Errors Of Intermediary Metabolism Research Articles

The ratio of maximal handgrip force and maximal cycloergometry power as a diagnostic tool to screen for metabolic myopathies

Metabolic myopathies comprise a diverse group of inborn errors of intermediary metabolism affecting skeletal muscle, and often present clinically as an inability to perform normal exercise. Our aim was to use the maximal mechanical performances achieved during two functional tests, isometric handgrip test and cycloergometer, to identify metabolic myopathies among patients consulting for exercise-induced myalgia. Eighty-three patients with exercise-induced myalgia and intolerance were evaluated, with twenty-three of them having a metabolic myopathy (McArdle, n = 9; complete myoadenylate deaminase deficiency, n = 10; respiratory chain deficiency, n = 4) and sixty patients with non-metabolic myalgia. In all patients, maximal power (MP) was determined during a progressive exercise test on a cycloergometer and maximal voluntary contraction force (MVC) was assessed using a handgrip dynamometer. The ratio between percent-predicted values for MVC and MP was calculated for each subject (MVC%pred:MP%pred ratio). In patients with metabolic myopathy, the MVC%pred:MP%pred ratio was significantly higher compared to non-metabolic myalgia (1.54 ± 0.62 vs. 0.92 ± 0.25; p < 0.0001). ROC analysis of MVC%pred:MP%pred ratio showed AUC of 0.843 (0.758–0.927, 95% CI) for differentiating metabolic myopathies against non-metabolic myalgia. The optimum cutoff was taken as 1.30 (se = 69.6%, sp = 96.7%), with a corresponding diagnostic odd ratio of 66.3 (12.5–350.7, 95% CI). For a pretest probability of 15% in our tertiary reference center, the posttest probability for metabolic myopathy is 78.6% when MVC%pred:MP%pred ratio is above 1.3. In conclusion, the MVC%pred:MP%pred ratio is appropriate as a screening test to distinguish metabolic myopathies from non-metabolic myalgia.

Neurological Involvement in Inherited Metabolic Diseases: An Overview

Neurological involvement is a typical feature of several inherited metabolic diseases. The onset of signs and/or symptoms may appear as early as the first days of life or after an interval of normal or near-normal growth and development. Metabolic decomposition usually presents with a severe clinical phenotype, which include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. This spectrum of manifestations is often fatal; however, severe neurological sequelae and/or regression of neurodevelopmental milestones can be the prominent signs in those who survive. Overall, treatable inborn errors of metabolism can be divided in three groups, namely: (Group 1) inborn errors of intermediary metabolism giving rise to acute or chronic intoxication; (Group 2) inborn errors of intermediary metabolism affect in genergetic processes; and (Group 3) inborn errors involving cellular organelles, including lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. The spectrum of neurological manifestations includes developmental delay, seizures and epilepsy, pyramidal and extrapyramidal signs, movement disorders, vision and hearing impairment, peripheral neuropathy, and psychiatric abnormalities. The main anatomical/imaging patterns reflects selective vulnerability of nervous system substance and include atrophy, (predominantly) symmetrical abnormalities, and dysmyelination, As several patients with neurometabolic diseases responds favorably to therapeutic trials, early detection and early intervention is of utmost importance to prevent catabolic-related damage and to revert to normal or near-normal parameters neurodevelopmental milestones.

The monitoring of trace elements in blood samples from patients with inborn errors of metabolism

Patients having inborn errors of intermediary metabolism (IEMs) may have element deficiencies related to dietary treatment. Our objective was to study several elements [cobalt (Co), copper (Cu), zinc (Zn), selenium (Se), manganese (Mn), molybdenum (Mo) and magnesium (Mg)] in patients with IEMs with and without dietary treatment and to compare these results with those established in a healthy paediatric population. We studied 72 patients with IEMs (age range 2 months-44 years; median 10.5 years), with and without protein-restricted dietary treatment. Control values were established in 92 subjects (age range 1 day-42 years; median 6.5 years). Dietary treatment consisted of a natural protein-restricted diet supplemented with a special formula, depending on the specific metabolic defect. Samples were analysed with an Agilent 7500ce-ICP mass spectrometer. Significant differences were observed when we compared patients under dietary treatment and control values for Se and Co (P < 0.0001). No differences were observed for the other elements when the different groups were compared, except for Co (IEM patients without dietary treatment vs control group; P = 0.003). For Se and cobalamin, the daily intake of our patients (Se 48 ± 16 µg/day; cobalamin 3.5 µg/day) was slightly higher than the recommended daily averages (RDAs) (40 µg/day and 1.8 µg/day, respectively). We concluded that IEM patients under dietary treatment showed significantly lower selenium values in spite of correct supplementation, reinforcing the idea that these patients should be regularly monitored, at least for this element. Further investigations seem advisable about Se and Co availability in special diets.

BACK TO BASICS

Many inborn errors of intermediary metabolism present during periods of poor oral intake or intercurrent illness. Under these conditions, the body switches to a predominantly catabolic state, when glycogen, fat, and protein are mobilized as alternative energy sources. If a genetic defect already exists in any of these catabolic pathways, the problem is accentuated because the catabolic state demands a high flux of metabolite through these pathways. Therefore, a cardinal principle in the management of children who have IEM is to prevent them from lapsing into a catabolic state. This can be done through: 1) aggressive nutrition management to promote positive nitrogen balance and decrease accumulation of toxic metabolites, and 2) immunizations to minimize the possibility of viral or bacterial illness. When catabolism does occur, high-dose glucose infusion is a potent method for turning off the catabolic state. This simplistic view of the catabolic pathways neglects many details in each of the metabolic pathways and diseases cited in the article and questions. Nevertheless, it should provide a useful framework for explaining some of the clinical findings encountered in caring for this special group of patients. A partial list of more commonly encountered IEMs is contained in the Table. The different parts of the biochemical pathways discussed previously are combined into Figure 6.

Metabolic and degenerative diseases associated with epilepsy.

Identifying the specific etiology of epilepsy is often difficult. The search for the cause often leads the clinician to suspect inborn errors of intermediary metabolism and other degenerative metabolic diseases. Although these uncommon diseases are often difficult to determine, a correct diagnosis is critical for treatment and genetic counseling. A review of the relevant biochemistry will aid in understanding the pathophysiology of seizures in these conditions. The stream-lined approach to the initial laboratory evaluation that is offered will enable the clinician to screen for most metabolic and degenerative diseases that are associated with epilepsy.

The clinical significance of aminoaciduria

Summary Hyperaminoaciduria is significant as a manifestation of aberrant cellular function in the kidney and in other organs (bone, liver, and brain in particular). The various patterns of hyperaminoaciduria may be described in terms of the endogenous renal clearances of the individual amino acids. Normally, those amino acids with the higher plasma concentrations or with the higher endogenous renal clearances or with both appear in the urine in the greater concentrations. The pattern of generalized renal aminoaciduria results when mechanisms common to the reabsorption of all amino acids are impaired. This pattern is nonspecific and may be seen in a variety of syndromes, the most common of which are the Fanconi syndrome and vitamin D deficiency states. Generalized renal hyperaminoaciduria may be distinguished from the generalized “overflow” aminoaciduria of severe hepatic cell damage and from the specific patterns of renal and systemic origin. A classification of aminoaciduria on this functional basis is presented. The finding of generalized renal hyperaminoaciduria in diseases of varied etiology suggests that this type of aminoaciduria is a very sensitive manifestation of impaired renal tubular function. Although the aminoaciduria results from renal injury, defects involving many organs may be present in these diseases. Indeed, cerebral and hepatic features may predominate the clinical picture in some of these diseases (e.g., galactosemia, lead encephalopathy, and Wilson's disease). The occurrence of the triad of renal aminoaciduria, glycosuria, and hypophosphatemia provides further evidence of an interrelationship between the renal tubular mechanisms for the reabsorption of these substances. Still other derangements of renal tubular function may be present when this triad is found. This emphasizes the need for complete studies of renal function in clinical problems in which any one discrete tubular function is obviously deranged. Distinctive “patterns of aminoaciduria” are found in various forms of rickets and osteomalacia. As the therapy differs in each, urinary amino acid studies may be helpful in therapeutic management. Likewise, specific patterns of aminoaciduria facilitate the accurate diagnosis of some forms of cerebral defect which have similar clinical features (e.g., phenylketonuria and “maple syrup urine disease”). The study of patterns of aminoaciduria has proved to be a valuable technique in genetic surveys and in the unraveling of obscure metabolic disorders in which the metabolism of individual amino acids and closely related intermediates is involved. As the technique of paper chromatography becomes more widely used, it may be anticipated that still other errors of intermediary metabolism will be identified among syndromes that are without distinctive clinical features. Semiquantitative paper chromatographic estimation of urinary acid patterns is adequate for most clinical problems in which aminoaciduria is suspected.