Muscle carnitine deficiency in old age: Case report and therapeutic results

A muscle carnitine deficiency was discovered in a 67-year-old retired factory worker with a clinical picture of late-onset myopathy. The diagnosis was made by muscle biopsy and free carnitine assay.

Therapy including a medium chain triglycerides diet and 6 g/day of D, L-carnitine per os produced a remarkable clinical improvement confirmed by a control muscle biopsy 15 months later.

Our patient is the oldest one described with muscle carnitine deficiency. The differential diagnosis of a late-onset myopathy should include lipid myopathies, some of which can be treated successfully.     

Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondril myopathy

Plasma carnitine “insufficiency,” (plasma esterified carnitine to free carnitine ratio above 0.25) was found in 21 48 (43.8%) patients with mitochondrial myopathy, of whom 4 also showed both total and free carnitine deficiencies in plasma. In addition, plasma levels of SCAC and LCAC were higher in patients with mitochondrial myopathy than in controls (P < 0.001 and P <0.01, respectively). Patients diagnosed as having plasma carnitine insufficiency or deficiency were treated with L-carnitine (50–200 mg/kg per day in four daily doses). Muscle weakness improved in 19 of 20 patients, failure to thrive in 4 of 8, encephalopathy in 1 of 9, and cardiomyopathy in 8 of 8 patients. Plasma carnitine “insufficiency” provides an additional clue to the diagnosis of mitochondrial myopathy and an indication for L-carnitine therapy. © 1993 John Wiley & Sons, Inc.     

Familial combined deficiency of muscle carnitine and carnitine palmityl transferase (CPT)

ABSTRACT— Two patients, brother and sister, aged 19 and 16, with combined, partial deficiency of carnitine palmityltransferase (CPT) are reported. Both patients had recurrent exercise-related myoglobinuria. The brother had also experienced an episode of transient renal failure associated with myoglobinuria. Both had elevated CK and myoglobin in plasma between attacks. There was a normal production of lactate in ischaemic forearm exercise, but elevated levels of NH₃, resulting in an increased NH₃/Iactate ratio; 48-h fasting caused no significant changes in cholesterol, triglycerides or glucose, no rise of CK, and a normal ketogenic response, indicating no hepatic enzyme deficiency. Muscle biopsy showed slight changes of myopathy in both patients, with scattered atrophic fibres, but no lipid accumulation or other specific changes, Biochemical analysis of muscle tissue revealed a reduction of carnitine to 48% and 40% and a reduction of CPT to 55% and 59% of normal values, which is similar to the findings in the only previous report of combined partial carnitine and CPT deficiency. The heterogenity of the laboratory findings in CPT deficiencies and the value of the various diagnostic procedures in metabolic myopathies are discussed.     

原发性肉碱缺乏致脂质沉积性肌病的临床与病理特点

目的 分析原发性肉碱缺乏致脂质沉积性肌病（LSM）的临床与病理特点。方法 回顾性分析4例可能LSM患者的临床资料。结果 本组患者为亚急性或慢性起病，主要表现为近端肌无力，疲劳不能耐受；血清肌酶有不同程度的升高；肌电图示肌源性损害；病理检查示肌纤维内可见大量细小空泡和裂隙形成；MGT染色无破碎红纤维，油红O染色显示空泡为大量脂滴充填；受累纤维以Ⅰ型纤维为主。电镜证实肌纤维内脂滴堆积，可伴有线粒体的轻度增多。改善能量和糖皮质激素治疗有效。结论原发性肉碱缺乏致LSM是一种以易疲劳和肌无力为主要临床表现的脂质代谢障碍性肌病，病理改变以肌纤维内脂滴堆积为主，一般不伴有线粒体结构的明显异常。糖皮质激素治疗可获得良好疗效。     

Analysis of organic acids,amino acids,and carnitine in dogs with lipid storage myopathy

Abnormal accumulations of lipid droplets, localized predominantly in histochemical type 1 fibers, were observed in fresh frozen sections of muscle biopsies from 25 dogs with myalgia, weakness, and muscle atrophy. Compared to controls, lactic acidemia, hyperalaninemia, lactic and pyruvic aciduria, variably increased urinary excretion of carnitine esters, and muscle carnitine deficiency were present. These findings support a metabolic block in oxidative metabolism resulting in lactic acidemia in dogs with lipid storage myopathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1202–1205, 1998.     

Primary carnitine deficiency: adult onset lipid storage myopathy with a mild clinical course

We studied two adult patients with myalgia and muscular fatigability during prolonged physical exercise. Serum creatine kinase was increased and muscle biopsy revealed a lipid storage myopathy affecting predominantly the type I fibres. Skeletal muscle carnitine content was reduced to 15% and 21% of the normal mean values, while serum carnitine levels were either normal or decreased. Four months of oral therapy with L-carnitine (3 g per day) resolved the clinical symptoms completely in both patients, and a subsequent muscle biopsy confirmed a marked reduction of lipid storage, along with increased muscle carnitine levels. The analysis of renal carnitine excretion and the exclusion of possible secondary carnitine deficiencies in both patients are compatible with mild defects of the carnitine transporter in one patient and of carnitine biosynthesis in the other. Since myalgia and muscular fatigue are frequent but unspecified complaints of otherwise clinically unremarkable adult patients, it is important to identify myopathies associated with primary carnitine deficiency because they may be amenable to treatment.     

Muscle carnitine deficiency and lipid storage myopathy in patients with mitochondrial myopathy

Abnormal carnitine distribution in muscle was found in 22 of 77 patients (29%), with mitochondrial myopathy. Furthermore, total (TC) and free (FC) carnitine levels in muscle were lower in patients than in controls (P < 0.01). Muscle long-chain acylcarnitines (LCAC) were significantly increased in these patients (P < 0.01). Muscle carnitine deficiency was found in 31.5% of patients with lipid storage myopathy (LSM) and in 25.6% of patients with ragged-red fibers (RRF). Therefore, carnitine deficiency can be found in patients with mitochondrial myopathy even in the absence of LSM. Muscle levels of TC and FC were lower in patients with respiratory chain defects than in those with normal respiratory chain (P < 0.01). In contrast, LCAC levels were significantly increased (P < 0.05). Carnitine levels did not differ significantly, among patients with different respiratory-chain defects. Consequently, these patients, owing to their biochemical block, reduce progressively the muscle carnitine pool and subsequent LCAC rise, due to long-chain fatty acid (LCFA) accumulation.     

Behavioural modifications in relation to hypothyroidisim and hyperthyroidism in adult rats

1. 1. Behavioural experiments were carried out on adult rats made hypothyroid and hyperthyroid. The hypothyroid rats in an “open field” situation reduced the number of squares crossed and boluses defecated, the hyperthyroid rats reduced the number of squares crossed. A swimming endurance was conducted to evaluate the physical resistence of the rats: only hypothyroidism affected the performance.

2. 2. Two operant tests were studied: a) an “extinction” trial (60 min), in which the rats trained in a fixed ratio schedule (FR 1:10), were no longer rewarded with pellets of food and b) the “reversal” test in which the contingency for food delivery was switched four times from one lever, where responses were previously reinforced, to the other lever where responses had no programmed consequences.

3. 3. Both hypo and hyperthyroid conditions caused a lower rate of responses during the “extinction” trial, while in the “reversal” test only hyperthyroid rats showed improved performances.

4. 4. Our data clearly demonstrate behavioural changes in adult hypothyroid and hyperthyroid rats.

Platysmal myoclonus in subclinical hyperthyroidism.

Hyperthyroidism is associated with various movement disorders, such as chorea and tremors. We report on a young Chinese woman with an unusual presentation of myoclonus, involving both platysmal muscles, in association with subclinical hyperthyroidism. The myoclonus was preceded by symptoms of hyperthyroidism, namely weight loss, menstrual disturbances, and heat intolerance. The movements abated with clonazepam and hyperthyroidism was treated with carbimazole. The myoclonus recurred briefly when she stopped taking clonazepam, but she has since remained well and euthyroid.     

Infantile Pompe's disease, lipid storage, and partial carnitine deficiency

A diagnosis of infantile Pompe's disease (glycogenosis type II) was made by muscle biopsy on a 6-month-old infant boy seen with hypotonia, weakness, and developmental regression. Histochemistry and electron microscopy revealed a vacuolar myopathy with massive glycoge accumulation associated with increased neutral lipid as demonstrated on Oil Red O reactions. Pleomorphic, hypertrophic mitochondria with distortion of cristae and electron-dense deposits within the matrix were identified. Acid alpha-1,4-glucosidase activity was absent but associated with increased neutral maltase activity and a variable compensatory rise in activity of other lysosomal enzymes. Biochemical studies demonstrated low free carnitine, normal acylcarnitine, increased activity of carnitine palmityl and acyl transferases, and other enzymes of beta-oxidation with the notable exception of low normal beta-hydroxyacyl-CoA dehydrogenase activity. The explanation for the lipid accumulation is uncertain but is likely related to the combination of low carnitine concentration in muscle, low beta-hydroxyacyl CoA dehydrogenase, representing a rate limiting enzyme of beta-oxidation, and nonspecific defective mitochondrial function.     

Carnitine,carnitine acyltransferases,and rat brain function

The concentrations of free, short chain, and long chain acylcarnitines and the enzyme activities of carnitine acetyltransferase (CAT) and carnitine palmityltransferase (CPT) were studied in different rat brain regions. The fate of tritium-labeled carnitine was studied in different brain regions in vivo after i.p. injection in 3-month-old Sprague-Dawley rats. The tritium counts were particularly high in the hypothalamic region. At 24 h after hydrocortisone injection, a significant increase in counts was observed in the hypothalamus (P < 0.01). A high concentration of total carnitine was found in the hypothalamus (4.00 nmol/mg noncollagen protein) and in other regions such as the spinal cord (1.29 nmol/mg noncollagen protein), cerebellum (1.19), and olfactory tracts (0.66) carnitine concentration was much lower. Carnitine content was proportional to CPT, an inner mitochondrial enzyme. The activity of the enzyme CAT was found to be high in rat hippocampus and hypothalamus. This enzyme in brain may be involved in the transport of acyl groups outside the mitochondria and in the regulation of pyruvate utilization, contributing to acetylcholine synthesis or regulation.     

Novel mutations in the gene encoding very long‐chain acyl‐CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase ii deficiency

Introduction: Twenty‐six patients with clinical symptoms of adult onset carnitine palmitoyltransferase II (CPTII) deficiency were examined. All patients had skeletal muscle CPTII enzyme activity levels indicative of heterozygosity for CPT2 mutations, however sequence analysis identified no pathogenic mutations within the CPT2 gene. Methods: Because the reaction product of CPTII is the substrate for very long‐chain acyl‐CoA dehydrogenase (VLCAD), we examined the ACADVL gene in these patients by sequence analysis. Results: Missense mutations within the ACADVL gene were identified in 3 of the patients. Conclusions: The locations of the altered amino acid residues within the crystal structure of VLCAD are on the surface of the molecule and may be involved in interactions with neighboring molecules. These findings support the importance of considering that mutations may be present in the ACADVL gene when a significant partial deficiency is found in CPTII activity, but no mutations in the CPT2 gene can be identified. Muscle Nerve, 2013     

Bilateral chorea-ballism associated with hyperthyroidism.

We describe a 50-year-old patient with four episodes of recurrent bilateral chorea-ballism (BCB) and associated hyperthyroidism. Reappearance of BCB, associated with increased serum levels of thyroid hormones and lack of relevant changes on brain computed tomography/magnetic resonance imaging scans, suggested that the involuntary movements were likely due to thyrotoxicosis-induced biochemical changes.     

Phenotypic variability among first-degree relatives with carnitine palmitoyltransferase II deficiency

Carnitine palmitoyltransferase (CPT) II deficiency disorders are clinically very variable. To examine the cause(s) of variable symptoms in first-degree relatives with CPT II deficiency, four sisters with various combinations of mutations and polymorphisms in the CPT2 gene were studied, together with 20 sedentary and 24 trained healthy female subjects. One sister, whose symptoms began at age 7 years, was more severely affected than her older sister, whose symptoms began at age 16 years; both were compound heterozygotes for the common S113L mutation and Q413fs, and for the common CPT2 polymorphisms, V3681 and M647V. A third sister became hypoglycemic with fasting, was heterozygous for the S113L mutation, and homozygous for the polymorphism variants. The fourth sister was asymptomatic, heterozygous for the Q413fs mutation, and homozygous for the normal polymorphisms. Residual CPT II activity in skeletal muscle and cultured skin fibroblasts from the two myopathic sisters, and palmitate oxidation in fibrobasts, were abnormally low; cellular and total body fat oxidation were also diminished. Muscle function and fat oxidation were nomal at rest, but a switch to carbohydrate utilization occurred at lower exercise intensities than in sedentary and trained individuals, respectively. Reliance on carbohydrates during stress and hormonal alterations may explain, in part, the variance in ages of onset and serverity of symptoms in myopathic patients.     

CPEO and carnitine deficiency overlapping in MELAS syndrome

Mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features including stroke-like episodes with migraine-like headache, nausea, vomiting, encephalopathy and lactic acidosis. We report a 27-year-old woman who presented with partial seizure, stroke-like episodes including hemiparesis, hemianopia and hemihypethesia, sensorineural hearing loss, migraine-like headache, and lactic acidosis. Brain computed tomographic scan showed encephalomalacia in the right parieto-occipital area and recent hypodensity in the left temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed ragged-red fibers and paracrystaline inclusions in the mitochondria. Genetic study revealed an A to G point mutation at nucleotide position (np) 3243 of mitochondrial DNA. External ophthalmoplegia and ptosis were also found during two exaggerated episodes in this patient. Therefore, the overlapping syndrome of chronic progressive external ophthalmoplegia in the MELAS syndrome is considered in this case. Furthermore, we also found carnitine deficiency in this patient and she was responsive well to steroid therapy. Muscle biopsy also revealed excessive lipid droplets deposits. Therefore, the carnitine defiency may occur in MELAS syndrome with the A to G point mutation at np 3243. We recommend the steroid or carnitine supplement therapy be applied to the MELAS syndrome with carnitine deficiency.     

Carpal tunnel syndrome and hyperthyroidism

We carried out a prospective study to determine the frequency and evolution of carpal tunnel syndrome (CTS) in patients with hyperthyroidism. An initial survey revealed CTS in 5% of these patients when hyperthyroidism was diagnosed. During the clinical and neurophysiologic follow-up for a two-year period, four more patients developed CTS; of these, two had uncontrolled hyperthyroidism, and the other two had iatrogenic hypothyroidism. The clinical and neurophysiologic evolution suggests a relationship between both diseases. The symptoms of CTS remitted if endocrinopathy is controlled. Surgery is, in general, not necessary. CTS can be considered another peripheral neurological manifestation associated with hyperthyroidism.     

Short-term variability of blood pressure and heart rate in hyperthyroidism

The effect of hyperthyroidism on the short-term variability of blood pressure and heart rate was evaluated in 12 untreated hyperthyroid patients during thyrotoxicosis and after a 61/2 month treatment designed to achieve a stable euthyroid state. Beat-by-beat finger blood pressure was measured with a Finapres device. The pulse interval, from which pulse rate was derived, was obtained from the blood pressure signal. Due to the significant change in heart rhythm associated with thyrotoxicosis, both pulse interval (taken as a surrogate of heart period) and pulse rate (taken as a surrogate of heart rate) were computed. Power spectral analysis showed a reduction in the overall heart period variability in the supine position in the hyperthyroid compared to the euthyroid state. This effect was observed in the low-frequency (0.005–0.068 Hz), midfrequency (0.068–0.127 Hz) and high-frequency (respiratory) domains as well, with a significant reduction of the modulus of these bands of 31%, 35% and 47%, respectively. The heart rate spectral modulus also exhibited a reduction of the high-frequency component (31%) in the supine position in the hyperthyroid subjects. These changes in heart rhythmicity corroborate a vagal deficit in hyperthyroidism. In addition, blood pressure spectral power exhibited a significant deficit in the orthostatism-induced mid-frequency systolic blood pressure rise in the hyperthyroid state (64%) compared with the euthyroid state. This observation may reflect a reduced vascular sympathetic activation with standing. The resulting vasodilatation could well contribute to normalize blood pressure in thyrotoxicosis in which cardiac output is increased.     

Gene expression in the developing cerebellum during perinatal hypo- and hyperthyroidism

The intensity of p75NGFR receptor-like immunoreactivity and the mRNAs encoding p75NGFR, Tα1 α-tubulin, GAP-43 and the myelin proteins MBP and PLP were measured in the developing cerebellum to study the effects of perinatal thyroid hormone imbalance in rats. Results compared to age-matched controls provide in vivo evidence for differential gene regulation by thyroid hormone in the developing cerebellum. We found that p75NGFR immunoreactivity was strikingly elevated in hypothyroid rats, whereas p75NGFR mRNA content remained only twice as high as that of control levels on postnatal day 15 (P15). When p75NGFR immunoreactivity was still elevated in hypothyroid rats, Purkinje cells exhibited proximal axonal varicosities, axonal twisting and differences in axonal caliber. The mRNAs encoding proteins involved with neurite growth-promoting elements, Tα1 α-tubulin and GAP-43, were also increased in hypothyroidism, possibly reflecting a neuronal response to a deficiency in, or damage to, cerebellar neurons, or a general delay in their down regulation. Similar increases were not observed for the myelin specific genes. MBP and PLP mRNAs were first detected on P2 of hyperthyroid rats, and they increased with age. Hypo- or hyperthyroidism did not affect the initial onset of MBP and PLP expression, however, hyperthyroidism increased levels of PLP and MBP mRNAs between P2 and P10. By contrast, the most consistent decrease in MBP and PLP mRNAs in rats with thyroid hormone deficiency was observed only on P10. At later times (P14 and P30), the two mRNA levels were similar to controls in all groups. These results are consistent with a role for thyroid hormone in the earlier stages of cerebellar myelination. Hypothyroidism led to specific increases in Tα1 α-tubulin and GAP-43 mRNAs, and in the immunoreactivity and mRNA levels of p75NGFR receptor — all changes that may play a role in the observed abnormal neuronal outgrowth.     

重症肌无力患者甲状腺功能和甲状腺抗体情况的临床分析

目的　了解重症肌无力 ( MG)患者甲状腺功能及甲状腺抗体的情况。方法　回顾性分析了 2 67例临床确诊 MG患者的甲状腺素水平 ,对其中 2 64例患者检测了甲状腺球蛋白抗体 ( TGAb)和甲状腺过氧化物酶抗体( TPOAb)或甲状腺微粒体抗体 ( TMAb)。结果　 5 5例 ( 2 0 .6% )患者有甲状腺功能异常 ,48例 ( 1 8.2 % )至少有 1项上述抗体阳性。甲状腺功能异常的 MG患者中 , 、 、 型抗体阳性者较多 ( P <0 .0 1 )。甲状腺抗体阳性者较抗体阴性者 MG发病晚 ( P <0 .0 5 ) ;甲状腺抗体阴性 MG患者有甲状腺功能障碍者 MG发病早于功能正常组 ( P <0 .0 5 )。甲状腺功能异常、抗体阳性的 MG患者病程较抗体阴性者长 ( P <0 .0 5 ) ;甲状腺抗体阳性者伴发胸腺增生或胸腺瘤的几率明显增高 ( P <0 .0 5 )。结论　MG合并甲状腺功能异常并不少见 ,甲状腺抗体阳性、功能异常的 MG患者病程长 ,伴发胸腺增生或胸腺瘤的几率高 ,临床应予以重视。