Autosomal recessive ataxias: 20 types, and counting

Abstract

-More than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in Neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.KEY WORDS: autosomal recessive ataxias, cerebellar ataxia, cerebellum, Friedreich ataxia.Ataxias autossômicas recessivas: 20 tipos e muito mais resumo -Mais de 140 anos após a primeira descrição da ataxia de Friedreich, as ataxias autossômicas recessivas se transformaram em um dos mais complexos campos da Neurogenética. Atualmente, este grupo de doenças é composto por mais de 20 entidades clínicas e possui um número ainda maior de genes associados. Algumas doenças são muito raras, tendo sido observadas apenas em populações isoladas, enquanto que outras são encontradas no mundo todo. Um número expressivo de ataxias é tratável, e a responsabilidade em se fazer um diagnóstico correto é alta. A finalidade desta revisão é a de atualizar o neurologista a respeito dos principais aspectos clínicos e fisiopatológicos destas doenças e de apresentar um algoritmo para auxiliar a sua investigação e o seu diagnóstico.

Hereditary ataxias: overview

“…28 The autosomal recessive ataxias may present with additional extra-central nervous system signs and symptoms. Table 2 summarizes information for 13 typical autosomal recessive disorders in which ataxia is a prominent feature.…”

Sleep disorders in cerebellar ataxias

“…Recessive ataxias may be divided into five groups: Congenital, mitochondrial, metabolic, degenerative, and related to defects in DNA repair 17 . A limited number of data is available concerning sleep disorders in recessive ataxias.…”

“…It has been described a sleep disordered breathing manifesting as repetitive tachypnea followed by central apnea, and isolated tachypnea during asleep, interestingly detected only in non-REM sleep 19 . Friedreich ataxia (FA) is the commonest recessive ataxia worldwide, manifesting as progressive sensory and cerebellar ataxia, arreflexia, Babinski sign, often associated with cardiomyopathy, scoliosis and pes cavus 17 . Data on sleep disorders in patients with FA is poor.…”

Spinocerebellar Ataxia with Axonal Neuropathy (SCAN1): A Disorder of Nuclear and Mitochondrial DNA Repair

“…Many result from cerebellar degeneration or the impairment of a portion of the neuroaxis that contributes to cerebellar inflow or outflow (Embirucu et al, 2009). In the cerebellum, the dysfunction and death of Purkinje cells, granule cells or interneurons can cause SCA.…”

“…DSBR corrects double-strand breaks (DSB) in the DNA backbone; MMR corrects mismatches of normal bases; NER repairs bulky helix distorting DNA lesions, and BER repairs damage to a single nucleotide and handles single-strand DNA breaks (SSB). Dysfunction of each of these DNA repair processes causes or has been associated with progressive neurodegenerative disease (Table 1) (Jeppesen et al, 2011 (Embirucu et al, 2009;Katyal and McKinnon, 2007;Subba Rao, 2007) 3.1 Double-strand break repair DSBR corrects DNA double-strand breaks (DSBs) induced by exogenous sources such as ionizing radiation and genotoxic compounds or by endogenous sources such as reactive oxygen species, replication fork collapse, and errors of meiotic recombination (Ciccia and Elledge, 2010). The two major DSBR pathways in mammalian cells are homologous recombination (HR) and non-homologous end-joining (NHEJ).…”