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Systemic primary carnitine deficiency (SPCD)Systemic primary carnitine deficiency
Orphanet Orphanet is an organisation and knowledge base dedicated to rare diseases as well as corresponding diagnosis, orphan drugs, clinical trials and expert networks. Orphanet was founded in France in 1997 by Inserm, the French National Institute of H ...
is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving
carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...
across the
plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. Carnitine is an important amino acid for fatty acid metabolism. When carnitine cannot be transported into tissues,
fatty acid oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters ...
is impaired, leading to a variety of symptoms such as chronic muscle weakness,
cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
,
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
and liver dysfunction. The specific transporter involved with SPCD is OCTN2, coded for by the '' SLC22A5'' gene located on
chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 182 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...
. SPCD is inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
manner, with mutated
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s coming from both parents. Acute episodes due to SPCD are often preceded by metabolic stress such as extended fasting, infections or vomiting. Cardiomyopathy can develop in the absence of an acute episode, and can result in death. SPCD leads to increased carnitine excretion in the urine and low levels in plasma. In most locations with expanded
newborn screening Newborn screening (NBS) is a public health program of screening (medicine), screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for ...
, SPCD can be identified and treated shortly after birth. Treatment with high doses of carnitine supplementation is effective, but needs to be rigorously maintained for life.


Signs and symptoms

The presentation of patient with SPCD can be incredibly varied, from asymptomatic to lethal cardiac manifestations. Early cases were reported with liver dysfunction, muscular findings (weakness and underdevelopment), hypoketotic
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
, cardiomegaly,
cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
and marked
carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...
deficiency in plasma and tissues, combined with increased excretion in urine. Patients who present clinically with SPCD fall into two categories, a metabolic presentation with hypoglycemia and a cardiac presentation characterized by
cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
. Muscle weakness can be found with either presentation. In countries with expanded newborn screening, SPCD can be identified shortly after birth. Affected infants show low levels of free carnitine and all other acylcarnitine species by
tandem mass spectrometry Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzer are performed with an additional reaction step in between these analyses to increa ...
. Not all infants with low free carnitine are affected with SPCD. Some may have carnitine deficiency secondary to another metabolic condition or due to maternal carnitine deficiency. Proper follow-up of newborn screening results for low free carnitine includes studies of the mother to determine whether her carnitine deficiency is due to SPCD or secondary to a metabolic disease or diet. Maternal cases of SPCD have been identified at a higher than expected rate, often in women who are asymptomatic. Some mothers have also been identified through newborn screening with cardiomyopathy that had not been previously diagnosed. The identification and treatment of these asymptomatic individuals is still developing, as it is not clear whether they require the same levels of intervention as patients identified with SPCD early in life based on clinical presentation.


Genetics

SPCD is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
condition, meaning a mutated
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
must be inherited from each parent for an individual to be affected. The gene responsible for the OCTN2 carnitine transporter is '' SLC22A5'', located at 5q31.1-32. ''SLC22A5'' is regulated by
peroxisome proliferator-activated receptor alpha Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gen ...
. The transporter, OCTN2, is located in the apical membrane of the renal tubular cells, where it plays a role in tubular reabsorption. The defective OCTN2 is unable to recapture carnitine prior to its excretion in urine, leading to the characteristic biochemical findings of massively increased urine carnitine levels and significantly decreased plasma carnitine levels. Decreased levels of plasma carnitine inhibit
fatty acid oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters ...
during times of excessive energy demand. Carnitine is needed to transport long chain fatty acids into the
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
, where they can be broken down to produce acetyl-CoA. Individuals with SPCD cannot produce
ketone bodies Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver ( ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acet ...
as energy due to the interruption of fatty acid oxidation. Although SPCD is an autosomal recessive condition,
heterozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
s have been shown to be at an increased risk for developing
benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
cardiomyopathy compared to wild type individuals.


Diagnosis

The first suspicion of SPCD in a patient with a non-specific presentation is an extremely low plasma carnitine level. When combined with an increased concentration of carnitine in urine, the suspicion of SPCD can often be confirmed by either molecular testing or functional studies assessing the uptake of carnitine in cultured
fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...
.


Treatment

Identification of patients presymptomatically via
newborn screening Newborn screening (NBS) is a public health program of screening (medicine), screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for ...
has allowed early intervention and treatment. Treatment for SPCD involves high dose
carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...
supplementation, which must be continued for life. Individuals who are identified and treated at birth have very good outcomes, including the prevention of cardiomyopathy. Mothers who are identified after a positive newborn screen but are otherwise asymptomatic are typically offered carnitine supplementation as well. The long-term outcomes for asymptomatic adults with SPCD is not known, but the discovery of mothers with undiagnosed cardiomyopathy and SPCD has raised the possibility that identification and treatment may prevent adult-onset manifestations.


Incidence

Worldwide, SPCD is most common in the
Faroe Islands The Faroe Islands ( ) (alt. the Faroes) are an archipelago in the North Atlantic Ocean and an autonomous territory of the Danish Realm, Kingdom of Denmark. Located between Iceland, Norway, and the United Kingdom, the islands have a populat ...
, where at least one out of every 1000 inhabitants of the Faroes have the disorder, according to the Faroese Ministry of Health. Scientists believe that around 10% of the Faroese population are carriers of variants which cause SPCD. These people are not ill, but may have a lower amount of carnitine in their blood than non-carriers. The first Faroese patient was diagnosed with SPCD in 1995, and since then several young people and children in the Faroese Islands have died of cardiac arrest because of SPCD. The addition of SPCD to newborn screening panels has offered insight into the incidence of the disorder around the world. In
Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...
, the incidence of SPCD in newborns was estimated to be approximately 1:67,000, while maternal cases were identified at a higher frequency of approximately 1:33,000. The increased incidence of SPCD in mothers compared to newborns is not completely understood. Estimates of SPCD in
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
have shown a similar incidence of 1:40,000.


History

Carnitine deficiency has been extensively studied, although most commonly as a secondary finding to other metabolic conditions. The first case of SPCD was reported in the 1980s, in a child with fasting hypoketotic hypoglycemia that resolved after treatment with carnitine supplementation. Later cases were reported with cardiomyopathy and muscle weakness. Newborn screening expanded the potential phenotypes associated with SPCD, to include otherwise asymptomatic adults.


References


External links


GeneReviews/NCBI/NIH/UW entry on Systemic Primary Carnitine Deficiency
{{Fatty-acid metabolism disorders Autosomal recessive disorders Hepatology Fatty-acid metabolism disorders