Different phenotypes of Friedreich's ataxia within one ‘pseudo‐dominant’ genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features

Illarioshkin, S. N.; Bagieva, G. kH.; Klyushnikov, S. A.; Ovchinnikov, Igor V.; Markova, E D; Ivanova-Smolenskaya, I. A.

doi:10.1046/j.1468-1331.2000.t01-1-00113.x

Cited by 13 publications

(15 citation statements)

References 20 publications

(38 reference statements)

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“…Two sibling pairs were treated as having the same triplet repeat length, a reasonable assumption based on reported families and our clinical experience. 17,19 We also obtained clinical and demographic data on patients. Control participants were selected from unaffected family members of patients and from employees of the University of Pennsylvania, and included 16 asymptomatic individuals, 2 of whom carried single expanded GAA repeats.…”

Section: Methodsmentioning

confidence: 99%

Near infrared muscle spectroscopy in patients with Friedreich's ataxia

et al. 2002

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Friedreich's ataxia is a progressive neurodegenerative disorder of the afferent cerebellar pathways associated with mitochondrial dysfunction at the cellular level. We have used noninvasive continuous near infrared muscle spectroscopy (NIRS) to investigate the delivery and utilization of oxygen in response to exercise in this disorder. Patients performed an incremental treadmill walking protocol in which levels of muscle deoxygenation or oxygenation were continuously measured in the medial calf muscle. The kinetics of recovery from exercise-induced deoxygenation, called the half-time of recovery (t(1/2)) were determined. The t(1/2) was prolonged in patients with Friedreich's ataxia compared with controls, and the degree of prolongation correlated with the length of the shorter GAA repeat, a genetic measure that correlates with the age of onset of disease. The t(1/2) also correlated inversely with patient age and with the maximum treadmill speed attained. Several patients also displayed features consistent with inadequate oxygen utilization by muscle. These results suggest that NIRS may be an effective tool for monitoring the biochemical and functional features of Friedreich's ataxia in parallel.

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Section: Methodsmentioning

confidence: 99%

Near infrared muscle spectroscopy in patients with Friedreich's ataxia

et al. 2002

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“…The knowledge that almost all cases of FRDA are caused by the same dynamic mutation provided another way to interpret phenotypic heterogeneity [ 16 ]. According to Illarioshkin et al, the cooccurrence of distinct clinical variants of the disorder is associated with different combinations of the mutated alleles inherited from parents [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Disease forms which do not meet these criteria are referred to as atypical Friedreich ataxia. Skeletal deformities, cardiomyopathy, and diabetes are the most common systemic conditions associated with FRDA [ 4 ]. The disease is characterized by clinical variability regarding the age at onset, the rate of progression, and presence/absence of areflexia, muscle weakness, or cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

“…The disease is characterized by clinical variability regarding the age at onset, the rate of progression, and presence/absence of areflexia, muscle weakness, or cardiomyopathy. However, the clinical manifestations tend to be similar in affected siblings in the same family [ 4 ], indicating the crucial role of genetic factors for phenotypic expression of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Kurt

Çevik

Aksoy

et al. 2016

Case Reports in Neurological Medicine

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Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient. EMG showed demyelinating sensorimotor polyneuropathy in another patient. The GAA expansion-negative 11-year-old female patient had mental-motor retardation, epilepsy, and ataxia. None of the patients had significant cardiac symptoms. Description of FRDA families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease. Furthermore, the genetic heterogeneity observed in this family draws attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before delivering comprehensive genetic counseling.

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“…Two main clinical consequences emerge from this genotypic variability: (1) inter and intra‐familial phenotypic heterogeneity, in that disease severity correlates partially and inversely with the size of expanded alleles (particularly the shorter one); 5 and (2) a high population frequency of carriers may lead to a pseudodominant transmission, challenging its diagnosis. While the clinical heterogeneity of FA is well known, descriptions of pseudodominance are scarce 6–11 …”

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confidence: 99%

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

Malaquias

Oliveira

Santos

et al. 2023

Movement Disord Clin Pract

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BackgroundBackground: 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. Cases Cases: 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). Literature Review Literature Review: 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). Conclusions Conclusions: 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.Friedreich ataxia (FA) (OMIM# 229300) is the commonest autosomal recessive (AR) ataxia in Caucasians, with an estimated prevalence of 0.5-1:100,000. 1,2 Most frequently, it is caused by a biallelic intronic (GAA) n expansion in FXN (OMIM Â 606829), resulting in decreased expression of frataxin, a protein involved in mitochondrial iron metabolism. 1 Typical FA starts before age 25, and involves the peripheral nervous system, posterior columns, cerebellum and pyramidal tracts. It is characterized by dysarthria, square wave jerks, muscle weakness, impaired proprioception and vibration, abolished deep tendon reflexes (DTR), Babinski sign and progressive gait and limb ataxia. 1 Non-neurological features include skeletal anomalies (scoliosis, pes cavus), neurosensorial deafness, hypertrophic cardiomyopathy, optic atrophy and diabetes. 1 Atypical FA is rare (about 15% of patients) and comprises late-onset FA (LOFA) and very LOFA (vLOFA), when starting after 25 and 40 years of age, respectively. These atypical forms are characterized by milder symptoms, slower progression and paucity of extra-neurological involvement. 3 FA is highly challenging at a genetic level as, (1) in a minority of patients it may be due to a compound heterozygous GAA repeat expansion with a point mutation; 1 (2) the range of pathogenic expanded alleles is wide (66-1700 GAAs), with expansions ranging from 44 to 66 being unstable and conferring high risk for disease; 4 and (3) the frequency of heterozygotes in the general population is estimated at 1/100. 1,2,5 Two main clinical consequences emerge from this genotypic ...

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Different phenotypes of Friedreich's ataxia within one ‘pseudo‐dominant’ genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features

Cited by 13 publications

References 20 publications

Near infrared muscle spectroscopy in patients with Friedreich's ataxia

Near infrared muscle spectroscopy in patients with Friedreich's ataxia

Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

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

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