Amino acid metabolism in Friedreich's ataxia.

A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreich's ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the presence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other beta-amino acids in Friedreich's ataxia.     

Purine metabolism in Friedreich's ataxia

In a detailed investigation of nucleotide synthesis, interconversion and degradation, no difference was found between subjects with Friedreich's Ataxia and normal controls. It appears improbable that this disorder is related to a primary defect in purine metabolism.     

Glucose and insulin metabolism in Friedreich's ataxia.

Our prospective survey of 50 ataxic patients confirms the previous finding of frequent clinical or chemical diabetes in Friedreich's ataxia. Eighteen percent of our typical cases have clinical diabetes and 40% at least an abnormal glucose tolerance curve. However, this finding does not appear to be specific to that form of ataxia. Furthermore, we have shown that most patients with ataxia have normal or low fasting insulin levels, but a hyperinsulinic response to a glucose load.     

Friedreich's ataxia and iron metabolism

The possible causes of abnormal iron metabolism in patients with Friedreich's ataxia are considered. Reduced expression of a frataxin homologue in yeast is associated with mitochondrial iron accumulation at the expense of cytosolic iron, and the same phenomenon can be demonstrated in these patients. A decrease in cytosolic iron causes the expression of a high-affinity iron-uptake protein, and therefore Friedreich's ataxia can be considered to be a disease of abnormal intracellular iron distribution. Friedreich's ataxia is of autosomal recessive inheritance, and the gene associated with it has been mapped to chromosome 9. This encodes the protein frataxin which regulates mitochondrial iron transport. The commonest mutation causing this disorder is an expanded GAA repeat in the gene for this protein. Different point mutations may account for some of the variations in the phenotypic features that are often found, and these variations are discussed. These findings have raised therapeutic possibilities in a condition for which previously there was no specific treatment. There are intracellular enzymes which are very sensitive to injury by oxygen-free radicals. Treatment has therefore been tried with ibebenone which acts as a free-radical scavenger, with some evidence of improvement. Iron chelating agents, such as deferoxamine, have also been given, but the finding of normal serum iron and ferritin casts doubt on the rationale of this. However the finding that the accumulation of iron in the mitochondria of the cells in patients with this form of ataxia will cause oxidative stress and cell death, gives hope for more effective treatment in the future, possibly with gene therapy.     

Glucose metabolism alterations in Friedreich's ataxia

We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.     

Friedreich's ataxia

Friedreich's ataxia is one of the most frequent hereditary ataxias of childhood. The disease is inherited in an autosomal recessive mode. The current state of knowledge concerning genetics, pathophysiology, pathology, clinical course, differential diagnosis, genotype-phenotype correlation, and therapy is presented.     

Friedreich's ataxia

Friedreich’s ataxia, the most common hereditary ataxia, is caused by expansion of a GAA triplet located within the first intron of the frataxin gene on chromosome 9q13. There is a clear correlation between size of the expanded repeat and severity of the phenotype. Frataxin is a mitochondrial protein that plays a role in iron homeostasis. Deficiency of frataxin results in mitochondrial iron accumulation, defects in specific mitochondrial enzymes, enhanced sensitivity to oxidative stress, and eventually free-radical mediated cell death. Friedreich’s ataxia is considered a nuclear encoded mitochondrial disease.

This review discusses the major and rapid progress made in Friedreich’s ataxia from gene mapping and identification of the gene to pathogenesis and encouraging therapeutic implications.     

Brain lesions in Friedreich's ataxia.

An estimate is given of the frequency of pathological changes (assessed by cell populations and from myelin staining) in the brains of 15 cases of Friedreich's ataxia. Mention is made of the special problem of distinguishing primary degenerative lesions from those due to circulatory disturbances arising from the patients cardiac disease.     

Oculomotor abnormalities in Friedreich's ataxia.

A clinical neuro-ophthalmological and electro-oculographic study was made on fourteen patients with Friedreich's ataxia. None had evidence of optic nerve dysfunction. No patient complained of oscillopsia although all had ocular motor deficits of varying degrees, which appeared to be related to the severity of the general manifestations of the disease. The defects comprised square wave jerks, jerky pursuit with inability to maintain eccentric gaze resulting in gaze paretic nystagmus and rebound nystagmus. There was failure to suppress by fixation the vestibulo-ocular reflex. The slow phase velocity of caloric nystagmus was always of reduced velocity. There was inability to augment the slow phase velocity of optokinetic nystagmus with increasing stimulus velocity. Abnormalities of the saccadic system were manifest particularly as hypermetria. These signs in combination are suggestive of disease involving the cerebellar flocculus and vermis or their brain stem connections. No abnormalities were found in 17 parents or siblings.     

Electroencephalographic findings in Friedreich's ataxia.

Electroencephalographic tracings of 50 patients who presented the classical features of Friedreich's ataxia were reviewed. Mild nonspecific abnormalities were found in 33% and consisted of: a) Abnormal slow or irregular background rhythms in 15 patients (30%). b) Intermittent paroxysmal rhythms, considered to be projected from diencephalic or upper midbrain structures, in 4 patients (8%). c) Unilaterally absent driving responses in 2 affected siblings (4%). There was no response to intermittent photic stimulation in 60% of the patients. This finding is not considered a definite abnormality, and its significance remains unclear. Four patients (8%) had epileptic seizures, but of these only two had interictal epileptic abnormalities. There was no correlation between the duration and severity of the disease and the presence of electroencephalographic abnormalities. Friedreich's ataxia is mainly a spinal disorder. Involvement of supraspinal and in particular brain stem or diencephalic structures may be more extensive in those patients who show electrographic abnormalities. This would require confirmation with comparative data based on pathological observations. Impaired function of brain stem inhibitory mechanism may be responsible for the slightly raised incidence of seizures in patients with Friedreich's ataxia and other cerebellar degenerations.     

The heart in Friedreich's ataxia.

Seventeen patients with Freidreich's ataxia were investigated for cardiac abnormalities using non-invasive methods. Clinical examination, routine chest radiographs and electrocardiograms were a poor guide to underlying heart involvement but using continuous ambulatory electrocardiographic monitoring, echocardiography and isotope ventriculography all patients were found to have abnormalities, even when the neurological signs were minimal.     

Hemodynamic findings in Friedreich's ataxia.

Thirteen patients with classical Friedreich's ataxia underwent cardiac catheterization with recordings of retrograde cardiac pressures, measurements of cardiac output and calculation of the left ventricular volumes and mass. The cardiomyopathy in Friedreich's ataxia falls into the hypertrophic group of cardiomyopathies with decreased compliance of ventricular myocardium, varying degrees of concentric and asymmetric hypertrophy and outflow tract obstruction. Although there is no clear parallel between the degree of abnormal hemodynamic findings and the degree of neurological impairment, severely handicapped patients may present a diffusely hypertrophied and hypokinetic left ventricular myocardium.     

Echocardiographic findings in Friedreich's ataxia.

Echocardiographic examination of 21 patients with Friedreich's ataxia (age 7 to 28 years) showed cardiac abnormalities in 90% of the cases. They were characterized by varying degrees of septal hypertrophy in 81%, left ventricular free wall hypertrophy in 61%, and a slight reduction of left ventricular internal dimension in 57% of the cases. Asymmetric septal hypertrophy (ASH) with a septal/left ventricular free wall ratio of over 1.3 was found in 29% of the cases, and systolic anterior motion (SAM) of the mitral valve in three patients. Two other patients showed evidence of a different type of cardiomyopathy with marked symmetric left ventricular hypertrophy and marked left ventricular enlargement.     

Cardiomyopathy in Friedreich's ataxia

Friedreich's ataxia (FRDA), an autosomal recessive disorder, is characterized by spinocerebellar degeneration and cardiomyopathy. Here we explore some of the putative mechanisms underlying the cardiomyopathy in FRDA that have been elucidated using different experimental models. FRDA is characterized by a deficiency in frataxin, a protein vital in iron handling. Iron accumulation, lack of functional iron-sulphur clusters, and oxidative stress seem to be among the most important consequences of frataxin deficiency explaining the cardiac abnormalities in FRDA.     

Erythrocyte membrane lipids in Friedreich's ataxia.

In a study of the lipid composition of erythrocyte membranes in Friedreich's ataxia, the concentration of the major membrane components (phospholipids, cholesterol and protein) in ataxic patients, family members, and control subjects were found to be the same. The total fatty acid distribution was also normal. However, an altered distribution of phospholipid classes in erythrocytes was noted (an increase of PI + PS and a decrease of PE in Friedreich's ataxia patients).     

Clinical laboratory findings in Friedreich's ataxia.

All clinical laboratory tests carried out in 4 groups of patients with the diagnosis of typical or atypical Friedreich's ataxia have been found to be within the normal range. In this prospective study of 50 patients, a number of findings previously reported to be abnormal in the literature, have not been confirmed.     

Small fibers involvement in Friedreich's ataxia.

Although the involvement of large myelinated sensory fibers in Friedreich's ataxia (FA) is well documented, an impairment of unmyelinated fibers has not been described. We demonstrate an involvement of cutaneous unmyelinated sensory and autonomic nerve fibers in FA patients. We performed a morphological and functional study of cutaneous nerve fibers in 14 FA patients and in a population of control subjects. We used immunohistochemical techniques and confocal microscopy applied to punch skin biopsies from thigh, distal leg, and fingertip, and compared the density of epidermal nerve fibers (ENFs) with the results of mechanical pain sensation and thermal and tactile thresholds performed on hand dorsum, thigh, distal leg, and foot dorsum. We observed in our patients a statistically significant loss of ENFs, a reduced innervation of sweat glands, arrector pilorum muscles and arterioles, and an impairment of thermal and tactile thresholds and mechanical pain detection.