Patient's question:
At 4 months old, what diseases can be detected through a carnitine profile?Doctor's answer:
Carnitine profiling can detect carnitine deficiency metabolic disordersSymptoms of carnitine deficiency syndrome:
Hypoglycemia, hyperammonemia, acidosis, low total/free carnitine, myopathy, cardiomyopathy, encephalopathy, and Reye-like syndrome, etc.
Treatment:
Oral administration of L-Caritie 25mg/kg every 6 hours can correct the deficiency state;
Children with hereditary metabolic diseases leading to secondary carnitine deficiency.
Supplement
A case of systemic carnitine deficiency
The girl, 10 years old, was admitted to the hospital on February 2, 1998, due to repeated vomiting and fatigue for two and a half years. She had a history of one episode of convulsions and a blood glucose level of 2 mmol/L. Recently, she had significant weight loss and fatigue. Intelligence was normal. There was no special past medical history, and no family history of similar diseases. Physical examination: Moderate nutrition and development, clear consciousness, normal cardiopulmonary function, liver palpable 2.5 cm below the costal margin, moderate in texture, weakened muscle strength in limbs, positive Gower sign. Laboratory tests: ECG showed low limb voltage, EMG and EEG were normal, cardiac and abdominal ultrasound were normal, cranial CT and MRI showed cerebral atrophy, peripheral blood routine, serum potassium, sodium, chloride, and calcium were normal, triglycerides, high-density and low-density lipoprotein cholesterol were normal. Urine metabolic product screening was negative. 24-hour urine free cortisol, blood insulin, C-peptide were normal, total and direct bilirubin were normal, SGPT, SGOT, CPK, and LDH were mildly to moderately elevated, fasting blood glucose 2.97–4.11 mmol/L, blood lactate 2.05–3.4 mmol/L, blood ammonia 48.72 μmol/L, urine routine: protein (+), white blood cells (+), red blood cells 0–2/HP, occult blood (+). Initial diagnosis: Hereditary muscle disease, mitochondrial encephalomyopathy?
Muscle biopsy: Light microscopy pathology report showed muscles with a pale red appearance and low tension, HE staining revealed varying-sized vacuoles within muscle fibers, oil red O staining showed large and small red lipid droplets filled with muscle fibers, some of which had fused into pools, PAS staining showed decreased glycogen content in muscle fibers, ATPase staining confirmed complete muscle fiber typing, type I fibers had more lipid droplets and vacuoles. Electron microscopy showed: dissolution and fragmentation of myofibrils, and clusters of lipid (Figure 1, 2) and a small number of mitochondria were observed in the interstitial and dissolved areas. No inflammatory changes were observed between muscle fibers, Z-lines were clear. Impression: Lipid accumulation myopathy. Based on clinical and pathological findings, the diagnosis was confirmed as systemic carnitine deficiency.
Hospital course: Starting from the 12th day of admission, due to low-grade fever and poor appetite, combined with wound pain after muscle biopsy, vomiting, coma, convulsions, and sluggish light reflex response occurred successively. Hypoglycemia (0.28, 0.44, 0.83 mmol/L) occurred three times. 25% glucose 60 ml and symptomatic treatment were administered immediately, and the condition improved. During the third recurrence, due to ineffective glucose administration, heart rate slowed, and respiration became shallow, and the patient was urgently transferred to the emergency center. Five minutes after transfer, before the microglucose and biochemical results were available, the child experienced cardiac and respiratory arrest. Tracheal intubation and artificial ventilation were performed, external cardiac massage for 56 minutes, and an internal pacing catheter and basic life support were initiated, followed by recovery of heartbeat. After cardiopulmonary resuscitation, multiple organ failure (MOF) involving the heart, liver, kidneys, brain, lungs, and gastrointestinal tract occurred successively. From the 9th day of admission to the PICU, treatment for the primary disease was started, with L-Caritie 200 mg/(kg/day) administered intravenously for 80 days, followed by oral maintenance. For MOF, continuous veno-venous hemofiltration dialysis for 5 days, ventilator treatment for 78 days, metabolic and nutritional support for over 90 days, and comprehensive treatment with Chinese and Western medicine for 115 days were provided for anti-infection and anti-inflammatory mediators. Three months after carnitine administration, liver function and myocardial enzyme parameters were almost normal, blood carnitine and acylcarnitine levels were normal, blood amino acid profile was normal, and cranial CT still showed cerebral atrophy. The Wechsler Intelligence Quotient for school-aged children was 109, MOF was resolved, and systemic carnitine deficiency was controlled for discharge.
Discussion: Carnitine deficiency syndrome is a rare metabolic disorder, often caused by hereditary metabolic diseases. It can be classified into primary and secondary types. Primary carnitine deficiency is directly caused by defects in carnitine absorption, synthesis, and transport mechanisms [1-5]. It is inherited in an autosomal recessive manner. Secondary carnitine deficiency is caused by other metabolic or organ diseases, such as hereditary fatty acid, amino acid, and carbohydrate metabolism disorders, and mitochondrial encephalomyopathy [1, 2, 6]. Additionally, carnitine deficiency state may be referred to when various systemic or cardiac, renal, hepatic, or iatrogenic factors (e.g., hemodialysis, anticonvulsant drugs) lead to insufficient carnitine [1, 6].
Pathogenesis: Carnitine is a carrier for fatty acids entering mitochondria, and its deficiency leads to cellular energy metabolism disorders. On the other hand, the accumulation of acyl-CoA and acylcarnitine, among other metabolic intermediates, causes tissue and cellular damage. Currently, literature reports common enzyme activity abnormalities that can cause carnitine deficiency include: (1) Carnitine palmitoyltransferase 1 (CPT1) located on the outer mitochondrial membrane [1, 2, 5]. Deficiency of this enzyme impairs the mechanism by which carnitine, as a carrier, transports long-chain fatty acids into the mitochondria. (2) Carnitine palmitoyltransferase 2 (CPT2) located on the inner mitochondrial membrane. Deficiency of this enzyme prevents the conversion of acylcarnitine to free carnitine. Abnormal ratio of free and acylated carnitine in the blood. (3) Carnitine transport system (caritietrasptsystem or traspoter) located on the cell membrane [7, 8]. Deficiency or abnormality of this system prevents carnitine from being reabsorbed from the blood through muscle cell membranes or from glomerular filtrate through renal tubular endothelial cell membranes, leading to carnitine deficiency in muscle cells or excessive excretion of carnitine by the kidneys. Carnitine levels in the blood may be normal, while levels in muscle tissue are reduced, and levels in urine are elevated. (4) Carnitine-acylcaritietraslocase located on the inner mitochondrial membrane [7-9]. Deficiency of this enzyme impairs the transport of acyl-CoA and free carnitine through the inner mitochondrial membrane. (5) Other enzyme abnormalities leading to fatty acid metabolism disorders: such as acyl-CoA synthetase (acyl-CoAsythetase) [7, 8] deficiency in mitochondria, which impairs the fatty acid acylation process; medium- and long-chain acyl-CoA dehydrogenase deficiency (MCAD, LCAD) [1, 2, 7], which impairs the β-oxidation process of fatty acids. (6) Other enzyme defects leading to amino acid and glucose metabolism disorders, and mitochondrial energy metabolism disorders. Such as glyoxylate CoA dehydrogenase deficiency leading to glyoxylateuria, and pyruvate deficiency leading to isovaleric acidemia [6, 10, 11].
The muscle pathology changes in this case were consistent with lipid accumulation myopathy, without glycogen accumulation or mitochondrial morphological changes, normal blood amino acid profile, and negative urine metabolic product screening. Combined with the above clinical manifestations, the diagnosis was confirmed as systemic carnitine deficiency. The good response to carnitine treatment further suggests that this case was not caused by medium- and long-chain acyl-CoA dehydrogenase deficiency. Comprehensive laboratory tests for systemic carnitine deficiency should include the determination of free and acylated carnitine in blood, urine, and relevant tissues, as well as the determination of related enzymatic activities. Due to the critical condition at the time and limited laboratory conditions in the country, enzyme activity tests were not performed.
Clinical manifestations of this condition include damage and failure of various organs (primarily the heart, muscles, liver, and brain). Primary carnitine deficiency inherited in an autosomal recessive manner often exhibits genetic heterogeneity (geeticheterogeeity), with varying clinical manifestations: it can manifest as liver disease, cardiomyopathy, myopathy, or systemic carnitine deficiency, with varying severity. The onset age of systemic carnitine deficiency can range from newborns a few days old [7-9] to adults [12, 13]. The child appears healthy, but under certain conditions of insufficient carnitine intake or other disease triggers, fatal recurrences such as hepatic encephalopathy or muscle weakness may occur. The mortality rate of the first recurrence is 25%. Diagnosis of this disease can be confirmed by culturing fibroblasts and white blood cells to measure decreased enzyme activity. It is noteworthy that some cases may develop myopathy before showing recurrent fasting hypoketotic hypoglycemia, while others may present with progressive cardiomyopathy or endocardial elastic fiber hyperplasia, dying in childhood or early adulthood due to cardiopulmonary failure [3, 4].
This case showed significant improvement in myocardial enzyme indicators, reduced hyperlipidemia, and alleviated jaundice, with stronger heart sounds one week after L-Carnitie administration. At this time, the child was in the stage of severe ARDS and systemic infection with MOF. Two and a half months after administration, myocardial enzyme levels were almost normal, liver and renal function, and blood lipids were completely normal, and the liver had shrunk from the costal margin to 1.5 cm below the umbilicus. Chest X-ray showed normal heart size, and ECG ST-T changes disappeared. Blood free carnitine was 62.54 μmol/L, acetylated carnitine was 5.937 μmol/L, and total carnitine was 110.3 μmol/L, all within the normal range. We believe that carnitine treatment has controlled the primary disease and played an important role in treating the severe MOF in this case. Literature reports indicate that carnitine is effective not only for hereditary enzyme deficiency cases but also for cardiogenic shock, severe myocardial metabolic disorder heart failure, Reye's syndrome, and severe infections [3, 4, 6].
This case was cured after more than three months of L-Carnitie and comprehensive organ function support treatment, suggesting that in children with unexplained hypoglycemia, cardiomyopathy, coma, or myopathy, carnitine deficiency should be considered, and experimental carnitine treatment can be administered after blood samples are taken [12].
Author Affiliations: Chen Xiannan, Geng Rong, Qian Suyun: 100045 Beijing Children's Hospital Affiliated to Capital Medical University, Emergency Center; Wu Husheng, Xiao Jing: Department of Neurology; Lang Zhiqi: Electron Microscopy Laboratory; Lü Danyun: National Sports Commission Medical Sports Research Institute
References: Pediatric Neurology Department