Transcript 1 Systemic Primary Carnitine Deficiency

Systemic Primary
Carnitine Deficiency
Synonyms: CDSP, CUD,
Carnitine Uptake Defect
Carnitine Primary Deficiency
•
Primary deficiency: a genetic defect in the transport of Carnitine across the cell
membrane: OCTN2.
Early recognition and treatment with high doses oral L-Carnitine is life –saving.
Summary
Disease characteristics
•
Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that
results in defective fatty acid oxidation. It encompasses a broad clinical spectrum
including:
• Metabolic decompensation in infancy typically presenting between age three months and
two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy,
hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or
common illnesses such as upper respiratory tract infection or gastroenteritis;
• Childhood myopathy involving heart and skeletal muscle with onset between age two and
four years;
• Fatigability in adulthood; or
• Lack of symptoms.
•
The latter two categories often include mothers diagnosed with systemic primary
carnitine deficiency after newborn screening has identified low carnitine levels in their
infants.
Diagnosis/testing
•
Plasma carnitine levels are extremely reduced in systemic primary carnitine deficiency.
•
The diagnosis is confirmed by the demonstration of reduced fibroblast carnitine
transport or biallelic mutations in SLC22A5, the only gene in which mutations are
known to cause systemic primary carnitine deficiency .
Management (I)
•
Treatment of manifestations:
– Metabolic decompensation and skeletal and cardiac muscle functions improve with
100-400 mg/kg/day oral levocarnitine (L-carnitine) if it is started before
irreversible organ damage occurs.
– Hypoglycemic episodes are treated with intravenous dextrose infusion;
– cardiomyopathy requires management by specialists in cardiology.
•
Prevention of primary manifestations:
– The manifestations of systemic primary carnitine deficiency can be prevented by
use of oral L-carnitine supplementation to maintain normal plasma carnitine
concentrations.
Management (II)
•
Surveillance:
(1) echocardiogram and electrocardiogram: annually during childhood and less
frequently in adulthood;
(2) plasma carnitine concentration: monitor frequently until levels reach the normal
range, then, measure three times a year during infancy and early childhood, twice
a year in older children, and annually in adults;
(3) serum creatine kinase concentration and liver transaminases: consider measuring
during acute illnesses.
•
Agents/circumstances to avoid: Fasting longer than age-appropriate periods.
•
Evaluation of relatives at risk: Measure plasma carnitine levels in siblings of an
affected individual.
•
Pregnancy management: close monitoring of plasma carnitine levels and increased
carnitine supplementation as needed to maintain normal plasma carnitine levels.
Genetic counseling
•
Systemic primary carnitine deficiency (CDSP) is inherited in an autosomal recessive
manner.
•
At conception, each sib of an affected individual has 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.
•
Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at
increased risk are possible if the disease-causing mutations in the family are known.
Diagnosis
Clinical 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 cardiomyopathy
•
Adults with unexplained fatigability
•
Sudden death
Testing (I)
•
Plasma 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).
•
Urine organic acid analysis. Nonspecific dicarboxylic aciduria has been reported in
some affected individuals.
•
Fibroblast carnitine transport (uptake). Carnitine transport in skin fibroblasts from
affected individuals is typically reduced below 10% of control rates.
•
Newborn screening. Newborn screening using tandem mass spectrometry (MS/MS)
detects low levels of free carnitine (C0) and can identify:
– Infants with systemic primary carnitine deficiency (CDSP)
– Mothers with systemic primary carnitine deficiency (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. Thus, unaffected infants born to affected
mothers can have low carnitine levels shortly after birth.
Testing (II)
•
Heterozygous carriers. Heterozygous carriers usually have about 50% carnitine
transport activity in fibroblasts and can have borderline low plasma carnitine levels.
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.
•
Molecular Genetic Testing
Gene. SLC22A5 is the only gene in which mutations are known to cause
systemic primary carnitine deficiency.
Clinical testing
• Sequence analysis
Yang 2013-Zhejiang Province
Clinical Description
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.
Systemic primary carnitine deficiency (CDSP) has been typically associated with
infantile metabolic presentation in about half of affected individuals and childhood
myopathic presentation in the other half.
However, adults with systemic primary carnitine deficiency (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.
1: 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 L-Carnitine and dextrose infusion
during episodes of metabolic decompensation, they may develop coma and die.
2: Childhood myopathic (cardiac) presentation
•
The average age of myopathic presentation is between age two and four years,
indicating that the myopathic manifestations of systemic primary carnitine deficiency
(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.
•
L-Carnitine (if necessary infusion, followed by) oral supplemtation completely reverts
the symptoms.
2: Childhood myopathic (cardiac) presentation
Chest radiographs
A) 4 years with a heart size upper
limits of normal.
B) 6.5 years severe cardiomegaly,
and low plasma total carnitine
(1.0 nmol/mL)
C) the cardiac size decreased to
normal by six months of oral LC
treatment (100 mg/Kg/day)
D) 10.5 years the cardiac size
remained normal for more than 5
years with LC therapy.
Pierpont 2000
2: Childhood myopathic (cardiac) presentation
HEART ECHOCARDIOGRAM
Pre-treatment
Kinali 2004
Post-treatment
2: Childhood myopathic (cardiac) presentation
4-months old
male infant:
at presentation
10 days
L-Carnitine
treatment
Zales 1995
6 months
L-Carnitine
treatment
3: Adulthood presentation
•
Several women have been diagnosed with systemic primary carnitine deficiency
(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.
An asymptomatic adult male with systemic primary carnitine deficiency (CDSP) has
also been reported.
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.
•
Affected women can have decreased stamina or worsening of cardiac arrhythmia
during pregnancy, suggesting that systemic primary carnitine deficiency (CDSP) may
manifest or exacerbate during pregnancy.
Atypical manifestations
Other manifestations reported in individuals with systemic primary carnitine deficiency
(CDSP) include:
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Anemia,
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Proximal muscle weakness and global developmental delays,
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Respiratory distress,
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Arrhythmias and electrocardiographic (ECG) abnormalities
Prognosis
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Infantile metabolic and childhood myopathic presentations of systemic primary
carnitine deficiency (CDSP) can be fatal if untreated.
•
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 2002, Stanley 2004, Longo 2006
Pathophysiology
•
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, resulting in hepatic steatosis and myopathy
Genotype-Phenotype Correlations
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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.
Incidence
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The incidence of systemic primary carnitine deficiency (CDSP) in China
(Zhejang Province): 1 in 35,000 newborns.
•
The incidence of PCD is about 1/50,000 based on NBS studies in USA.
•
The incidence is below 1 in 100,000 newborns in many European countries; however,
the incidence of systemic primary carnitine deficiency (CDSP) is very high in Faroe
Island with the carrier frequency of about 1:20, and estimated disease prevalence of
1:1300.
•
For Asian countries, the incidence is 1 in 40,000 newborns in Japan and 1 in 67,000
newborns in Taiwan.
Yang 2013
Differential Diagnosis (I)
Systemic primary carnitine deficiency (CDSP) needs to be differentiated from secondary
carnitine deficiency seen in the following situations:
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Inherited metabolic disorders including
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organic acidemias and
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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.
Differential Diagnosis (II)
Systemic primary carnitine deficiency (CDSP) needs to be differentiated from secondary
carnitine deficiency seen in the following situations:
•
Pharmacologic therapy (e.g. cyclosporine, pivampicillin)
•
Malnutrition
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Hemodialysis and renal tubular dysfunction e.g. renal Fanconi syndrome
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Prematurity. 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
Management
Evaluations 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
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Serum creatine kinase (CK) concentration
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Liver transaminases
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Pre-prandial blood glucose concentration
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Medical genetics consultation
Treatment of Manifestations (I)
L-carnitine supplementation.
•
The main treatment for systemic primary carnitine deficiency (CDSP) is oral
levocarnitine (L-carnitine) supplementation.
•
Typically a high dose, 100-400 mg/kg/day, divided in three doses is required.
Individuals with systemic primary carnitine deficiency (CDSP) respond well if oral Lcarnitine supplementation is started before irreversible organ damage occurs.
•
Metabolic decompensation and skeletal and cardiac muscle functions improve with Lcarnitine supplementations.
•
Oral L-carnitine supplementation in infants with systemic primary carnitine deficiency
(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.
Treatment of Manifestations (I)
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.
Other treatments:
•
Hypoglycemic episodes are treated with intravenous dextrose infusion.
•
Cardiomyopathy requires management by specialists in cardiology.
Treatment of Manifestations (note)
1. An unaffected infant born to a mother with systemic primary carnitine deficiency
(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.
2. Asymptomatic adults with systemic primary carnitine deficiency (CDSP) have been
reported. Because some fatty acid oxidation defects can remain asymptomatic until it
results in sudden death or another acute presentation during stress, it is prudent to
treat asymptomatic individuals with systemic primary carnitine deficiency (CDSP)
with L-carnitine supplementation to prevent the possibility of decompensation during
intercurrent illness or stress.
Prevention of Primary Manifestations
Maintaining appropriate plasma carnitine concentrations through oral L-carnitine
supplementation and preventing hypoglycemia (with frequent feeding and avoiding
fasting) typically eliminate the risk of the following complications:
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metabolic,
•
hepatic,
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cardiac, and
•
muscular
Note: Hospitalization to administer intravenous L-carnitine and glucose is recommended
for individuals with systemic primary carnitine deficiency (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.
Surveillance
•
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 creatine kinase (CK) concentration and liver transaminases:
Consider measuring during acute illnesses.
Agents/Circumstances to Avoid
Individuals with systemic primary carnitine deficiency
(CDSP) should avoid fasting longer than age-appropriate
periods.
Evaluation of Relatives at Risk
Siblings of affected individuals should be tested by
measuring plasma carnitine concentrations. If the
carnitine levels are low, further evaluation for systemic
primary carnitine deficiency (CDSP) is needed by either
fibroblast carnitine transport assay or molecular genetic
testing if the disease-causing mutations have been
identified in the family.
Pregnancy Management
•
Pregnancy 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.
•
Affected women can have decreased stamina or worsening of cardiac arrhythmia
during pregnancy, suggesting that systemic primary carnitine deficiency (CDSP) may
manifest or exacerbate during pregnancy.
•
Therefore, all pregnant women with systemic primary carnitine deficiency (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.
Molecular Genetic Pathogenesis (I)
•
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.
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OCTN2 is the protein product of SLC22A5.
•
Systemic primary carnitine deficiency (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.
Molecular Genetic Pathogenesis (II)
•
Normal allelic variants. SLC22A5 comprises ten exons spanning approximately 3.2 kb.
•
Pathologic allelic variants. More than 100 mutations have been reported.
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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.
•
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.
Zhonghua Er Ke Za Zhi. 2012 Jun;50(6):405-9.
[Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up].
LS, Ye J, Qiu WJ, Zhang HW, Wang Y, Ji WJ, Gao XL, Li XY, Jin J, Gu XF.
Department of Pediatric Endocrinologic and Genetic Metabolism, Shanghai Jiao
Tong University School of Medicine, Shanghai, China.
OBJECTIVE: Many children were found to have low free carnitine level in blood by
tandem mass spectrometry technology. In some of the cases the problems occurred
secondary to malnutrition, organic acidemia and other fatty acid oxidation metabolic
diseases, and some of cases had primary carnitine deficiency (PCD). In the present
article, we discuss the diagnosis of PCD and evaluate the efficacy of carnitine in the
treatment of PCD.
METHOD: We measured the free carnitine (C0) and acylcarnitine levels in the blood of
270 000 neonates from newborns screening program and 12 000 children with suspected
clinical inherited metabolic diseases by tandem mass spectrometry.
The mutations of carnitine transporter protein were tested to the children with low C0 level
and the diagnosis was made.
The children with PCD were treated with 100 - 300 mg/kg of carnitine.
Zhonghua Er Ke Za Zhi. 2012 Jun;50(6):405-9.
[Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up].
LS, Ye J, Qiu WJ, Zhang HW, Wang Y, Ji WJ, Gao XL, Li XY, Jin J, Gu XF.
Department of Pediatric Endocrinologic and Genetic Metabolism, Shanghai Jiao
Tong University School of Medicine, Shanghai, China.
RESULT:
Seventeen children were diagnosed with PCD, 6 from newborn screening program and
11 from clinical patients. Mutations were found in all of them. The average C0 level [(2.9 ±
2.0) µmol/L] in patients was lower than the reference value (10 µmol/L), along with
decreased level of different acylcarnitines. The clinical manifestations were diverse. For
the 6 patients from newborn screening, 4 were asymptomatic, 1 showed hypoglycaemia
and 1 showed movement intolerance from 2 years of age. For the 11 clinical patients, 8
showed hepatomegaly, 7 showed myasthenia, 6 showed cardiomyopathy, 1 showed
chronic abdominal pain, and 1 showed restlessness and learning difficulty. Among these
patients, 14 cases were treated with carnitine. Their clinical symptoms disappeared 1 to
3 months later. The C0 level in the blood rose to normal, with the average from (4.0 ± 2.7)
µmol/L to (20.6 ± 8.3) µmol/L (P < 0.01). However, the level was still lower than the
average level of healthy children [(27.1 ± 4.5) µmol/L, P < 0.01].
Zhonghua Er Ke Za Zhi. 2012 Jun;50(6):405-9.
[Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up].
LS, Ye J, Qiu WJ, Zhang HW, Wang Y, Ji WJ, Gao XL, Li XY, Jin J, Gu XF.
Department of Pediatric Endocrinologic and Genetic Metabolism, Shanghai Jiao
Tong University School of Medicine, Shanghai, China.
CONCLUSION:
Seventeen patients were diagnosed with PCD by the test levels of free carnitine and acylcarnitines
in blood with tandem mass spectrometry, and gene mutation test. Large dose of carnitine had a
good effect in treatment of the PCD patients.
Nine patients had FAO disorders, of which PCD was the most common (8/9, 89%).
Convulsions were the most obvious symptom, and one presented with cardiomyopathy.
Cardiac and neurological symptoms disappeared rapidly after oral L-carnitine, with no
occurrence of metabolic disorders or sudden death. One 26-months old girl was detected
with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Her initial presentation
was febrile convulsions, and her blood C6, C8, C10 levels were elevated at screening.
She developed normally with normal biochemical analysis after treatment with oral
carnitine and standard diet recommendation.