Late-onset Friedreich's Ataxia Research Articles

An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease

Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77–0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients’ group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.

Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics.

Friedreich's ataxia (FRDA) is a common cause of autosomal recessive cerebellar ataxia. The phenotype is dependent on the repeat size and duration of the disease. We aimed to study the clinical, electrophysiologic, and radiologic profiles in a large Indian cohort of genetically proven FRDA patients. A retrospective cross-sectional, descriptive analysis of genetically proven FRDA patients was performed. A detailed review of all the hospital case records was done to analyze the clinical, radiologic, and electrophysiologic details. A total of 100 FRDA patients were selected for the analysis. Eighty-six patients had an age at onset between 5 and 25 years. Eight patients (8%) were classified as late-onset FRDA and six patients (6%) as early-onset FRDA. The median age at presentation was 19 years. The median age at onset was 14 years, and the median duration of illness was 4 years. All patients had gait ataxia as the initial symptom. Gait ataxia, loss of proprioception, and areflexia were seen in all patients. Dysarthria, nystagmus, amyotrophy, spasticity, extensor plantars, pes cavus, and scoliosis occurred in one-third of patients. Cardiomyopathy (18%) and diabetes (5%) were less common. Sensory polyneuropathy (87.5%) was the most common nerve conduction abnormality. Cortical somatosensory evoked responses were absent in all 43 tested patients (100%). Brainstem auditory evoked response test was done in 24 patients and it showed absent reactions in six patients (25%). Visual evoked potential was tested in 24 patients and it showed absent P100 responses in five patients (21%). Cerebellar and cord atrophy was seen on magnetic resonance imaging in 50% of patients. Most FRDA patients (86%) had an age at onset of less than 25 years, with typical symptoms of gait ataxia, areflexia, and loss of proprioception found in all patients. Dysarthria, nystagmus, amyotrophy, spasticity, extensor plantars, pes cavus, scoliosis, cardiomyopathy, and diabetes were not seen in all patients. Cerebellar atrophy can occur in FRDA patients. Knowledge regarding the clinical, radiologic, and electrophysiologic profile of FRDA will aid in proper phenotypic characterization.

Pseudodominance in Friedreich Ataxia-Impact of High Prevalence of Carriers and Intrafamilial Clinical Variation.

Friedreich ataxia (FA) is the most common form of autosomal recessive (AR) ataxia. It is a rare disease, but carriers are frequent (1/100). Pseudodominance in FA has seldomly been reported; it may pose additional challenges for diagnosis. A family with two consecutive generations affected by FA is described. The proband and two younger siblings had typical FA, characterized by infantile-onset ataxia, hyporeflexia, Babinski sign, cardiomyopathy, and loss of ambulation in the second decade of life. Another female sibling had delayed-onset (>25 years old), with mild cerebellar and sensitive ataxia since her mid-30s. Their father presented very late-onset FA (>40 years old), with sensitive axonal neuropathy. All five patients had biallelic (GAA)n expansion in FXN. The first three had larger expansions (>800 repeats), while the latter two had one shorter expanded allele (~90 repeats). Pseudodominant inheritance has been described in 13 neurological disorders. Seven are movement disorders, of which three were associated with high frequency of carriers (FA, Wilson's disease and PRKN-related parkinsonism). Clinicians should be aware of the possibility of pseudodominance when facing an apparent autosomal dominant pedigree, particularly in disorders with high frequency of carriers and variable expression. Otherwise, genetic diagnoses may be delayed.

Natural History of Friedreich Ataxia: Heterogeneity of Neurologic Progression and Consequences for Clinical Trial Design.

Background and ObjectivesThe understanding of the natural history of Friedreich ataxia (FRDA) has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this study was to acknowledge the broad genetic diversity of the population, especially for younger individuals, and to provide analyses stratified by age to guide population selection in future studies.MethodsBased on a large natural history study, the FRDA Clinical Outcome Measures study that at the current data cut enrolled 1,115 participants, followed up for 5,287 yearly visits, we present results from the modified FRDA Rating Scale and its subscores. The secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk, and the 9-hole peg test. Long-term progression was modeled using slope analyses within early-onset, typical-onset, intermediate-onset, and late-onset FRDA. To reflect recruitment in clinical trials, short-term changes were analyzed within age-based subpopulations. All analyses were stratified by ambulation status.ResultsLong-term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages at onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability subscore of the mFARS. The analyses of short-term changes showed slower progression with increasing population age due to decreasing genetic severity. Future clinical studies could reduce population diversity, interpatient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification.DiscussionThe understanding of the diversity within FRDA populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in FRDA.

Three Adult-Onset Autosomal Recessive Ataxias: What Adult Neurologists Need to Know.

In this review we seek to raise awareness of 3 autosomal recessive ataxias that look different clinically when presenting in adulthood rather than childhood. A study found a high allelic frequency for repeat expansions in the RFC1 gene, a cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, which presents exclusively in adults. This implies that autosomal recessive etiologies of adult-onset cerebellar ataxias may be more common than previously thought. Adult-onset cerebellar ataxias are commonly caused by mutations inherited in either an autosomal dominant or X-linked pattern, as most autosomal recessive mutations cause disease at earlier ages. However, some autosomal recessive etiologies such as late-onset Tay-Sachs disease, very late-onset Friedreich ataxia, and autosomal recessive spastic ataxia of Charlevoix-Saguenay emerge in adulthood, with age at presentation influencing the progression and clinical signs of the disease. This review will cover the genetics, clinical presentation, and necessary diagnostic steps required to identify 3 causes of autosomal recessive cerebellar ataxia that manifest differently in adults vs children.

Degenerative and acquired sporadic adult onset ataxia.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.

Nonataxia symptoms in Friedreich Ataxia: Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS).

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. 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. 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. 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.

Huntington's Disease, Huntington's Disease Look-Alikes‎, and Benign Hereditary Chorea: What's New?

The differential diagnosis of chorea syndromes is complex. It includes inherited forms, the most common of which is autosomal dominant Huntington's disease (HD). In addition, there are disorders mimicking HD, the so-called HD-like (HDL) syndromes. Here we review main clinical, genetic, and pathophysiological characteristics of HD and the rare HD phenocopies in order to familiarize clinicians with them. Molecular studies have shown that HD phenocopies account for about 1% of suspected HD cases, most commonly due to mutations in C9orf72 (also the main cause of frontotemporal dementia and amyotrophic lateral sclerosis syndromes), TATA box-binding protein (spinocerebellar ataxia type 17 [SCA17]/HDL4), and JPH3 (HDL2). Systematic screening studies also revealed mutations in PRNP (prion disease), VPS13A (chorea-acanthocytosis), ATXN8OS-ATXN8 (SCA8), and FXN (late-onset Friedreich's Ataxia) in single cases. Further differential diagnoses to consider in patients presenting with a clinical diagnosis consistent with HD, but without the HD expansion, include dentatorubral-pallidoluysian atrophy and benign hereditary chorea (TITF1), as well as the recently described form of ADCY5-associated neurodegeneration. Lastly, biallelic mutations in RNF216 and FRRS1L have recently been reported as autosomal recessive phenocopies of HD. There is a growing list of genes associated with chorea, yet a substantial percentage of patients remain undiagnosed. It is likely that more genes will be discovered in the future and that the clinical spectrum of the described disorders will broaden.

Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes.

Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25% of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17% (18/106) and cFDRA for 83% (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17%, p = 0.29) and cardiomyopathy (16.6 vs. 28.4%, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61%, p = 0.003, and pes cavus 22 vs.75%, p < 0.001) as were spasticity and sustained reflexes, found in 22% of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17% of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.

Delayed-onset Friedreich's ataxia revisited.

Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia. Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken. Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated. Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as "delayed-onset Friedreich's ataxia." As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.

Very late-onset Friedreich ataxia: later than life expectancy?

Friedreich ataxia (FA) is an autosomal-recessive hereditary ataxia with a prevalence of around 1 case per 30,000. It is a severely debilitating disease characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, muscular weakness and pyramidal signs, and is due to GAA triplet expansion in the frataxin (FXN) gene located on chromosome 9q13 [1]. Patients usually begin the disorder at puberty or before the age of 25 years in most studies, but rare cases of ‘Late-Onset Friedreich ataxia’ (LOFA) have been described. LOFA patients were recognized to have a median age of onset of 28.8 years (range of 25.5–48), have a milder phenotype and often retained lower limb reflexes [2, 3]. Very late–Onset Friedreich ataxia (VLOFA) has also been reported [4, 5], with the first manifestations appearing in the seventies. Here we report an 82-year-old lady who presented with balance difficulties that led to some loss of independence. Symptoms began at about age 80 with subsequent mild dysarthria. She denied any similar familial history, rending autosomal dominant disease unlikely. On examination, cognition was normal, but she had hypometric ocular saccades, dysarthria, generally brisk deep tendon reflexes except for bilateral absent ankle jerks and a bilateral Babinski sign. There was also reduced ability for rapid, alternating motor tasks. There was no loss of sensations, including proprioception. The patient also showed important gait ataxia. The Scale for the Assessment and Rating of Ataxia (SARA) was rated 15 (gait: 3; stance: 1; sitting: 1; speech disturbance: 2; finger chase: 1; nose-finger test: 2; fast altering hand movements: 2; heel-sheen slide: 3). There was no pes cavus, scoliosis, deafness or diabetes. The nerve conduction study was normal, including amplitude of the sural nerve action potentials. Cardiac echography and EKG were normal. Friedreich ataxia was considered as a diagnosis based on ataxia with a bilateral Babinski sign and absent Achilles reflexes and normal blood vitamin E levels with undetectable serum antinuclear auto-antibodies (against Hu, Yo, Ma2, CV2/CRMP5, Ri, Tr, and GAD). The diagnosis was confirmed when an unstable GAA triplet expansion was demonstrated on both alleles of the FXN gene, with 170 and 1,300 tri-nucleotides, respectively. The small GAA expansion probably explains why the patient developed FA in her eighties, as other studies suggest a correlation between the size of the expanded tri-nucleotide repeats and severity of the disease and an inverse correlation with the age of onset [6, 7]. To our knowledge (excluding one possible but not proven case) [8], this lady represents the highest age of onset for a diagnosed FA patient. Even though FA is typically encountered in young patients, this report confirms that it cannot be excluded based on the advanced age of the patient, and should remain a possible differential diagnosis of older patients with ataxia, along with other genetic causes, such as SCA6 [9].

Cognition in Late-Onset Friedreich Ataxia

Friedreich ataxia (FRDA) is the most common hereditary ataxia. Since the discovery of the genetic cause of this disease, the phenotypic spectrum seems to be wider, including late-onset forms such as late-onset Friedreich ataxia--LOFA (25-39 years at onset). The neuropathological and clinical patterns in patients with LOFA are similar to those in patients with typical FRDA, but LOFA patients tend to have an overall milder, slowly evolving disease. Given the lack of data about cognitive performance of LOFA, we aimed to investigate whether differences in age at disease onset may be related also to differences at a cognitive level. Twenty-nine typical FRDA and seven LOFA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. There were no significant differences in disease duration between the two groups of patients. Every patient group was matched in gender, age, years of education, and estimated IQ with a healthy-participant control group. Results indicate that both patient groups shared slowed motor processing speed and impaired conceptual thinking and verbal fluency. However, only typical FRDA patients showed a diminished cognitive processing speed and impaired visuoperceptive and visuoconstructive abilities. This pattern indicates that a later disease onset is associated to a milder cognitive impairment. Thus, our findings are in concordance with those related to clinical differences between typical FRDA and LOFA.

Reviewing the genetic causes of spastic-ataxias

Although the combined presence of ataxia and pyramidal features has a long differential, the presence of a true spastic-ataxia as the predominant clinical syndrome has a rather limited differential diagnosis. Autosomal recessive ataxia of Charlevoix-Saguenay, late-onset Friedreich ataxia, and hereditary spastic paraplegia type 7 are examples of genetic diseases with such a prominent spastic-ataxic syndrome as the clinical hallmark. We review the various causes of spastic-ataxic syndromes with a focus on the genetic disorders, and provide a clinical framework, based on age at onset, mode of inheritance, and additional clinical features and neuroimaging signs, that could serve the diagnostic workup.

A Combined Nucleic Acid and Protein Analysis in Friedreich Ataxia: Implications for Diagnosis, Pathogenesis and Clinical Trial Design

BackgroundFriedreich's ataxia (FRDA) is the most common hereditary ataxia among caucasians. The molecular defect in FRDA is the trinucleotide GAA expansion in the first intron of the FXN gene, which encodes frataxin. No studies have yet reported frataxin protein and mRNA levels in a large cohort of FRDA patients, carriers and controls.Methodology/Principal FindingsWe enrolled 24 patients with classic FRDA phenotype (cFA), 6 late onset FRDA (LOFA), all homozygous for GAA expansion, 5 pFA cases who harbored the GAA expansion in compound heterozygosis with FXN point mutations (namely, p.I154F, c.482+3delA, p.R165P), 33 healthy expansion carriers, and 29 healthy controls. DNA was genotyped for GAA expansion, mRNA/FXN was quantified in real-time, and frataxin protein was measured using lateral-flow immunoassay in peripheral blood mononuclear cells (PBMCs). Mean residual levels of frataxin, compared to controls, were 35.8%, 65.6%, 33%, and 68.7% in cFA, LOFA, pFA and healthy carriers, respectively. Comparison of both cFA and pFA with controls resulted in 100% sensitivity and specificity, but there was overlap between LOFA, carriers and controls. Frataxin levels correlated inversely with GAA1 and GAA2 expansions, and directly with age at onset. Messenger RNA expression was reduced to 19.4% in cFA, 50.4% in LOFA, 52.7% in pFA, 53.0% in carriers, as compared to controls (p<0.0001). mRNA levels proved to be diagnostic when comparing cFA with controls resulting in 100% sensitivity and specificity. In cFA and LOFA patients mRNA levels correlated directly with protein levels and age at onset, and inversely with GAA1 and GAA2.Conclusion/SignificanceWe report the first explorative study on combined frataxin and mRNA levels in PBMCs from a cohort of FRDA patients, carriers and healthy individuals. Lateral-flow immunoassay differentiated cFA and pFA patients from controls, whereas determination of mRNA in q-PCR was sensitive and specific only in cFA.

Novel, complex interruptions of the GAA repeat in small, expanded alleles of two affected siblings with late‐onset Friedreich ataxia

Friedreich ataxia (FA) is an autosomal recessive disorder associated with expanded GAA repeats in intron 1 of the FRDA gene. Two siblings presented with a mild form of FA at >60 years of age. Both had a large expansion (>600 repeats) and a small expansion (120 repeats) by long-range PCR. Sequence analysis of the small allele revealed multiple, complex interruptions in the GAA repeat. These 2 patients presented later than predicted from their allele size alone, when compared with a large cohort of FA patients. Accounting for the interruptions in the GAA repeat, though, did not make the age of onset consistent with that noted in other patients. Three additional patients with late onset FA and small expanded alleles also exhibited interrupted GAA repeats that were not associated with inappropriately late onset. Our observations suggest that interrupted GAA repeats do not clearly impact the age of onset in FA.

Ataxie avec sensibilité au gluten, mythe ou réalité ?

Gluten ataxia refers to the association of idiopathic ataxia despite exhaustive investigations with gluten sensitivity defined by anti-gliadin antibodies (AGA) presence in blood. This is a controversial concept. We screened 33 patients, who were hospitalized in 2003 and had subacute or chronic ataxia for presence of circulating AGA. Twelve patients were positive and their clinical and biological features were studied. Among the twelve patients, we concluded that gluten ataxia was present in only eight, including one case of celiac disease. Among these eight patients, five had the usual features of gluten ataxia (progressive cerebellar ataxia affecting mainly lower limbs), but one patient presented unusual left cerebellar hemisyndrome and the two others displayed polyneuropathy with proprioceptive ataxia. Cerebellar atrophy was confirmed with magnetic resonance imaging in five cases and association with other antibodies was found in six cases. Among the four other patients positive for AGA, investigations revealed one case of multiple sclerosis, one case of late-onset Friedreich ataxia, one case of basilar tuberculous meningitis and one case of type 2 diabetes. Screening for AGA presence should be systematically performed at presentation of patients with unknown etiology ataxia; in the event AGA are present without any other etiology, treatment with gluten-free diet must be discussed. However, the responsibility of AGA in the pathogenesis of neurological signs is highly debatable and further experimental work is required. Two pathophysiological hypotheses are suggested: (1) overexpression of cerebellar epitopes, in case of primary cerebellar pathology, leading to excessive immune response directed against these epitopes; and (2) molecular mimicry with cross-reactivity of antigens usually directed against gliadin, but also recognizing Purkinje cells epitopes.

Late-Onset Friedreich Ataxia

Friedreich ataxia (FA), the most common hereditary ataxia, is caused by pathological expansion of GAA repeats in the first intron of the X25 gene on chromosome 9. Since the discovery of the gene, atypical features are increasingly recognized in individuals with FA, and up to 25% of patients with recessive or sporadic ataxia do not fulfill the Harding or Quebec Cooperative Study on Friedreich's Ataxia criteria for FA. Late-onset FA (LOFA) is defined as onset after age 25 years. To describe and further delineate the clinical and magnetic resonance imaging findings in patients with LOFA and to review the literature. Clinical evaluation and comparison of clinical data and investigations. Ataxia clinics at UCLA and Cedars-Sinai Medical Center. Thirteen patients with LOFA with 13 sex-matched and Inherited Ataxia Progression Scale-matched patients with typical FA. Gait and limb ataxias were seen in all the participants. Dysarthria, loss of vibration sense, and abnormal eye movements were also common in both groups. Patients with LOFA more often had lower limb spasticity (40% vs 0%; chi2 = 4.0; P = .04) and retained reflexes (46.1% vs 7.7%; chi2 = 3.46; P = .05). They had no complaint of sphincter disturbances, and there was no evidence of cardiomyopathy on echocardiograms (chi2 = 4.0; P = .04). Five of 9 patients with LOFA had cerebellar atrophy on neuroimaging. Patients with gait and limb ataxias, dysarthria, loss of vibration sense, and fixational instability after age 25 years should be considered for molecular testing for GAA expansion in the FA gene. In contrast to previous studies, cerebellar vermian atrophy is not an uncommon finding.

Very late‐onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type

Very late-onset Friedreich's ataxia (VLOFA) is characterized by symptomatic onset after 40 years of age and, usually, a benign phenotype. We describe a sporadic case with onset at 53 years of age and a novel VLOFA phenotype mimicking multiple system atrophy (MSA) of cerebellar type associated with minimal GAA1 expansion. We detected several atypical features for a diagnosis of MSA, which should alert to the possibility of an inherited ataxia.

Friedreich ataxia with minimal GAA expansion presenting as adult-onset spastic ataxia

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.

Hereditary Ataxias

Hereditary Ataxias