiac) presentation. The average age of myopathic presentation is between age two and four years, indicating that the myopathic manifestations of CDSP may develop over a longer period of time. Myopathic manifestations include dilated cardiomyopathy, hypotonia, skeletal muscle weakness, and elevated serum creatine kinase (CK). Death from cardiac failure can occur before the diagnosis is established, indicating that this presentation can be fatal if not treated. Older children with the infantile presentation may also develop myopathic manifestations including elevated CK, cardiomyopathy, and skeletal muscle weakness [Roe & Ding 2001, Stanley 2004, Longo et al 2006]. Adulthood presentation. Several women have been diagnosed with CDSP after newborn screening identified low carnitine levels in their infants. About half of those women complained of fatigability, whereas the other half were asymptomatic. One woman was found to have dilated cardiomyopathy and another had arrhythmias [Vijay et al 2006, Schimmenti et al 2007, El-Hattab et al 2010, Lee et al 2010]. An asymptomatic adult male with CDSP has also been reported [Spiekerkoetter et al 2003]. Pregnancy-related symptoms. Pregnancy is a metabolically challenging state because energy consumption significantly increases. In addition, during pregnancy the plasma carnitine levels are physiologically lower than those of non-pregnant controls [Schoderbeck et al 1995]. Affected women can have decreased stamina or worsening of cardiac arrhythmia during pregnancy, suggesting that CDSP may manifest or exacerbate during pregnancy [Schimmenti et al 2007, El-Hattab et al 2010].Atypical manifestations. Other manifestations reported in individuals with CDSP include:Anemia [Cano et al 2008],Proximal muscle weakness and global developmental delays [Wang et al 2001],Respiratory distress [Erguven et al 2007], Arrhythmias and electrocardiographic (ECG) abnormalities [Schimmenti et al 2007, Lee et al 2010]. Heterozygous carriers. Heterozygous carriers are asymptomatic. Although it was speculated that benign left ventricular hypertrophy could be associated with a heterozygous pathogenic SLC22A5 allele in middle-aged adults [Koizumi et al 1999], a more recent study by Amat di San Filippo et al [2008] revealed that heterozygosity for mutations in this gene is not associated with cardiomyopathy. Prognosis. Infantile metabolic and childhood myopathic presentations of CDSP can be fatal if untreated (see Management). The long-term prognosis is favorable as long as affected individuals remain on carnitine supplements. Repeated attacks of hypoglycemia or sudden death from arrhythmia have been described in affected individuals discontinuing carnitine supplementation [Roe & Ding 2001, Cederbaum et al 2002, Stanley 2004, Longo et al 2006].
Fibroblast carnitine transport is reduced in all affected individuals. However, it has been demonstrated that carnitine transport is higher in the fibroblasts of asymptomatic individuals than in the fibroblasts of symptomatic individuals. Nonsense and frameshift mutations are typically associated with lower carnitine transport and are more prevalent in symptomatic individuals whereas missense mutations and inframe deletions may result in protein with retained residual carnitine transport activity and are more prevalent in asymptomatic individuals [Rose et al 2012]....
Genotype-Phenotype Correlations Fibroblast carnitine transport is reduced in all affected individuals. However, it has been demonstrated that carnitine transport is higher in the fibroblasts of asymptomatic individuals than in the fibroblasts of symptomatic individuals. Nonsense and frameshift mutations are typically associated with lower carnitine transport and are more prevalent in symptomatic individuals whereas missense mutations and inframe deletions may result in protein with retained residual carnitine transport activity and are more prevalent in asymptomatic individuals [Rose et al 2012].
Systemic primary carnitine deficiency (CDSP) needs to be differentiated from secondary carnitine deficiency seen in the following situations [Flanagan et al 2010]:...
Differential DiagnosisSystemic primary carnitine deficiency (CDSP) needs to be differentiated from secondary carnitine deficiency seen in the following situations [Flanagan et al 2010]:Inherited metabolic disorders including organic acidemias and fatty acid oxidation defects including very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, carnitine-acylcarnitine translocase (CACT) deficiency, long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and carnitine palmitoyltransferase II (CPT II) deficiency.Pharmacologic therapy (e.g. cyclosporine, pivampicillin)Malnutrition Hemodialysis and renal tubular dysfunction e.g. renal Fanconi syndromePrematurity. Premature neonates may have low 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]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Infantile metabolic CDSPChildhood myopathic CDSPAdult-onset CDSP
To establish the extent of disease and needs of an individual diagnosed with systemic primary carnitine deficiency (CDSP), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with systemic primary carnitine deficiency (CDSP), the following evaluations are recommended:Echocardiogram and electrocardiogram Serum creatine kinase (CK) concentrationLiver transaminasesPre-prandial blood glucose concentrationMedical genetics consultationTreatment of ManifestationsL-carnitine supplementation. The main treatment for CDSP is oral levocarnitine (L-carnitine) supplementation. Typically a high dose, 100-400 mg/kg/day, divided in three doses is required. Individuals with CDSP respond well if oral L-carnitine supplementation is started before irreversible organ damage occurs. Metabolic decompensation and skeletal and cardiac muscle functions improve with L-carnitine supplementations. Oral L-carnitine supplementation in infants with CDSP identified through newborn screening results in slow normalization of the plasma carnitine concentration. The carnitine dose needs to be adjusted according to the plasma carnitine concentrations, which should be measured frequently. L-carnitine supplementation has relatively few side effects: High doses of oral L-carnitine can cause increased gastrointestinal motility, diarrhea, and intestinal discomfort. Oral L-carnitine can be metabolized by intestinal bacteria to produce trimethylamine that has a fishy odor. Oral metronidazole at a dose of 10 mg/kg/day for 7-10 days and/or decreasing the carnitine dose usually results in the resolution of the odor [Longo et al 2006]. Note: (1) An unaffected infant born to a mother with CDSP can have low carnitine levels detected on newborn screening; in these infants oral L-carnitine supplementation is followed by a rise in plasma carnitine concentration within days or a few weeks [Stanley 2004, Schimmenti et al 2007, El-Hattab et al 2010]. (2) Asymptomatic adults with CDSP have been reported; however, the limited literature and the lack of follow-up make it unclear whether these individuals have potential health risks. Because some fatty acid oxidation defects such as medium chain acyl CoA dehydrogenase (MCAD) deficiency can remain asymptomatic until it results in sudden death or another acute presentation during stress [Ruitenbeek et al 1995, Feillet et al 2003], it is prudent to treat asymptomatic individuals with CDSP with L-carnitine supplementation to prevent the possibility of decompensation during intercurrent illness or stress [El-Hattab et al 2010].OtherHypoglycemic episodes are treated with intravenous dextrose infusion. Cardiomyopathy requires management by specialists in cardiology. Prevention of Primary ManifestationsMaintaining appropriate plasma carnitine concentrations through oral L-carnitine supplementation (See Treatment of Manifestations) and preventing hypoglycemia (with frequent feeding and avoiding fasting) typically eliminate the risk of metabolic, hepatic, cardiac, and muscular complications. Note: Hospitalization to administer intravenous glucose is recommended for individuals with CDSP who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of an illness such as gastroenteritis. SurveillanceNo clinical guidelines for surveillance are available. The following evaluations are suggested: Echocardiogram and electrocardiogram. Perform annually during childhood and less frequently in adulthood. Individuals with cardiomyopathy require management and follow up by specialists in cardiology. Plasma carnitine concentration. Monitor frequently until levels reach the normal range, thereafter, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults. Serum CK concentration and liver transaminases. Consider measuring during acute illnesses. Agents/Circumstances to AvoidIndividuals with CDSP should avoid fasting longer than age-appropriate periods. Evaluation of Relatives at RiskSibs of affected individuals should be tested by measuring plasma carnitine concentrations. If the carnitine levels are low, further evaluation for CDSP is needed by either fibroblast carnitine transport assay or molecular genetic testing if the disease-causing mutations have been identified in the family. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnancy is a metabolically challenging state because energy consumption significantly increases. In addition, plasma carnitine levels are physiologically lower during pregnancy than those of non-pregnant controls [Schoderbeck et al 1995]. Affected women can have decreased stamina or worsening of cardiac arrhythmia during pregnancy, suggesting that CDSP may manifest or exacerbate during pregnancy [Schimmenti et al 2007, El-Hattab et al 2010]. Therefore, all pregnant women with CDSP, including those who are asymptomatic, require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain normal plasma carnitine levels. Therapies Under InvestigationSearch Clinical Trials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Systemic Primary Carnitine Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC22A55q31.1Solute carrier family 22 member 5ARUP Laboratories SLC22A5 Mutation Database SLC22A5 homepage - Mendelian genesSLC22A5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Systemic Primary Carnitine Deficiency (View All in OMIM) View in own window 212140CARNITINE DEFICIENCY, SYSTEMIC PRIMARY; CDSP 603377SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 5; SLC22A5Molecular Genetic Pathogenesis Carnitine is required for the transfer of long-chain fatty acids from the cytoplasm to the mitochondrial matrix for beta-oxidation. During periods of fasting, fatty acids are the predominant substrate for energy production via oxidation in the liver, cardiac muscle, and skeletal muscle. Carnitine is transported inside the cells by an organic cation transporter (OCTN2) present in the heart, muscle, and kidney. OCTN2 is the protein product of SLC22A5. CDSP is a disorder of the carnitine cycle caused by the lack of functional OCTN2 resulting in urinary carnitine wasting, low plasma carnitine levels, and decreased intracellular carnitine accumulation. Normal allelic variants. SLC22A5 comprises ten exons spanning approximately 3.2 kb. Pathologic allelic variants. More than 100 mutations have been reported in the Human Gene Mutation Database (HGMD) (see Table A) and the SLC22A5 Database at the ARUP Laboratories (see Table A). About half of these mutations are missense mutations. Nonsense mutations, splice site mutations, insertions, and small deletions comprise the remaining half of reported mutations. One large deletion encompassing the entire SLC22A5 has been reported [Li et al 2010].Normal gene product. SLC22A5 encodes the high affinity sodium-dependent carnitine transporter, organic cation transporter 2 (OCTN2). OCTN2 is a transmembrane protein that comprises 557 amino acids; it includes 12 transmembrane domains and one ATP binding domain. Abnormal gene product. SLC22A5 mutations result in dysfunctional OCTN2 and decreased carnitine transport in various tissues.