**5. Chronic progressive ataxias**

Chronic progressive ataxias are usually inherited ataxias that include a heterogeneous group of clinically and genetically distinguished neurodegenerative disorders. Depending on its inherence chronic ataxias are classified in autosomal dominant, autosomal recessive, and X-linked ataxias (**Table 4**).


### **Table 4.**

*Causes of chronic progressive ataxias.*

### **5.1 Autosomal dominant ataxias**

Autosomal dominant ataxias usually presenting as spinocerebellar ataxia (SCAs). SCAs are rare in children and the clinical clue for the diagnosis is the identification of family history [7]. Most common SCAs are caused by an expansion of a CAG trinucleotide repeat in the respective gene, therefore an anticipation phenomenon can occur in some families.

Infantile and childhood onset has been described in SCA2, SCA7, SCA10, SCA13, SCA14, SCA21, SCA25, SCA28, SCA42, SCA44, and DRPLA (dentatorubral-pallidoluysian atrophy) [52].

### **5.2 Autosomal recessive ataxias**

Autosomal recessive ataxias are a group of complex genetic ataxia disorders associated with variable central and peripheral involvement and systemic manifestations. A new clinical and pathophysiological classification of autosomal recessive cerebellar ataxia has recently become available [53] and is a very useful tool for the initial clinical approach to a patient presenting with ataxia. There is a long list of disorders associated with autosomal recessive ataxias, some of which are described below.

Autosomal recessive ataxias are a group of complex genetic ataxia disorders associated with variable central and peripheral involvement and systemic manifestations. A new clinical and pathophysiological classification of autosomal recessive cerebellar ataxia has recently become available [53]. This classification separates autosomal recessive ataxias in two groups: primary autosomal recessive cerebellar ataxias and complex multisystem disorders that are associated with ataxia. There is a long list of disorders associated with autosomal recessive ataxias, some of which are described below.

### **5.3 Primary autosomal recessive cerebellar ataxias**

### *5.3.1 Friedreich ataxia*

Friedreich Ataxia (FA) is caused by mutations in the FXN gene (9q21.11), which encodes the synthesis of frataxin, a protein that is involved in mitochondrial function. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9 [54].

FA age of onset has a wide range, which can go from 5 to 25 years of age, although cases of late-onset (after 25 years of age) and very late onset (after 40 years of age) have been described [55]. Usually, the onset of symptoms is between the ages of 10 and 16 with gait instability [54]. The classical phenotype of FA is associated with progressive sensory and cerebellar ataxia, with areflexia, loss of position or vibration sensation, pes cavus, Babinski sign, and scoliosis. Patients usually become wheelchair-bound after a mean disease duration of 10–15 years [56]. Other neurological manifestations include dysmetria, dysarthria, and auditory and optic neuropathy. FA patients also have systemic complications, including cardiomyopathy and diabetes [57]. MRI usually shows spinal atrophy [54]. Currently, there is no effective treatment to delay neurodegeneration in Friedreich's ataxia, but different newer treatments are now being studied.

### *5.3.2 Ataxia telangiectasia*

Ataxia-telangiectasia (AT) is the second most common autosomal recessive hereditary ataxia in children [7]. AT is caused by a mutation in the AMT gene, which encodes a kinase protein involved in DNA repair [58]. The onset of symptoms is usually in early childhood, classical neurological signs include progressive cerebellar ataxia, oculomotor apraxia, chorea and cognitive dysfunction [59]. Scleral and cutaneous telangiectasias are characteristic of AT, although they may be absent initially. Other systemic manifestations include variable immunodeficiency with recurrent infections, radiosensitivity, susceptibility to malignancies, poor growth and insulin-resistant diabetes [60]. Serum elevation of carcinoembryonic antigen and alpha-fetoprotein are constant markers. Immunoglobulins are typically decreased and MRI classically shows marked atrophy of the cerebellum [61]. AT patients have a poor prognosis, and average life expectancy was reported to be approximately 25 years [60]. No curative therapy is available for ataxia-telangiectasia.
