Carnitine Deficiency, Systemic Primary

A number sign (#) is used with this entry because primary systemic carnitine deficiency (CDSP) is caused by homozygous or compound heterozygous mutation in the SLC22A5 gene (603377) on chromosome 5q31.

Description

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.

Clinical Features

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.

Shibbani et al. (2014) reported 8 patients from 5 Lebanese families with primary carnitine deficiency who had an exclusive cardiac phenotype. Two of the families had been reported by Yamak et al. (2007). Seven patients presented with cardiac failure due to cardiomyopathy between ages 8 months and 10 years; an 11-month-old affected twin sib of 1 of the patients had cardiomyopathy but was asymptomatic. A literature review of 61 cases of the disorder, including the 8 Lebanese patients, showed that cardiomyopathy is the most common clinical presentation, with 42.6% of patients having cardiac manifestations only, and 62.3% having cardiac plus other phenotypes. These findings suggested that heart muscle is more susceptible to carnitine deficiency than liver or skeletal muscle, most likely due to its constant need for energy expenditure and dependence on fatty acids. While carnitine levels were associated with type of mutation, there was no correlation between carnitine levels and severity of the phenotype. Shibbani et al. (2014) suggested that environmental stress, such as recurrent infection, may also contribute to the disease manifestations.

Inheritance

The reduction in plasma carnitine levels in the parents of the patients reported by Waber et al. (1982) and Treem et al. (1988) indicated autosomal recessive inheritance.

Biochemical Features

Eriksson et al. (1989) showed absence of carrier-dependent uptake of carnitine in fibroblasts from a patient with hereditary carnitine deficiency. The mother and probably the healthy sister had impaired uptake. These findings showed that the defect in this form of carnitine deficiency was an inability to establish a concentration gradient across the cell membrane.

Tein et al. (1990) also demonstrated impaired uptake of carnitine by skin fibroblasts in childhood carnitine-responsive cardiomyopathy.

Garavaglia et al. (1991) found negligible uptake of carnitine by cultured fibroblasts in 2 affected boys from different families: one had cardiomyopathy and myopathy, and the other had hypoglycemia and myopathy but no cardiomyopathy.

Shoji et al. (1998) studied serum and urinary carnitine levels in a 9-year-old female proband and 26 family members from a Japanese family with primary systemic carnitine deficiency. There were 2 significantly different phenotypes, in terms of serum free-carnitine levels; levels were low (29.5 +/- 5.0 microM) in 14 and normal (46.8 +/- 6.2 microM) in 12. There was no correlation of urinary free-carnitine levels with the low serum-level phenotype (putative heterozygote), but in normal phenotypes (wildtype), urinary levels decreased as the serum levels decreased; renal resorption of free carnitine appeared to be complete in wildtype individuals when the serum free-carnitine level was less than 36 microM.

To define the mechanisms producing partially reduced plasma carnitine levels in the parents of patients with primary carnitine deficiency, Scaglia et al. (1998) examined carnitine transport in vivo and in the fibroblasts of a patient and his heterozygous parents. Fibroblasts from heterozygotes were shown to have a decreased capacity to accumulate carnitine and heterozygotes had increased urinary losses of carnitine.

Diagnosis

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.

Clinical Management

In a study of 11 affected individuals with genetically confirmed systemic carnitine deficiency, Lamhonwah et al. (2002) found strong indications that strict compliance with carnitine therapy from birth could prevent the development of the pathologic phenotype, including cardiomyopathy.

Mapping

By linkage analysis in a Japanese family in which 1 individual had systemic carnitine deficiency, Shoji et al. (1998) identified a candidate locus, termed SCD, on chromosome 5q. Use of a dominant mode of inheritance for heterozygous family members yielded a 2-point lod score of 4.98 and a multipoint lod score of 5.52 at D5S436. Haplotype analysis revealed that the responsible genetic locus lies between D5S658 and D5S434. The closest microsatellite marker, D5S436, was located at 5q31.1. This region on 5q is syntenic with the murine jvs gene located on chromosome 11 of the mouse. The study indicated the practicality of linkage mapping when only a single clinical case is present, provided that it is possible to convert the trait into a dominant by the identification of heterozygotes.

Molecular Genetics

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.

Amat 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, Amat 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.

Population Genetics

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.

History

Nyhan (1988) noted that hypoketotic hypoglycemia and secondary carnitine deficiency can be associated with other inherited defects in fatty acid oxidation, in particular MCAD deficiency (201450), which is the most common disorder of fatty acid oxidation. In fact, 4 of the most intensively studied patients with presumed systemic carnitine deficiency (Engel et al., 1981; Rebouche and Engel, 1981) were subsequently found to have secondary carnitine deficiency due to MCAD deficiency (Hale et al., 1985; Zierz et al., 1986). A feature that distinguishes patients with primary systemic carnitine deficiency from those with enzymatic defects in intramitochondrial beta-oxidation of fatty acids is the very low level of urinary dicarboxylic acids in the former.

Animal Model

Koizumi et al. (1988) described a spontaneous mutation in the mouse characterized by microvesicular fatty infiltration of viscera, particularly liver and kidney, and death, usually before weaning. The mutation was designated juvenile visceral steatosis (jvs) and was found to be associated with severe systemic carnitine deficiency. Daily administration of L-carnitine started on the tenth day after birth kept the jvs mice alive. Horiuchi et al. (1994) suggested that the primary defect in the jvs mouse is impaired renal transport for carnitine, as had been suggested in human systemic carnitine deficiency. Nikaido et al. (1995) mapped the jvs gene to mouse chromosome 11. The central part of mouse chromosome 11 is homologous to 5q and 17q in humans. Okita et al. (1996) refined the location of the jvs mutation on mouse chromosome 11 as a first step toward positional cloning of the gene.

Horiuchi et al. (1993) noted that jvs mice treated with L-carnitine before weaning showed cardiac hypertrophy at 3 months.

Since the mouse jvs locus was assigned to the region of murine chromosome 11 that is syntenic to human 5q31 where the OCTN2 gene maps, Lu et al. (1998) isolated the mouse Octn2 gene and screened for mutations in the jvs mouse. They demonstrated a change of codon 352 from CTG (leu) to CGG (arg), located within the sixth transmembrane domain of Octn2.