In children with Friedreich ataxia, muscle and ataxia parameters are associated

Abstract

FRDA Friedreich ataxia ICARS International Cooperative AtaxiaRating Scale MUD Muscle ultrasound density MUV Muscle ultrasound volume SEP Sensory evoked potential AIM In children with Friedreich ataxia (FRDA), ataxia is assessed using the surrogate marker the International Cooperative Ataxia Rating Scale (ICARS). We aimed to determine whether ICARS scores in children with FRDA are confounded by muscle weakness.METHOD In 12 children with FRDA (10 males, two females; mean age 13y 6mo, SD 2y 6mo) and 12 age-matched children without FRDA (nine males; three females), we determined the association between muscle and ataxia parameters (i.e. muscle ultrasound density (MUD), muscle force, sensory evoked potentials, and ICARS scores). Children with FRDA were included on the basis of FXN gene analysis. Children in the comparison group were included on basis of uneventful pregnancy and normal cognitive and neurological development. RESULTSIn children with FRDA, muscle ultrasound density was homogeneously increased in the biceps, quadriceps, and tibialis anterior muscles (median 4SD). FRDA muscle weakness was significantly more pronounced in proximal than in distal muscles ()2SD vs )0.5SD respectively; p=0.004), with a stronger impairment of leg muscles than of arm muscles ()2SD vs )0. SD respectively; p=0.001). Comparing MUD between children with FRDA and an age-matched comparison group revealed a relatively strong increase in MUD in the proximal leg muscles in the FRDA group. Under the condition of persistently absent sensory evoked potentials, leg ICARS subscores in the FRDA group appeared to be positively associated with leg muscle force until a maximal plateau level of ICARS subscores was reached.INTERPRETATION In children with FRDA, ataxia scales based on ICARS are confounded by muscle weakness. Longitudinal ICARS evaluations in children with FRDA do not necessarily indicate altered ataxia.Friedreich ataxia (FRDA) is an autosomal, recessively inherited disorder that is associated with progressive ataxia, muscle weakness, and hypertrophic cardiomyopathy. In about 98% of affected individuals, FRDA is associated with a homozygous GAA trinucleotide expansion in the first intron of the FXN gene on chromosome 9q13; in the remaining 2%, FRDA is associated with a heterozygous GAA expansion in intron 1 on one allele and another inactivating mutation on the other allele.1 The genetic defect hampers frataxin transcription, resulting in deficient mitochondrial iron-sulphur-containing enzymes, respiratory chain dysfunction, and oxidative stress. Frataxin is strongly expressed in the central and peripheral nervous system and muscles. Consequently, disturbed central and peripheral innervation 3,4 and oxidative muscle stress 5 may influence FRDA disease manifestation. This could explain why FRDA encompasses a variety of disease symptoms involving motor and sensory neuropathic, myopathic, spastic, choreatic, and ataxic features. To achieve optimal therapeutic gain, medication strategies for ataxia should be introduced at an early stage....

Prevalence of ataxia in children

“…Third, more research concerning the measurement and treatment of childhood ataxia is needed. There are few reports specific to children regarding the measurement 37 and treatment of ataxia (pharmacologic [38][39][40][41][42] and nonpharmacologic [43][44][45] ). This may reflect the fact that the overall prevalence and importance of childhood ataxia has likely been underestimated in the past, despite the fact that ataxia is associated with significant economic cost and decreased quality of life.…”

Ataxia rating scales are age‐dependent in healthy children

“…19,20 Altogether, in young children under 12 years of age, several physiological neurodevelopmental processes can explain why ataxia rating scales are confounded by age. 11,21 Although such age-related influences do not necessarily overlap with advanced ataxic scores in patients with EOA, one may need to consider such influences before attributing intra-individual longitudinal quantitative 'improvements' to potential treatment effects.…”

Bioenergetics of the Calf Muscle in Friedreich Ataxia Patients Measured by 31P-MRS Before and After Treatment with Recombinant Human Erythropoietin

“…Clinically, FRDA is determined by progressive ataxia of gait and extremities, dysarthria and areflexia [1]. Muscle weakness is evident particularly in the lower limbs [2], [3], though signs of weakness or fatigue may be masked by more prominent features of ataxia. FRDA is a caused by a GAA trinucleotid expansion in intron 1 of the frataxin gene [4] leading to reduced expression of the mitochondrial protein frataxin.…”