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.

Twenty-six of 50 patients were investigated with nerve conduction studies and electromyography using a standard protocol and were compared to the findings in 50 normal control subjects. Almost all cases of typical Friedreich's ataxia had absent sensory action potentials (SAP) in the digital (92%) or sural (96%) nerves. The others had markedly decreased S.A.P's. In these same patients motor conduction auvelocities were either normal or only slightly decreased. In the second, atypical group of 9 patients, the motor conduction velocities were considerably decreased.

Because of the absence of sensory action potentials in Friedreich's ataxia, and that the absence was noted in our very mild cases, it is proposed that this measure be used to facilitate early diagnosis.

The cardiovascular signs and symptoms were recorded in 36 patients with typical Friedreich's Ataxia (Group la, lb). Seventeen patients were asymptomatic and this did not correlate with the severity of the disease. No pathognomonic clinical constellation was found to reveal the underlying cardiomyopathy.

Electrocardiographic and vectocardiographic changes are frequent in Friedreich's ataxia. In one of 35 patients both tests were normal. The vectocardiogram is more explicit in demonstrating the severity of the QRS changes with a right ventricular hypertrophy pattern present in 60% of cases. Serial examination and ECG tracings are recommended to monitor the cardiomyopathy in this progressive neurological disorder, in order to detect the onset of congestive heart failure, significant tachyarrythmias, or obstructive cardiomypathy.

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.

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.

Angiograms of 12 patients with typical Friedreich's ataxia were analyzed. The results corroborate previous reports and justify the conclusion that the cardiomyopathy is of the hypertrophic type. In 10 of 12 cases, the hypertrophy is concentric, and non obstructive. Less frequently (2 cases), this hypertrophy is accompanied by diffuse hypokinesis and depressed ejection fraction.

Pulmonary function tests were carried out on 20 patients with Friedreich's ataxia. The lung volume, diffusing capacity, flow rate, flowvolume curve, and blood gases were measured. In each patient the degree of scoliosis was measured and the pulmonary function tests were analyzed in relation to the scoliosis. A control group of 13 subjects with idiopathic scoliosis was used for comparison. In both groups, the degree of scoliosis was similar.

A single case of typical Friedreich's ataxia was analyzed for cardiac changes and compared to the findings from the literature. Macroscopically, there was a cardiomegaly with some degree of ventricular hypertrophy and probable mild dilatation of the auricles. The more important and constant histologic changes were myocardial fibrosis and degeneration of the cardiac muscle cells. Granular deposits of calcium salts and iron were found in the muscle cells. A cardiomyopathy hypertrophic in type and occasionally obstructive appears to be an integral part of 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.

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.

In our studies, high total bilirubin values in the plasma were noted in cases of Friedreich's ataxia. A bimodal distribution of the values indicated the possible presence of two subgroups of patients. In these kindred, we demonstrated an elevation in unconjugated bilirubin with features similar to those reported in Gilbert's syndrome: normal liver function tests, elevation after fasting and day to day variability. We also report preliminary experiments indicating that bilirubin levels may be taurine dependent. We postulate that the defect could be a secondary component of the ataxic disease, possibly indicating a defect in membrane transport.

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 resence 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 β-amino acids in Friedreich's ataxia.

Friedreich's ataxia patients show evidence of an abnormally elevated and prolonged response of pyruvate and lactate to a glucose load, with normal fasting levels. However, there is a bimodal distribution of this response with high and low pyruvate responders. This trait appears to be determined genetically, However, although in vivo tests suggest low oxidation of pyruvate, we were unable to confirm any in vitro impairment of each of the components of the pyruvate dehydrogenase (PDH) complex. We conclude that the defect is in the metabolic regulation of PDH, probably at the E3 (lipoamide dehydrogenase) step.

The prospective investigation of 50 cases of possible Friedreich's ataxia has permitted the clinical and biochemical delineation of the typical disease and an hypothesis on its pathogenesis. A tentative definition of the disorder could read: “Friedreich's ataxia is a progressive degenerative disease always inherited in an autosomal recessive fashion and characterized by a cardiomyopathy and a ganglioneuropathy with dying back phenomenon. It is probably secondary to a defect in the membrane transport of taurine and β -alanine and/or a defect in the regulation of pyruvate oxidation.” The existence of two pathogenetically distinct distinct entities with the same phenotype is a strong possibility.