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ObjectiveThis review focuses on the possible association between restless legs syndrome (RLS) and movement disorders, including Parkinson disease (PD), other parkinsonian syndromes, essential tremor, choreic and dystonic syndromes, Tourette syndrome, and heredodegenerative ataxias.MethodsReview of PubMed from 1966 to September 2018 and identification of references of interest for the topic. A meta-analysis of eligible studies on the frequency of RLS in patients with PD and controls using Meta-DiSc1.1.1 software and using the PRISMA guidelines was performed.Results and conclusionsAlthough there are substantial clinical, neuroimaging, neuropathologic, and genetic differences between RLS and PD, many reports describe a higher than expected prevalence of RLS in patients with PD, when compared with the general population or with matched control groups; several studies have also suggested that RLS could be an early clinical feature of PD. RLS symptoms are frequent in multiple system atrophy, essential tremor, Tourette syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 as well. Finally, possible genetic links between PD and RLS (the presence of allele 2 of the complex microsatellite repeat Rep1 within the α-synuclein gene promoter) and between Tourette syndrome and RLS (several variants in the BTBD9 gene) have been reported in 2 case–control association studies, although these data, based on preliminary data with small sample sizes, need to be replicated in further studies.

OBJECTIVE: To provide a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms. METHODS: From the large database of the European Friedreich's Ataxia Consortium for Translational Studies, 650 patients with genetically confirmed FRDA were included. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Logistic regression modeling was used to identify predictors for the presence of the most common clinical features. RESULTS: The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems. CONCLUSIONS: This joint European effort demonstrates the multisystem nature of this neurodegenerative disease encompassing most the central nervous, neuromuscular, cardiologic, and sensory systems. A distinct and deeper knowledge of this rare and chronic disease is highly relevant for clinical practice and designs of clinical trials., SCOPUS: ar.j, info:eu-repo/semantics/published

A 16-year-old boy with hypertrophic cardiomyopathy, gait abnormalities, and balance problems was found to have Friedreich ataxia. Though Friedreich ataxia typically renders patients areflexic, this child had upper motor neuron findings of spasticity in both lower extremities, with crossed adductors, and 4+ deep tendon reflexes at the patella and Achilles bilaterally. This unusual presentation of an uncommon genetic disorder led to uncertainty of the patient's true diagnosis until genetic testing confirmed that he had 2 alleles with the Friedreich ataxia mutation.

Measurement and mapping of integrated activity across the length of motor and sensory systems (cortex to periphery) has value in a range of disorders from stroke to demyelination to traumatic injury. Examples include central motor conduction time using transcranial magnetic resonance imaging and somatosensory evoked responses. While clinical testing of conscious proprioception is part of the neurologic examination, objective testing of the proprioceptive pathways is challenging. Corticokinematic coherence (CKC) quantifies the coupling between oscillatory cortical activity, measured with EEG or magnetoencephalography (MEG), and limb kinematics (e.g., acceleration) during repetitive rhythmic voluntary or passive movements.1,2 CKC peaks at hand movement frequency (F0) and its first harmonic (F1). Besides finger movement, toe and ankle movements can also be assessed. CKC primarily reflects proprioceptive processing in the primary sensorimotor area (SM1)3 with an apparent latency of 50 to 100 milliseconds. There seems to be adequate session-to-session reproducibility.1 Movement rate has no effect on the coherence levels and the location of coherent sources.4 A stronger CKC at F1 in the dominant leg is noted in older compared with younger individuals and is associated with worse postural balance.5 Such a change may reflect inefficient and thus overcompensation of cortical processing of the proprioceptive afference or functional deficits in the peripheral proprioceptors and spinal circuits.5 The signal can be elicited even in neonates.6

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently.1–5 Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia.6–10 Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection.10–12 This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.

Objectives: We sought to document the prevalence and nature of sleep-disordered breathing (SDB) in individuals with Friedreich ataxia (FRDA) as well as establish the relationship, if any, between SDB and clinical parameters of FRDA. Methods: Eighty-two individuals with FRDA were administered the Epworth Sleepiness Scale on an annual basis for up to 3 years. Individuals were referred for a sleep study if they had an Epworth Sleepiness Scale score >8 or had clinical symptoms suggestive of SDB. Results: From this cohort, 21 individuals underwent a sleep study and 17 were diagnosed with obstructive sleep apnea syndrome, giving a minimum prevalence of 21%, which is greater than that found in the general population (3%–7%). Moreover, the presence of obstructive sleep apnea was significantly correlated with the duration of disease and clinical severity of FRDA. Conclusion: It is recommended that individuals with FRDA undergo regular screening for obstructive sleep apnea to identify the need for a sleep study and subsequent treatment if SDB is diagnosed.

Objective: To validate, examine the internal validity, and adapt to children the electronic version of the composite cerebellar functional severity (CCFS) score. Methods: In this multicenter study, we compared the validated manual device with the new electronic version (n = 46) and analyzed its kinetics in 146 patients with Friedreich ataxia through the EFACTS (European Friedreich9s Ataxia Consortium for Translational Studies) network, 77 patients with spinocerebellar ataxia, and 48 controls. We validated the CCFS in cerebellar ataxias in healthy children (n = 120) and children with Friedreich ataxia through the EFACTS network (n = 33). Results: We showed that the electronic CCFS is a reliable replacement for the manual version (intraclass correlation coefficient: 0.98 [0.97–0.99]), and that the electronic CCFS is consistent when performed several times (0.92 [0.84–0.97]). Analysis of kinetics data showed an acceleration and irregularity that is not relevant compared with total speed. The CCFS was tested after modification in a population of patients with Friedreich ataxia between 8 and 19 years old, and showed similar values as adult patients with Friedreich ataxia (1.203 ± 0.125 vs 1.228 ± 0.167) and significantly higher values than controls of the same age (0.863 ± 0.042). Conclusions: The electronic CCFS is a quantified measurement of cerebellar ataxia independent of age, usable in individuals aged from 7 to 80 years. The automated nature of the electronic test device makes it reproducible between operators and centers, as well as easy to use.

Objective: To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics. Methods: The authors assessed the properties of a candidate clinical outcome measure, the Friedreich Ataxia Rating Scale (FARS), and simple performance measures (9-hole peg test, the timed 25-foot walk, PATA test, and low-contrast letter acuity) in 155 patients with FA from six institutions, and correlated the scores with disease duration, functional disability, activity of daily living scores, age, and shorter GAA repeat length to assess whether these measures capture the severity of neurologic dysfunction in FA. Results: Scores for the FARS and performance measures correlated significantly with functional disability, activities of daily living scores, and disease duration, showing that these measures meet essential criteria for construct validity for measuring the progressive nature of FA. In addition, the FARS and transformed performance measures scores were predicted by age and shorter GAA repeat length in linear regression models accounting for sex and testing site. Correlations between performance measures were moderate in magnitude, suggesting that each test captures separate yet related dimensions of neurologic function in FA and that a composite measure might better predict disease status. Composite measures created using cohort means and standard deviations predicted disease status better than or equal to single performance measures or examination-based measures. Conclusions: The Friedreich Ataxia Rating Scale, performance measures, and performance measure composites provide valid assessments of disease progression in Friedreich ataxia.

The authors carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients with Friedreich ataxia. They found significant reductions of interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group, with no improvement in other heart ultrasound measures or neurologic condition. The absolute cardiac changes were modest, but the findings suggest that larger trials should assess whether idebenone reduces ventricular hypertrophy in patients with Friedreich ataxia.

Objective: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich9s ataxia (FA) among a large panel of ataxia families. Background: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. Methods: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. Results: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. Conclusions: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

To explore the clinical heterogeneity associated with the Friedreich's ataxia (FRDA) expanded repeat and provide preliminary guidance for future gene testing in patients suspected of having FRDA, we tested patients with typical FRDA (group I), late-onset FRDA or FRDA with retained (group II), as well as those with early onset "non-Friedreich's" recessive or sporadic ataxia (group III). Eighty-seven percent of families in group I tested positive for the FRDA triplet repeat expansion. Thirty-six percent of families in group II demonstrated the FRDA expansion. Only one of 11 patients in group III had the FRDA expansion. Clinical criteria did not clearly distinguish between expansion-positive and expansion-negative individuals in group I and II. Minimal criteria that were present in all the patients who tested positive were recessive or sporadic inheritance, progressive caudal-rostral gait and limb ataxia, and at least one of the following: dysarthria, Babinski sign, or cardiomyopathy. This study confirms recent findings that some patients in group II can carry the FRDA mutation. However, we did not observe the FRDA expansion in 64% of group II families or in 13% of families with typical FRDA (group I), suggesting other genetic or environmental causes for their ataxia.

Most patients with Friedreich's ataxia (FRDA) carry expanded GAA repeats in both homologues of the frataxin gene on chromosome 9. We determined the size of the GAA repeats in autopsied samples from the CNS of six FRDA patients. We observed heterogeneity of repeat sizes in different CNS regions, indicative of extensive mitotic instability. Samples from the same CNS subdivision (e.g., cortex, thalamus) contained a similar mixture of alleles, suggesting that the pattern of repeat size mosaicism reflects the developmental history of each sample. Regional differences in repeat size could not account for the characteristic distribution of pathology in FRDA, which appears instead to be related to the pattern of frataxin expression.

Article abstract Increased generation of reactive oxygen species may underlie the pathophysiology of Friedreich ataxia (FRDA). The authors measured concentrations of 8-hydroxy-2’-deoxyguanosine (8OH2’dG), a marker of oxidative DNA damage, in urine and of dihydroxybenzoic acid (DHBA), a marker of hydroxyl radical attack, in plasma of 33 patients with FRDA. They found a 2.6-fold increase in normalized urinary 8OH2’dG but no change in plasma DHBA as compared with controls. Oral treatment with 5 mg/kg/day of the antioxidant idebenone for 8 weeks significantly decreased urinary 8OH2’dG concentrations, indicating that 8OH2’dG may be useful in monitoring therapeutic interventions in patients with FRDA.–1721

Measuring the severity of neurologic dysfunction in patients with inherited ataxias, including Friedreich ataxia (FA), is difficult because of the variable rate of progression, the variable age at onset and the variety of neural systems that may be affected. The authors discuss the problems related to rating scales in the ataxias, report a neurologic rating scale for FA, and demonstrate acceptable interrater reliability of the instrument.

More than 95% of patients with Friedreich ataxia (FA) are homozygous for GAA trinucleotide repeat expansions within intron 1 of the FRDA gene located on chromosome 9q13.1 A clear relation between GAA expansion size and phenotype variability has been found, and the size of the smaller GAA expansion (GAA1 allele) is the major determining factor for the variability in age at onset and rate of disease progression.2-7⇓⇓⇓⇓⇓ Conversely, the role of the larger GAA expansion (GAA2 allele) in age at onset has not been well established. We have assessed the predictive value of GAA1 and GAA2 sizes in regard to age at onset of the disease. We selected a group of 40 patients homozygous for GAA expansion on the first intron of the FRDA gene, which was determined as described previously.1 Age at onset was defined as the age at which the first neurologic symptom was …

The observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. The authors found allele sizes within the proposed pathogenic range in three patients with ataxia of unknown etiology, in two individuals from pedigrees with either SCA2 or Friedreich's ataxia, and in two patients with Alzheimer's disease. Sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold is determined.

Friedreich’s ataxia (FA) is the most common inherited ataxia.1 It is autosomal recessive and manifests with early onset limb and gait ataxia. Associated features are absent reflexes, extensor plantar responses, pyramidal weakness, dysarthria, vibration and proprioceptive loss, and electrophysiologic evidence of an axonal sensory neuropathy. However, there can be considerable phenotypic variation in up to 25% of all cases,1 such as late onset (LOFA; 25 to 39 years) or very late onset (VLOFA; ≥40 years) ataxia, retained reflexes, and slow progression. We report a man with pathologic GAA expansions in both alleles of the frataxin gene who had the unusual combination of spastic tetraparesis without clinical evidence of cerebellar ataxia or sensory neuropathy and a very delayed age (49 years) at symptom onset. A 51-year-old man presented with a 11/2-year history of lower limb spasticity. There were no sensory, sphincter, or visual disturbances and no history of …

Article abstract The GAA triplet repeat expansion that causes Friedreich ataxia is found only in individuals of European, North African, Middle Eastern, or Indian origin (Indo-European and Afro-Asiatic speakers). Analysis of normal alleles of the GAA repeat and of closely linked markers suggests that expansions arose through a unique two-step process. A major implication of these findings is that Friedreich ataxia may not exist among sub-Saharan Africans, Amerindians, and people from China, Japan, and Southeast Asia.

An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.

Friedreich ataxia (FRDA) is the most common genetic cause of ataxia affecting approximately 1:30,000 people.1 Symptoms that affect mobility include ataxia, spasticity, and peripheral neuropathy. A variety of short walk tests and endurance tests are used as the basis of ambulation assessment in neurologic disease.2 Recently developed microprocessor-based accelerometers can accurately quantify activity in a community setting. These devices are the gold standard against which to measure other ambulatory measures.2 We compared a number of clinical measures of ambulation with community activity as measured by an accelerometer in a group of individuals with FRDA. The study was approved by the Southern Health Research Ethics Committee. We recruited attendees at a multidisciplinary FRDA clinic by invitation. All participants were homozygous for an expanded GAA repeat within the first intron of the FXN gene. The following tests were administered according to published instructions: the 25-foot walk test (25FWT),3 the timed up and go (TUG),4 the 6-minute timed walk (6MTW),5 and …

Molecular analysis of spinocerebellar ataxias revealed a pathologic GAA expansion in the gene encoding frataxin in six adult patients from three families. These patients, carrying expanded alleles in the low-range size, had an exceptionally late onset and lacked cardiomyopathy, pointing to phenotypic variability of Friedreich's ataxia. Both mitotic and gametic instability of the expanded triplet repeat were present in these families.

Article abstract-Lower limb areflexia is generally regarded as an essential criterion for the diagnosis of Friedreich's ataxia (FRDA). We describe a family with a recessive form of early-onset ataxia in which one member had a phenotype typical of FRDA whereas another, with retained tendon reflexes in the lower limbs, did not have electrophysiologic evidence of the usual severe afferent axonal neuropathy of FRDA. In contrast, somatosensory evoked potentials, eyemovement recordings, and MRI of the head and cervical cord provided results highly suggestive of FRDA in both patients. We performed genetic linkage analysis in this family, using markers tightly linked to the FRDA locus on chromosome 9. Inheritance of identical paternal and maternal genotypes by the affected members, but not by their unaffected siblings, provided supporting evidence that this disorder may result from mutation within the FRDA gene or is tightly linked to the investigated loci on chromosome 9.NEUROLOGY 1996;46: 118-121

The treatment of the hereditary ataxias remains challenging and difficult. Harding, in her book, The Hereditary Ataxias and Spastic Paraplegias ,1 quotes Whyte (1898): “Almost all writers on this part of the subject speak in most hopeless tone”; and she comments that very little has changed since then. Negative or, at best, conflicting results of previous trials with phosphatidylcholine, thyrotropin-releasing hormone, 5-hydroxytryptophan, amantadine, and buspirone have justified this pessimism. Recently, cautious optimism has been raised by studies of idebenone in Friedreich’s ataxia (FRDA). FRDA is the most common hereditary ataxia in Western countries. It is an autosomal recessive disorder characterized by progressive ataxia with onset usually around puberty, even though later-onset forms have been described. The disease course is relentlessly progressive, and most patients become wheelchair bound in their twenties. Cardiomyopathy is frequent and often symptomatic. Abnormal EKG occur in about 80% of the patients. Arrhythmias are frequent. Atrial fibrillation is particularly …

Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, the disease locus (FRDA) of which has been assigned to 9q13-q21.1 by genetic linkage analysis in affected families. We report two large inbred Tunisian families with FA manifestations that did not show the expected linkage. The disease locus could be excluded from a large (12 cMO) region around FRDA. This is the first report providing evidence for nonallelic genetic heterogeneity for the FA clinical phenotype. On subsequent analysis, all patients had very low levels of serum vitamin E whereas the parents and healthy sibs had normal vitamin E levels. This establishes that the selective vitamin E deficiency with normal fat absorption is an autosomal recessive trait, which is associated in the two families reported here with the FA phenotype.

We describe two sisters with early onset gait ataxia, rapid disease progression, absent or very mild dysarthria and upper limb dysmetria, retained knee jerks in one, slight to moderate peripheral nerve involvement, and diabetes. Molecular analysis showed that they are compound heterozygotes for GAA expansion and a novel exon 5a missense mutation (R165P). This mutation appears to be associated with an atypical but not milder Friedreich ataxia phenotype.

In Friedreich's ataxia, the muscle stretch reflexes are absent or hypoactive in the upper and lower extremities because of pathologic involvement of the dorsal root ganglion cells. Paradoxically, the masseter reflex remains unaffected and may even be hyperactive in some cases. The masseter reflex is hypothesized as unique among stretch reflexes in that its afferent nerve cell body (the mesencephalic nucleus) is located intra-axially within the brainstem rather than in the craniospinal ganglia, where the afferent nerve cell bodies subserving the other stretch reflexes are located. This study supported this hypothesis by demonstrating that the masseter reflex is (1) usually absent in patients who are areflexic as a result of primary disorders of peripheral nerve axons or myelin, and (2) preserved in other disorders that primarily involve the dorsal root ganglion cells.

From early childhood, eight patients in a kindred had paroxysmal bouts of ataxia, dysarthria, and nystagmus. The disorder was inherited as an autosomal dominant. Attacks occurred weekly and lasted 1 to 6 hours; there were slight cerebellar signs between attacks. Although the etiology was not determined, a serendipitous trial of acetazolamide completely abolished attacks, and all patients have remained free of attacks for as long as 5 years.

We performed behavioral audiometric tests and brainstem auditory evoked potentials in four patients with Friedreich ataxia. None of the patients had symptomatic hearing difficulties. Results of the audiometric tests pointed to a disorder of the eighth nerve. In none of the patients could we elicit normal-appearing waves of the brainstem auditory evoked potentials. These abnormalities could be attributed to degeneration of spiral ganglion neurons. Our patients had useful and functional hearing despite very abnormal brainstem auditory evoked potentials.

Eye movement abnormalities were quantitatively assessed in four patients with clinically pure cerebellar atrophy (group A), six patients with brainstem plus cerebellar atrophy (group B), and five patients with Friedreich9s ataxia (group C). Twelve patients had one or more types of spontaneous nystagmus: eight gaze nystagmus, three rebound nystagmus, two positional nystagmus, and one vestibular nystagmus. Caloric-induced and rotatory-induced nystagmus was hyperactive in group A and diminished in group C. Group B had mixed responses. All patients demonstrated significant fixation instability and impaired smooth pursuit. There was dysmetria of voluntary saccades, with flutter and "rebound" saccades. Nine of 15 patients had significant slowing of induced saccades, including two patients in group A. It is concluded that quantitative vestibulo-ocular tests can be useful in classifying the cerebellar atrophy syndromes.

This investigation is the first population-based study of survival in Friedreich9s disease (FD). All cases of FD diagnosed between 1945 through 1984 among residents of a defined area of northwestern Italy were ascertained (N = 58). These patients were followed to death or to December 31, 1984 (whichever came first) to determine the patterns of survival. The 10-, 20-, and 30-year survival rates were respectively 96%, 80%, and 61%, suggesting a better prognosis than previously reported. Survival of FD patients was poorer than expected from the general population. Survival for males was poorer than for females even after adjustment for expected survival. Age of onset was not a significant prognostic factor. Survival for patients diagnosed in 1960 or later was better than for those diagnosed before 1960; however, the difference was not statistically significant.

Twenty-one patients with Friedreich ataxia were examined and found to have a brisk jaw reflex. This previously unreported clinical finding contrasts with the impairment of tendon reflexes in the limbs and should not rule out the diagnosis of Friedreich ataxia.

We studied five children with classic Friedreich9s ataxia, using an audiologic test battery to determine the primary site of auditory dysfunction. None of the children had any hearing complaints, and all were tested soon after onset of symptoms. The audiologic test battery consisted of brainstem auditory evoked potential test, tympanometry, and acoustic reflex measurements. The results indicated that the brainstem was the primary site of auditory dysfunction.

Mitochondrial and cytoplasmic malic isoenzymes were assayed fluorometrically in digitonin-fractionated fibroblasts from three patients with Friedreich9s ataxia (FA). Normal activity was found, failing to verify an earlier report of reduced fibroblast mitochondrial malic enzyme activity in FA. The previously reported disturbance in fibroblast mitochondrial malic enzyme may be an epiphenomenon in patients with the FA phenotype. Further studies are necessary to define the primary genetic defect in this inherited disorder.

Malic enzymes were studied in skeletal muscle from seven patients with Friedreich9s ataxia (FA) and nine controls. Muscle contained three different malic enzymes. There were two strictly NADP+-dependent enzymes, one in the cytosol and one in mitochondria. These two enzymes are not allosteric. In FA muscle, activity of the mitochondrial NADP+-linked enzyme was significantly low and the cytosol NADP+-linked enzyme was significantly increased. A third malic enzyme, NAD+(P)-dependent, was found in the mitochondrial fraction. That enzyme had allosteric properties, and its activity was about the same in FA and control muscle.

The activity of lipoamide dehydrogenase was abnormally heat-labile in homogenized platelets from seven patients with as recessive ataxia conforming to the syndrome of Friedreich ataxia or clinical variants. Taken together, the abnormality and previous findings of low activity and abnormal kinetic properties are compatible with a change in the conformation of the enzyme in these patients.

Muscle pyruvate dehydrogenase complex (PDHC) activity was studied in 70 patients with different neuromuscular disorders. Children had higher total PDHC and lipoamide dehydrogenase (LAD) activities than adults. There were no significant differences in muscle PDHC activity in patients with Friedreich ataxia, patients with other ataxias, or age-matched controls. Kinetic analysis of LAD showed no differences in Km for lipoamide between Friedreich ataxia patients and controls.

Human sural nerve fascicles from healthy volunteers and patients with inherited hypertrophic neuropathy (HMSN-I and HMSN-III, respectively) and with Friedreich ataxia (FA) were transplanted into nude and T-cell-suppressed mouse nerve to determine whether transplanted Schwann cells would express the histologic and myelination abnormalities characteristic of these disorders. Sections above, at, and below the transplant were evaluated by phase and transmission electronmicroscope (TEM) morphometric analysis at times up to 3 months after transplant. The characteristic structure of the human perineurium and of the onion-bulb formation was maintained, indicating that human Schwann and perineurial cells survive transplantation and express themselves. Myelination in human nerve xenografts was delayed as compared to distal mouse nerve myelination, which may reflect genetic characteristics, delayed vascularization, or physical size of the transplant. A variable number of fibers regrew outside the fascicle, creating a problem in data interpretation, since differences may exist in populations of fibers to be compared in control and disease xenografts and in xenografts and distal mouse nerve. Although xenograft myelination began earlier in controls than in HMSN-III, the difference in myelination at 3 months was not significantly different, nor was there a significant difference in onset or degree of myelination in controls, HMSN-I, and FA nerve xenografts at intervals up to 3 months. Lack of significant differences, especially for HMSN-III and control nerves, may be attributed to small numbers and insufficient time after transplant. A study of more xenografts, harvested after longer periods of time, will thus be needed before concluding that Schwann cells play no major role in the hypomyelination of HMSN-III. Present evidence does not favor a major role of Schwann cells in the segmental demyelination of HMSN I and FA.

Amantadine hydrochloride (AH) was orally administered to 16 patients with Friedreich's ataxia. We evaluated patient response with the functional ataxia scoring scale and calculated a total disability score. The mean percent improvement of the total disability score was 29.5%; for ambulatory patients alone it was 45.5%. No significant side effects were encountered. AH appears to be a safe and effective symptomatic treatment of Friedreich's ataxia.

Article abstract Physostigmine was given to 12 patients with various spinocerebellar degenerations, and neurologic examinations were recorded on video tapes and assessed on a semiquantitative scale. Forty minutes after a single dose, the scores improved by 35.7 ± 4.7 percent (means ± SEM). Eight patients were then studied over sequential 3-month periods by a randomized double-blind trial of physostigmine versus placebo. With physostigmine, scores were 33.9 ± 8.3 percent better than before treatment or with placebo. Further investigations of cholinergic drugs seem warranted in patients with these diseases.

In a previously unreported family with olivopontocerebellar atrophy, the kindred contained over 600 individuals in five generations. Of 83 offspring of affected individuals who are over 38.8 years of age (the mean age of the onset of disease in this family), 47 had ataxia; there was autosomal dominant transmission. Clinical findings included lower bulbar palsies, hyperreflexia, ataxia, incoordination, scanning and explosive speech, and, in some, slow motor-nerve conduction velocities. There was cortical and cerebellar atrophy of pontine nuclei, inferior olives, and XII nuclei, and loss of Purkinje cells in the cerebellum. Seventy-three individuals of the III and IV generations were typed for HLA histocompatibility antigens. A maximum lod score of 1.97 was found at male recombination fraction 0.18 and female recombination fraction 0.36. When the lod score values reported in other studies were combined with the values in this family, the maximum lod score was found to be 4.681 at a recombination frequency of 0.22.

To seek clues of metabolic derangements in neurornuscular diseases, the oxidations of pyruvate and succinate were studied in biopsied muscle. Pyruvate oxidation in 7 of 19 spinocerebellar degenerations (0.327± 0.040 prnoles × gm-1 noncollagenous protein content × hr-l) and 8 of 19 motor neuropathies (0.367± 0.029) was less than in controls with myopathic disease (1.096±0.91) or normal muscle (1.707± 0.181) (means± S.E.M.). The rates were independent of several physiologic variables, of the ratios of Type I::Type ll fibers in the specimens, and of the degree of neuropathy. Succinate was oxidized normally. Serially cultured fibroblasts from three patients from families with Friedreich9s ataxia also oxidized pyruvate more slowly than did controls (0.11± 0.03 vs. 0.30± 0.02 cpm × mcg-19 protein × hr-1. These two families with ataxia appear to have a genetic defect that affects pyruvate oxidation in some unknown way.

Reduced activities of lipoamide dehydrogenase (LAD) relative to cytochrome oxidase have been found in 12 of 26 patients with inherited ataxias. One of the 12 patients had adult-onset ataxia plus ragged-red muscle fibers. The other 11 had Friedreich syndrome or early-onset variants of this, as did 6 patients with normal enzyme activity. However, the 11 patients with reduced enzyme activity were clinically more homogeneous than the 6 with normal activity.

To see whether kinetic assays of lipoamide dehydrogenase could be used for carrier detection or preclinical diagnosis, Michaelis-Menten constants (KmL and KmH) for the enzyme were determined in platelets from families with a form of recessive Friedreich ataxia and low activities of the enzyme. The KmL of patients' enzyme was 132 +/- 5 microM lipoamide (mean +/- SEM) versus 56 +/- 9 microM for controls (p less than 0.001), and KmH for the patients was 421 +/- 19 microM versus 147 +/- 14 microM for the controls (p less than 0.001). The activity and Km values of one patient's enzyme were abnormal 1 year before neurologic signs appeared. The Km values for the enzymes of the six parents were also elevated (average KmL, 105 +/- 10 microM; average KmH, 378 +/- 47 microM, p less than 0.02). The maximal activities of the parents' enzymes, relative to a mitochondrial marker, were intermediate between the mean maximal control activity and the mean activity for the affected offspring. The data suggest that the abnormalities of lipoamide dehydrogenase are inherited in a recessive pattern in these families.