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Friedreich's ataxia (FRDA) is one of the most devastating childhood onset neurodegenerative disease affecting multiple organs in the course of progression. FRDA is associated with mitochondrial dysfunction due to deficit in a nuclear encoded mitochondrial protein, frataxin. Identification of disease-specific biomarker for monitoring the severity remains to be a challenging topic. This study was aimed to identify whether circulating cell-free nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in blood plasma can be a potential biomarker for FRDA. Clinical information was assessed using International Cooperative Ataxia Rating Scale and the disease was confirmed using Long-range PCR for GAA repeat expansion within the gene encoding frataxin. The frataxin expression was measured using Western blot. Plasma nDNA and mtDNA levels were quantified by Multiplex real-time PCR. The major observation is that the levels of nDNA found to be increased, whereas mtDNA levels were reduced significantly in the plasma of FRDA patients (n=21) as compared to healthy controls (n=21). Further, plasma mtDNA levels showed high sensitivity (90%) and specificity (76%) in distinguishing from healthy controls with optimal cutoff indicated at 4.1×10(5)GE/mL. Interestingly, a small group of follow-up patients (n=9) on intervention with, a nutrient supplement, omega-3 fatty acid (a known enhancer of mitochondrial metabolism) displayed a significant improvement in the levels of plasma mtDNA, supporting our hypothesis that plasma mtDNA can be a potential monitoring or prognosis biomarker for FRDA.

Background Quality of life in Friedreich ataxia (FRDA) has been explored using various generic health status measurement tools, most commonly the Short Form Health Survey Version 2 (SF-36v2). The tool did not address many specific issues related to disease impact in people with FRDA. The Friedreich Ataxia Impact Scale (FAIS) was developed to examine clinically relevant areas in FRDA. The aims of the current study were to assess the relationship between the FAIS and clinical characteristics of FRDA, as well as to determine the responsiveness of the FAIS to change over one and two years. Methods One hundred and four individuals with FRDA, homozygous for the GAA expansion in intron 1 of FXN , completed the FAIS at baseline. Seventy individuals completed the FAIS again 12months later and 49 completed the FAIS at 24months. Clinical parameters and neurologic scales (Friedreich Ataxia Rating Scale (FARS)) were also recorded. Results The total FARS score, onset age and disease duration correlated significantly with FAIS subscales measuring symptoms and physical functioning. The physical and mental summary measures of the SF-36 V2 also correlated well with the FAIS subscales. Speech was the only subscale that demonstrated significant change over one and two years. Conclusions The FAIS provides valuable insight into the perspective of individuals with FRDA on their health status, and is an important measure of morbidity. It has, however, limited responsiveness to change and its use in intervention studies is questionable.

The dentate nucleus (DN) is the major relay station for neural connection between the cerebellum and cerebrum via the thalamus, and is a significant component of the neuropathological profile of Friedreich ataxia (FRDA). We have previously shown that the size of the superior cerebellar peduncle (SCP), which links the DN to cortical and subcortical structures via the thalamus, is significantly reduced in individuals with FRDA compared to control participants. This study used magnetization transfer imaging (MTI) to examine and contrast the integrity of white matter (WM) in the SCP and the corpus callosum (CC) (control region) in ten individuals with FRDA and ten controls. Individuals with FRDA demonstrated a significant reduction in the magnetization transfer ratio (MTR) in the SCP compared to control participants. However, there was no significant difference between groups in MTR in the CC. When comparing regions within groups, there was a significant reduction in MTR in the SCP compared to CC in participants with FRDA only. We suggest that the reduction in MTR in the SCP may be indicative of lack of myelin secondary to axonal loss and oligodendroglial dysfunction in WM tracts in individuals with FRDA.

Objectives To evaluate the relationship between disease features in Friedreich ataxia and aberrant glucose metabolism. Methods Fasting glucose, fasting insulin and random HbA1C were obtained in 158 patients with Friedreich ataxia. Regression analysis evaluated glucose, insulin, and homeostatic model assessment (HOMA) of insulin resistance (IR) and beta-cell function (s) in relation to age, BMI, sex, and genetic severity. Categorical glucose values were analyzed in relation to other FRDA-associated disease characteristics. Results In the FRDA cohort, age and GAA repeat length predicted fasting glucose and HbA1c levels (accounting for sex and BMI), while insulin and HOMA-IR were not predicted by these parameters. Within the cohort, average BMI was consistently lower than the national average by age and was marginally associated with insulin levels and HOMA-IR. Within juvenile subjects, insulin and HOMA-IR were predicted by age. Controlling for age and genetic severity, diabetes-related measures were not independent predictors of any quantitative measure of disease severity in FRDA. Glucose handling properties were also predicted by the presence of a point mutation, with 40% of individuals heterozygous for point mutations having diabetes, compared to 4.3% of subjects who carried two expanded GAA repeats. Interpretation In FRDA, aberrant glucose metabolism is linked to increasing age, longer GAA repeat length on the shorter allele, frataxin point mutations, and increasing BMI. The effect of age to some degree may be mediated through changes in BMI, with increasing age associated with increases in BMI, and with HOMA-IR and insulin increases in children.

A scale for the Assessment and Rating of Ataxia (SARA) was developed for evaluation of autosomal dominant cerebellar ataxias (ADCA) and was also recommended for clinical trials of Friedreich's ataxia patients (FRDA). FRDA, unlike ADCA, is characterized as being a sensory type of ataxia for which the disease-specific Friedreich ataxia rating scale (FARS) was developed. The objective of this study was to determine whether SARA and FARS scores are associated with posturographic parameters in FRDA patients.Adult patients with genetically confirmed FRDA (n=11) and ADCA (n=13) were evaluated by SARA, FARS and posturography.FRDA patients' postural stability parameters, in stance with visual control, correlated with balance impairment in FARS (r=0.622; p0.05) and SARA (r=0.735; p0.05). Without visual control, only FARS correlated with balance impairment (r=0.732; p0.05).The SARA, in FRDA patients, correlates with stance with visual control but not without visual control which emphasizes sensory ataxia. This suggests that application of the SARA in Friedreich's ataxia patients according to posturography is possible but presumably limited and FARS, although being a more time consuming scale, may have advantages over SARA in FRDA patients.

Friedreich's Ataxia (FRDA) is a very common cause of hereditary autosomal recessive ataxia among western Europeans. We aim to define the frequency of FRDA in Chinese Han population due to the lack of reports of FRDA in China. The GAA trinucleotide repeats in the FXN gene were analyzed by triplet repeat-primed PCR (TP-PCR) in 122 unrelated hereditary ataxia (HA) and 114 unrelated hereditary spastic paraplegia (HSP) patients. The GAA copy numbers in the FXN gene of all the subjects ranged from 5 to 16. There were no FRDA patients that could be diagnosed base on the results of TP-PCR. It suggests that FRDA is a very rare cause of inheritance ataxia and FRDA genetic analysis should not be used as a routine genetic diagnosis test in China.

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder most commonly caused by guanine-adenine-adenine (GAA) trinucleotide repeat expansions in both alleles of the FXN gene. Although progressive ataxia remains the hallmark clinical feature, patients with FRDA are at high risk of developing cardiomyopathy, often resulting in premature death. There is no specific treatment for FRDA-associated cardiomyopathy; even in advanced cardiac failure cardiac transplantation is not commonly pursued. This case series describes extended follow-up of three FRDA cases with end-stage heart failure but mild neurologic disease who underwent successful heart transplantation. We also review and examine the ethical considerations for heart transplantation in the setting of neurodegenerative disease.

Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87years) and 12 normal controls (age of death, 13 to 69years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.

Background Although cardiac dysfunction is widely accepted as the most common cause of mortality in Friedreich ataxia (FRDA), no studies have evaluated this since the advent of specific clinical and genetic diagnostic criteria. Methods We performed a retrospective study of FRDA patients to determine cause of death followed by a case–control analysis comparing characteristics of deceased patients with living, age- and sex-matched FRDA controls. Results Causes of death were cardiac dysfunction (59%), probable cardiac dysfunction (3.3%), non-cardiac (27.9%) or unknown (9.8%). Compared to non-cardiac deaths, cardiac deaths occurred earlier in the disease course (median 29 vs. 17 years respectively). Congestive heart failure and arrhythmia were common causes of cardiac-related death. Compared to living, matched FRDA controls, deceased patients had longer triplet repeat lengths and higher rates of arrhythmia and dilated cardiomyopathy. The presence of hypertrophic cardiomyopathy did not differ between deceased and living patients. Conclusion Cardiac dysfunction was the most frequent cause of death (59%), most commonly from congestive heart failure or arrhythmia. Arrhythmia and dilated cardiomyopathy were significantly more common in deceased patients compared to matched FRDA controls, while in contrast, the presence of cardiac hypertrophy did not differ. More research is needed to establish the clinical significance of hypertrophy in FRDA.

Evaluation of therapeutic agents for Friedreich Ataxia (FA) has been limited by a lack of adequate markers of disease progression. We assessed the capacity of health related quality of life (HRQOL) questionnaires to reflect disease status in FA. The SF-36 and several symptom-specific scales were administered to an FA cohort. Scores were compared with norms for the United States population, and to a disease-free control group of similar age and gender. FA patients had significantly lower SF-36 Physical Component Summary scores (PCS) and Physical Functioning Subscale (PFS) scores, and both PCS and PFS scores correlated significantly with disease duration and disability status. Mental Component Summary scores (MCS) did not differ between FA patients and controls. Among symptom-specific scales, scores for the Pain Effects, Bladder Control, and Modified Fatigue Impact scales were significantly worse among FA patients than controls, and generally correlated with markers of disease progression. Findings of this study are consistent with the phenotypic characteristics of FA, and suggest that HRQOL measures are potentially useful as clinical markers of disease status in FA.

The aim of the study was to explore excitability of a motor and a non-motor (visual) area in patients affected by Friedreich ataxia and to correlate neurophysiological data with clinical parameters. Seven patients (3M/4F) and ten healthy controls (5M/5F) participated in the study. The hot-spot for activation of right abductor pollicis brevis was checked by means of a figure-of-eight coil and the motor threshold (MT) on this point was recorded. The phosphene threshold (PT) was measured by means of a focal coil over the occipital cortex as the lower intensity of magnetic stimulation able to induce the perception of phosphenes. The patients showed a significantly higher mean PT (p

Movement disorders are well known features of some dominant hereditary ataxias (HA), specially SCA3/Machado-Joseph disease and dentatorubropallidolusyan atrophy. However, little is known about the existence and classification of movement disorders in other dominant and recessive ataxias. We prospectively studied the presence of movement disorders in patients referred for HA over the last 3 years. Only those patients with a confirmed family history of ataxia were included. We studied 84 cases of HA, including 46 cases of recessive and 38 cases of dominant HA. Thirty out of 46 cases of recessive HA could be classified as: Friedreich ataxia (FA), 29 cases; vitamin E deficiency, 1 case. Twenty-three out of 38 cases of dominant HA could be classified as: SCA 2, 4 cases; SCA 3, 8 cases; SCA 6, 4 cases; SCA 7, 6 cases and SCA 8, 1 case. We observed movement disorders in 20/38 (52%) patients with dominant HA and 25/46 (54%) cases with recessive HA, including 16 patients (16/29) with FA. In general, postural tremor was the most frequent observed movement disorder (27 cases), followed by dystonia (22 cases). Five patients had akinetic rigid syndrome, and in 13 cases, several movement disorders coexisted. Movement disorders are frequent findings in HA, not only in dominant HA but also in recessive HA.

Tuberous sclerosis (TS) is caused by point mutations in the TSC1 or TSC2 genes on chromosomes 9q33-34 or 16p13, respectively. Clinical manifestations can be quite variable but are primarily limited to cutaneous, neurologic, and cardiovascular abnormalities. Phenotypes range from neurologically devastated to those with silent lesions. A 34-year-old patient with genetically documented TSC1 developed progressive ataxia over a decade, without TS lesions to correlate with this finding. After evaluation of common causes including long-term antiepileptic regimens, DNA testing for hereditary ataxias was performed and revealed the presence of an additional mutation on chromosome 9. The patient was homozygous for the Friedreich ataxia (FA) mutation, with 500 and 700 GAA repeats in the FRDA gene on chromosome 9q13. There is no established relationship between these two disorders and the occurrence of two mutations on the same chromosome is probably coincidental but emphasizes the importance of searching for additional genetic causes when the phenotype does not fit with an established genetic diagnosis.

A deficiency in the protein frataxin causes Friedreich’s ataxia (FRDA). Missense mutations in f2% of disease alleles cause a functional deficiency of frataxin, while f98% of disease alleles have a guanine-adenine-adenine (GAA) repeat expansion in the first intron [1]. The expansion decreases frataxin expression by interfering with transcription [2]. A complete knockout of the murine frataxin gene causes embryonic lethality, indicating that at least some frataxin function is necessary for survival [3]. This summary focuses on the current hypotheses of frataxin function, the supporting experimental evidence, and the role of frataxin deficiency in FRDA. A more complete list of references can be found in the excellent recent review by Patel and Isaya [4].

Friedreich's ataxia (FRDA) and spinocerebellar ataxia type 2 (SCA 2) are among the most commonly diagnosed hereditary ataxias in Czech Republic. Although criteria differentiate the ataxias, disorder onset symptoms may be similar. Our goal was to determine whether and to what degree of validity posturographic examination may be utilized, with the aim of differential diagnosis; which specific posturographic parametres are suitable for differential diagnosis; and which differences in FRDA and SCA 2 patient posturographic findings may be established. 17 SCA 2 and 12 FRDA patients were examined with ten healthy controls. A multi-sensor tenzometric platform was used for posturographic examination. Toe standing position was added to basic tests, including standing position with and without visual control. There was no difference between patients in standing position with visual control but there were distinct differences between FRDA and SCA 2 patients, based on upright stance without visual control and medio-lateral deviation. There were no differences between patients in toe standing position, suggesting not only the cerebellum, but also deep sensation, helps to create the so-called adaptive controller. Posturography is attested to as a useful method for differential diagnosis of hereditary ataxias and provides neurophysiological findings in cerebellar and sensoric ataxias.

The pathogenic mutation in Friedreich's ataxia (FRDA) is a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. This autosomal recessive disease affects central and peripheral nervous systems, heart, skeleton, and endocrine pancreas. Long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short expansions have a later onset and a more benign course. Some are not diagnosed during life. The neurological phenotype reflects lesions in dorsal root ganglia (DRG), sensory peripheral nerves, corticospinal tracts, and dentate nuclei (DN). Most patients succumb to cardiomyopathy, and many become diabetic during the course of their disease. This review seeks to reconcile the diverse clinical features with pathological and molecular data. In the pathogenesis of the lesion in DRG, dorsal spinal roots, and sensory peripheral nerves, developmental defects and atrophy occur in combination. The progressive lesion of the DN lacks a known developmental component. Destruction of the DN, optic atrophy, and degeneration of the corticospinal tracts are intrinsic central nervous system lesions. Fiber loss in dorsal columns and spinocerebellar tracts, and atrophy of the neurons in the dorsal nuclei of Clarke are secondary to the lesion in DRG. The role of frataxin deficiency in the pathogenesis of FRDA is still unclear because the protein has multiple functions in the normal state, including biogenesis of iron-sulfur clusters; iron chaperoning; iron storage; and control of iron-mediated oxidative tissue damage.

Since the discovery of the gene mutation causing Friedreich's ataxia (FA), the rich spectrum of clinical manifestations of this autosomal recessive disorder is being increasingly recognized. Movement disorders besides ataxia, however, have not been fully characterized in patients with FA. We describe here two young male patients who, in addition to progressive ataxia, kinetic tremor and other typical features of FA, also manifest axial and limb dystonia. The primary purpose of this report is to draw attention to the broad spectrum of hyperkinetic movement disorders that can present as or be associated with FA.

Around a quarter of Friedreich ataxia (FA) patients, despite being homozygous for GAA expansion within the FRDA gene, show atypical presentations. Our aim is to describe the case of three brothers with long-term follow-up suffering from late onset FA manifested with spastic ataxia. The three patients belong to a family with occipital dysplasia (OD) and Chiari I malformation previously reported by us. We have carried out serial examinations since 1977. Electrophysiological and neuroimaging studies, and molecular genetic analyses of hereditary ataxias are available in all three patients. Onset of symptoms occurred between 25 and 35 years. The clinical picture consisted of progressive spastic gait, truncal and limb ataxia, dysarthria, nystagmus, hyperreflexia with knee and ankle clonus and extensor plantar response, and mild hypopallesthesia. Ages at present vary between 50 and 59. One patient is wheelchair-bound but the other two are able to walk with support. Leaving OD aside, skeletal anomalies are not prominent. All three patients showed cardiomyopathy. MR imaging revealed atrophy of the cerebellum and spinal cord. Motor and sensory nerve conduction velocities were normal. Central conduction time of both motor and sensory pathways was delayed or unobtainable. All three patients were homozygous for the GAA expansion, the smaller expanded allele ranging between 131 and 156 repeats. Four heterozygotic carriers were detected among non-ataxic relatives including one with OD; furthermore, an asymptomatic OD patient showed normal genotype. We conclude that adult onset spastic ataxia is a distinctive FA phenotype associated with minimal GAA expansion. This phenotype represents a new cause of selective distal degeneration of central sensory axons. The present concurrence of OD and FA reflects coincidental cosegregation of two different inherited disorders.

Fibroblasts obtained from patients with Friedreich's ataxia and normal control subjects were studied by immunocytochemistry for intermediate filament vimentin and also for in vitro proliferation. Trypsinized cells were seeded on coverslips and incubated for 1.5 h and 24 h. The expression of vimentin in cells was investigated by immunofluorescence microscopy. Cell proliferation was studied with BrdU antibody technique. Cells from patients with Friedreich's ataxia showed a slower outgrowth of vimentin filaments in comparison to cells from normal controls. These cells also incorporated less 5-bromo-2'-deoxyuridine (BrdU) into their DNA. The observations may be relevant to the clinical manifestations of the disease which involves many organs in addition to brain and spinal cord.

An electrophysiologic and histologic study was performed on 18 patients affected by early onset cerebellar ataxia with retained tendon reflexes (EOCA). Sensory and motor conduction velocity (SCV, MCV) was measured along peripheral nerves in all patients, somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) were recorded in 13; cortical stimulation (CS) in 12, and sural nerve biopsy in 4 patients were also performed. The results as a whole allow a division of EOCA patients into 2 groups: with (7 patients) and without (11 patients) peripheral neuropathy. Among EOCA patients with neuropathy a differential diagnosis with Friedreich's disease patients was not possible according to BAEPs and CS, while SSEPs could differentiate 2 out 5 patients in whom they were performed.

Somatosensory evoked potentials were recorded in response to stimulation of the median nerve at the wrist and the elbow in 14 cases of Charcot-Marie-Tooth disease (CMTD). Cervical and cortical latencies were used to derive conduction times and velocities over peripheral and central segments of the pathway. Sensory conduction velocities between the wrist and the elbow were distributed bimodally (12–27 m/s and 36–70 m/s), but did not correspond with the bimodality of motor conduction velocity values in 4 cases. Three patients had severely slowed sensory conduction in one arm but only moderate slowing in the other. In the majority of cases sensory conduction was considerably faster from the elbow to the spinal cord than from the wrist to the elbow. This was most apparent in 2 young patients, suggesting that demyelination secondary to axonal degeneration may gradually progress from distal to proximal segments. Compared with a group of Friedreich's ataxia (FA) patients, almost all CMTD cases could be distinguished by a greater degree of peripheral conduction slowing (not significant in FA). In FA there was a much higher incidence of impaired conduction over central segments of the somatosensory pathway, although evidence of this was also seen in 5 CMTD cases. Three of the latter had presented with atypical symptoms suggestive of CNS involvement, and also had delayed visual evoked potentials.

The use of orally administered choline chloride in the treatment of cerebellar and spinocerebellar ataxia was investigated by a short-term double-blind crossover trial in 20 patients with ataxia. These patients, who included 7 with Friedreich's ataxia, 7 with mixed spinocerebellar ataxia and 6 with primary cerebellar degeneration received placebo and 6 g/day or 12 g/day of choline with crossover at 6 weeks. Serum choline levels were measured 1 h after the first daily dose. Mild but significant improvement in upper limb co-ordination was noted in 3 patients with Friedreich's ataxia, 3 with mixed ataxia and 4 patients with primary cerebellar degeneration. Improvement in gait and lower limb co-ordination was observed in only 2 patients (one with cerebellar ataxia and 1 with mixed ataxia). There was no correlation between serum choline levels and clinical response to choline. Choline chloride produces a mild but functionally significant improvement in motor co-ordination in some patients with cerebellar and spinocerebellar ataxia.

This study extends previous observations of pyruvate metabolism in the spinocerebellar degenerations by screening for abnormalities of pyruvate oxidation using the rise in blood pyruvate after an oral glucose load and examining the activity of the lipoamide dehydrogenase (LAD) moeity of the pyruvate dehydrogenase complex in the serum of 31 patients with Friedreich's ataxia, hereditary spastic ataxia and primary cerebellar degeneration. Serum LAD activity was significantly reduced in 10 Friedreich's ataxia patients when compared to controls and to 10 patients with spastic ataxia, thus confirming previous studies. Two patients with Friedreich's ataxia and 2 with primary cerebellar degeneration had abnormal blood pyruvate curves after oral glucose loading. The findings suggest that abnormal pyruvate oxidation occurs in some cases of Friedreich's ataxia and primary cerebellar degeneration and that the abnormality of pyruvate metabolism is not necessarily reflected in the serum LAD activity of these patients. The relevance of these findings to the heterogeneity of the hereditary ataxias is discussed.

From a review of the literature and a consideration of the findings in this study, the following conclusions appear to be justified. 1. (1) Neurological findings in Friedreich's ataxia are of 3 general types: those found fairly constantly and in earlier stages of the disease; those found less frequently and usually later in the course of the illness; those tending to occur within given pedigrees and reflecting a hereditary predisposition in the family to degeneration of specific parts of the nervous system involved. 2. (2) Commonest findings among members of the family studies were: scoliosis, nystagmus, dysdiadochokinesia, mirror motion, fanning of toes with neutral response of the great toe, reduced reflexes, high arches and extraocular palsies. Those findings which correlate best with numbers of other findings were: reduced reflexes, hypermetria, intention tremor, sensory changes, nystagmus and extensor plantar responses. 3. (3) Neurological and musculo-skeletal defects are evaluated by a system of weighted criteria based on the literature. The incidence of significant numbers of these stigmata among persons qualifying for evaluation was 28 in 112 or 25%, with an equal distribution between sexes. Presence of significant numbers of stigmata in these persons is interpreted as a genetic potentiality for development of heredo-degenerative disease. In some cases, findings may represent a single dose effect of a lone recessive gene. 4. (4) Exogenous factors, representing physiological stresses, exert a phenotypic influence and are often found to precipitate onset of Friedreich's ataxia. 5. (5) It is suggested that variations among findings in Friedreich's ataxia result from the effect of differences in the fundamental constitutions of the individuals involved. These separately inherited genes, acting as genetic modifiers on the gene(s) primarily responsible for the clinical disease, may produce their own manifestations which, when present, not only constitute a part of the clinicopathologic state, but also reflect in part the genetic milieu wherein the ataxia-bearing gene(s) work their effect.

Nerve conduction studies were performed on the median, ulnar, and lateral popliteal nerves of 8 patients with Friedreich's ataxia. There was significant slowing of motor conduction, and impairment of sensory conduction. Sural nerve biopsies were performed on 5 of the patients. Histological examination demonstrated a reduction in the numbers of myelinated fibres, particularly those of large diameter. Teased single fibres showed no evidence of active degeneration, but a few fibres were seen to have regenerated after segmental demyelination. A striking feature of the myelinated fibres of two of the nerves was a significant reduction in internodal lengths. Quantitative electron-microscopic studies of the unmyelinated fibres demonstrated that they were present in normal numbers and that their axons were of normal diameter.

The authors describe the results of a genetic and epidemiological investigation of pigmentary degeneration of the retina and allied diseases (Bardet-Biedl syndrome, congenital tapeto-retinal amaurosis of Leber, retinitis punctata albescens, fundus albipunctatus cum hemeralopia, etc.) in Switzerland. About 90% of all cases of pigmentary degeneration of the retina are transmitted by the recessive mode, and 9% by the dominant mode of inheritance. One family alone presents a recessive sex-linked transmission of retinitis pigmentosa. In this family, the female heterozygotes show the typical tapetal reflex as described by Falls and Cotterman in 1948. The frequency of pigmentary degeneration of the retina in Switzerland can be estimated at 1 : 7000, the gene frequency at 1 : 84, and the frequency of heterozygotes at 1 : 42. About 10% of all cases are offspring of marriages between first cousins. There are some isolates in Switzerland with a high incidence of retinitis pigmentosa. One isolate, in particular, in the Canton of Valais, allowed us to demonstrate a phenotypical alternation between different types of pigmentary degeneration within several branches of a large family originating from a common ancestor. Among the hereditary affections associated with tapeto-retinal degenerations, congenital deafness is the most frequent (being associated with retinitis pigmentosa in 13%). The Bardet-Biedl syndrome was observed in 4 patients out of a population of 700,000 inhabitants (1 : 175,000). Finally, the authors stress the importance of an investigation of isolates, since they permit a more satisfactory classification of abiotrophic diseases.

Limited data exist on the spectrum of heredoataxias in Greece, including the prevalence and phenotype of Friedreich's ataxia (FRDA) and the prevalence and subtypes of dominant spinocerebellar ataxias (SCAs). We analyzed clinically and investigated genetically for FRDA and triplet-repeat expansion SCAs a consecutive series of 186 patients with suspected heredoataxia referred to Athens over 18 years. For prevalence estimates we included patients with molecular diagnosis from Cyprus that were absent from the Athens cohort. The minimum prevalence of FRDA was ~ 0.9/100,000, with clusters of high prevalence in Aegean islands. FRDA was diagnosed in 73 probands. The genotypic and phenotypic spectrum of FRDA was similar to other populations, with one patient compound heterozygote for a known point mutation in FXN (Asn146Lys). Undiagnosed recessive ataxias included FRDA-like and spastic ataxias. The minimum prevalence of dominant SCAs was ~ 0.7/100,000. SCA1 (4), SCA7 (4), SCA2, SCA6, and SCA17 (1 each) probands were identified. A molecular diagnosis was reached in 31% of dominant cases. Undiagnosed dominant patients included a majority of type III autosomal dominant cerebellar ataxias. FRDA is the commonest heredoataxia in the Greek population with prevalence towards the lower end of other European populations. Dominant SCAs are almost as prevalent. SCA1, SCA2, SCA6, SCA7 and SCA17 patients complete the spectrum of cases with a specific molecular diagnosis.

Previous studies in our laboratory had demonstrated alterations in the physical state of membrane proteins in erythrocytes in Huntington's disease. In order to assess the specificity of our findings, the results of electron spin resonance studies of protein and lipid components, scanning electron-microscopic studies, enzymatic analyses of membrane-bound sodium plus potassium stimulated, magnesium-dependent adenosine triphosphatase and protein kinase, and cell deformability studies of erythrocyte membranes have been performed in the neurological disorders, Huntington's disease, Friedreich's ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, and myotonic and Duchenne muscular dystrophy. Comparison of the results revealed that alterations in the biophysical and biochemical states of erythrocyte membranes in each disorder are specific to the particular disease state with the exception of those in Friedreich's ataxia and Alzheimer's disease. In the latter instance, the clinical and pathological alterations suggest that these two diseases have different primary defects. Our studies suggest that the molecular basis of each disease is different. In addition, the results suggest that biophysical and biochemical investigations of extraneural tissue in Huntington's disease and other neurological disordes have the potential of clarifying the molecular mechanisms by which these diseases arise.

Pattern-reversal visual evoked potentials (VEPs), recorded in 15 visually asymptomatic patients fulfilling the clinical and electrophysiological criteria of Charcot-Marie-Tooth disease (CMTD), were abnormal in 5 and possibly abnormal in another 3. Five patients showed a prolongation of P 100 latency, one a reduction of amplitude and one a possibly abnormal “scotomatous” waveform. In 9 cases abnormalities were detected on neuro-ophthalmological examination. These were poorly correlated with VEP abnormalities, except for patients with 2 or more clinical eye signs. Relative central scotomata were found in the patient with an abnormal waveform. VEP abnormalities, where present, were usually fairly comparable in the 2 eyes. In comparison with a group of Friedreich's ataxia cases there was a lower overall incidence of VEP abnormalities in CMTD, but little to suggest a qualitative difference in the nature of the visual pathway pathology. All 4 patients with unequivocally abnormal VEPs had experienced atypical symptoms suggestive of CNS involvement. In none of these was it possible to sustain an alternative diagnosis. It is concluded that a minor degree of visual pathway involvement may be present in many CMTD cases, in spite of the fact that optic atrophy is only rarely reported, and that the VEP latency may reflect the degree to which other parts of the CNS are involved.

The CSF findings in hereditary ataxias and allied disorders have hitherto mostly been reported as normal if one excludes Refsum's syndrome. The CSF-protein patterns found on isoelectric focusing and quantitative paper electrophoresis were studied in 12 patients with hereditary ataxias and hereditary spastic paraplegia. Using a recently-developed technique of isoelectric focusing of CSF-proteins in flat beds of polyacrylamide gel, the authors could show abnormal CSF-protein patterns in all but 1 of the present cases. The aberrant CSF-protein patterns found showed differences between the syndromes studied. Two unique patterns with conspicuous fractions in the acid range were observed in patients with Marie-Sanger-Brown's ataxia (mother and daughter) and Holmes' ataxia. A third CSF-protein pattern was found in a sibship with Friedreich's ataxia including a double fraction in the acid region (pI 5.9–6.1) in all 4 subjects and a highly alkaline fraction (HAF) with pI about 9.3, in 3 of them. Similar acid fractions (pI 5.9–6.1) were also detected in 3 of 4 patients with hereditary spastic paraplegia, a brother and sister showing a very similar CSF-protein pattern. Double fractions with pI 5.9–6.1 and/or HAF may also occur in other neurological diseases, mostly, however, associated with other distinctive features of their CSF-protein patterns. A possibility in the future of distinguishing hereditary CNS-diseases by examination of the CSF-protein pattern is suggested.

A study of 7 cases of Charcot-Marie-Tooth disease associated with a dyskinesia resembling benign essential tremor is presented. In 4 patients, the family history strongly suggested an autosomal mode of transmission, 2 cases were sporadic without an established genetic pattern and 1 was probably recessive. The distal parts of the upper and lower limbs showed imparied muscle strength with slight or no atrophy in 4 patients and conspicuous weakness and wasting in another 2. One patient was a chairbound. Although essential tremor and the tremor seen in these patients are clinically (phenotypically) similar it seems possible that they result from two different genotypes. Further, it seems that cases with Charcot-Marie-Tooth disease and "essential tremor" are not the result of the association of two separate dominant characteristics which are generally inherited as mendelian dominant traits. In spite of the diversity of the clinical manifestations of the peripheral neuropathy, the semiologically different types of essential tremor and the electrophysiological data, it is concluded that patients who develop a peripheral neuropathy on a familial basis and who exhibit clinical features of similar character, suffer from a common type of pathological disorder. Stress is laid upon the fact that Friedreich's ataxia and Charcot-Marie-Tooth disease share many clinical features. It is suggested that when Friedreich's ataxia and Charcot-Marie-Tooth disease seem to be present in the same individual and/or alternate in different members of the same family, the process is likely to be one of Charcot-Marie-Tooth disease. The value of the type of inheritance, natural history, clinical examination and electrophysiological data in differentiating Charcot-Marie-Tooth disease (with or without essential tremor) from other degenerative disorders is analyzed.

A report is given of an association of dyssynergia cerebellaris myoclonica associated with Friedreich's ataxia and mitochondrial myopathy in 2 patients. They had suffered from gradually increasing bursts of myoclonus since the wage of 14 and childhood, respectively. The other striking clinical features included generalized convulsions, mental deterioration, intention tremor, ataxia, muscular atrophy and deformity of feet. Muscle biopsies revealed ragged-red fibres in both cases. On electron microscopy these fibres contained subsarcolemnal aggregations of abundant abnormal mitochondria with proliferation of inner membranes or paracrystalline inclusions. One of these patients showed elevated blood lactate and pyruvate with an increased lactate/pyruvate ration, apparently of primary origin. These 2 cases resemble those reported briefly by Tsairis et al. (1974). An association of dyssynergia cerebellaris myoclonica associated with Friedreich's ataxia and mitochondrial myopathy in these 2 patients is unlikely to be coincidental but may represent one nosological entity. This myoclonus epilepsy syndrome associated with ragged-red fibres is compared with other possibly related mitochondrial encephalomyopathies.

A 31/2-year-old girl presented with frequent falls. She had an unsteady gait, delayed behavioural development absent tendon reflexes and in the legs decreased strength tone and equivocal plantar responses. She then developed ataxia, nystagmus, choreoathetosis, cranial nerve palsies, diminished strength and tone in the arms, sensory deficit in the limbs and autonomic nervous system dysfunction. She became progressively less responsive and succumbed at the age of 63/4 years. Examination of the central, peripheral and autonomic nervous system showed ubiquitous neuronal intranuclear hyaline inclusions and neuronal loss in several sites.

The mean percentage of linoleate to total fatty acids in phosphatidylcholine and lysophosphatidylcholine fractions of serum phospholipids from neuropathic patients with HMN (hereditary motor neuropathy, also called distal type of progressive muscular atrophy), HMSN-I and HMSN-II (two types of peroneal muscular atrophy), and FA (Friedreich's ataxia) was reduced by approximately 10--20% (P less than 0.001). On the other hand, the mean percentage of nervonic acid in sphingomyelin was elevated by 9--20%. No significant difference was observed in phosphatidylethanolamine between neuropathic patients and control subjects. The mean concentration of phosphatidylcholine and sphingomyelin was also significantly reduced in neuropathic patients (except in HMN and HMSN-III). A significant correlation between endogenous 2-linoleoyl-sn-glycerol-3-phosphocholine and cholesteryl linoleate synthesis in vitro suggests that the decreased activity of phosphatidylcholine acyltransferase (EC 2.3.1.43; LCAT) in neuropathic patients is influenced by the fatty acid composition of their lipoprotein substrate. Furthermore, the reduction of phosphatidylcholine and of cholesteryl linoleate synthesis in vitro in neuropathic patients was affected by age and sex. It is unlikely that the reduced linoleate level in serum phosphatidylcholine for most, possibly all, of the inherited neuropathies studied here reflects a specific biochemical disorder. Possibly it reflects a more generalized biochemical alteration common to inherited neuropathy. One possibility is that biosynthesis of new membrane in axonal regeneration, segmental remyelination and Schwann cell hyperplasia may reduce the serum linoleate pool.

We describe 2 clinicopathological cases of non-hereditary multiple telangiectasias of the nervous system. In the first case, the general course of the disease was characterized by spells over a period of 7 years and the major lesions successively involved cranial nerves, spinal cord and brain. Neuropathological examination showed both ischemic and hemorrhagic changes. Systematized degenerative changes were found and were similar to those observed in spinocerebellar heredodegenerations (Friedreich's ataxia). In the second case, the 3 years of evolution were characterized by spells of the encephalitic type only. A review of the literature indicates the rarity of this kind of disease, the usual localization of capillary malformations and the clinical polymorphism (epilepsy, strokes, multifocal syndromes masquerading as multiple sclerosis). The pathogenesis of pathological changes is discussed.

Sensory conduction velocity in the sural nerve (S-SCV) was measured in 10 cases of motor neuropathy, 35 cases of neuropathy with sensory symptoms and in 16 cases of subacute myelo-optico-neuropathy (SMON). In 2 cases of Friedreich's ataxis and 1 case of Charcot-Marie-Tooth disease, evoked sensory action potentials could not be recorded or S-SCV was reduced though sensation was normal; this finding suggests latent or subclinical involvement of the sensory nerves in these cases. In the other 7 cases of motor neuropathy, S-SCV was normal. In the cases of polyneuropathy with sensory symptoms, S-SCV was abnormal in 5 of 11 cases with subjective sensory complaints and in 6 of 10 cases with mild impairment of superficial sensation. No nerve potential could be evoked in 2 cases with severe impairment of superficial sensation, in 7 of 8 cases with mild impairment of deep sensation, and in 4 cases with severe impairment of deep sensation. These data suggest that S-SCV may be useful in confirming the extent of sensory nerve involvement in mildly-affected cases. In the case of SMON, though the S-SCVs could generally be correlated with the severity of the sensory symptoms, the degree of decrease in S-SCV was far less than in the cases of sensory neuropathy with similar symptoms. This discrepancy suggests that myelopathy in addition to peripheral neuropathy plays an important part in causing the sensory symptoms of SMON.