Childhood Ataxia

Abstract

Childhood ataxia is characterized by impaired balance and coordination primarily due to cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.

A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar Atrophy

“…Hereditary cerebellar ataxias comprise a heterogeneous group of neurodegenerative, metabolic, and genetic disorders ( 1 2 3 4 ). They are classified based on their pattern of inheritance, and about 50 genes have been identified ( 1 2 3 4 ). Autosomal dominant cerebellar ataxias are typically observed in patients aged 20–50 years ( 1 2 3 ).…”

“…They are classified based on their pattern of inheritance, and about 50 genes have been identified ( 1 2 3 4 ). Autosomal dominant cerebellar ataxias are typically observed in patients aged 20–50 years ( 1 2 3 ). During childhood, most of the hereditary cerebellar ataxias are autosomal recessive, X-linked, or mitochondrial ( 1 2 3 4 ).…”

“…Autosomal dominant cerebellar ataxias are typically observed in patients aged 20–50 years ( 1 2 3 ). During childhood, most of the hereditary cerebellar ataxias are autosomal recessive, X-linked, or mitochondrial ( 1 2 3 4 ). Autosomal recessive cerebellar ataxias are categorized into three subclasses according to age at onset and coexistence of cerebellar atrophy: ‘Friedreich's-ataxia-like,’ ‘Friedreich's-ataxia-like with cerebellar atrophy,’ and ‘early-onset ataxia with cerebellar atrophy ( 1 2 ).’ However, assessment of hereditary cerebellar ataxias is confusing, as there are many chemical studies and genes to consider ( 1 2 3 4 ).…”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…Furthermore, in TM iron overload is in the form of ferritin and more so in the form of haemosiderin and situated in lysosomes in the cytosol and not the mitochondria [84] . In contrast, polynuclear iron deposits of mainly ferritin and haemosiderin have been identified in both the mitochondria and cytosol of cardiac and other biopsy samples of FA patients [76,88,89] . Despite that cardiomyopathy is the main cause of death in both diseases, iron accumulation in the hearts of patients with FA is overall much lower in comparison to TM patients.…”

“…Deficit of frataxin is mostly related to many abnormalities associated with mitochondrial structure and function. The main and characteristic abnormality in FA is an increased iron accumulation and deposition in the mitochondria matrix and a corresponding increase in oxidative stress [3,4,88,89] . There is also deficit of mitochondrial respiratory chain complex activities and impairment of tissue energy metabolism, decrease in production of ATP, effects on the function of aconitase and other abnormalities which lead to mitochondrial misfunction, including also to a further increase in the production of free radicals and other reactive oxygen species.…”