Hereditary ataxias

Hereditary forms of cerebellar ataxias are classified according to the type of inheritance into (a) autosomal recessive ataxias; (b) autosomal dominant ataxias; and (c) ataxias caused by mutations in the mitochondrial genome.

Autosomal recessive ataxias

Autosomal recessive ataxias begin in childhood or before the age of 20. A large group of rare autosomal recessive ataxias has been described, among which Friedreich’s ataxia is the most common.

Friedreich’s ataxia

Friedreich’s ataxia is inherited according to the autosomal recessive type, and is characterized by progressive degeneration of cells in (a) dorsal root ganglia with consequent degeneration of the posterior columns of the spinal cord, and (b) degeneration of the corticospinal and cerebellospinal pathways (Figure 212), as well as (c) slightly less involvement of the cerebellum (loss of Purkinje cells and neurons of the nucleus dentatus).
This disease affects one in 50,000 people, but that’s why heterozygous carriers of the pathogenic mutation are relatively common (one in twenty people).
Clinical picture. Friedreich’s ataxia begins in the first or second decade of life, and onset before the age of 25 is accepted as a criterion for typical cases. The first sign of the disease is an unstable, clumsy walk on a wider base, with frequent falls, while clumsiness of the hands and slurred speech occur during the first years of the disease. The disease progresses slowly and the patient is unable to move independently after 10-15 years. In patients in the advanced stage of Friedreich’s ataxia, we find:
(a) ataxia, primarily gait;
(b) severe damage to proprioceptive and vibration sensibility, due to damage to the back columns of the spinal cord;
(c) weakness of the legs and, to a lesser extent, the arms, with extinguished abdominal reflexes and a positive Babinski sign, due to damage to the corticospinal pathways;
(d) extinguished muscle reflexes, often only on the legs, due to damage to the dorsal roots and peripheral nerves (pay attention to the comparative existence of extinguished reflexes and a positive sign of Babinski – the so-called Crouzon phenomenon); and
(e) other disorders, such as dysarthria, dysphagia, nystagmus, dystonia, flexion spasms, muscle atrophy and, in a number of patients, optic nerve atrophy and hearing loss.
In addition to the nervous system, damage to the myocardium occurs in about 50% of patients (pronounced interstitial fibrosis of the myocardium to the development of hypertrophic cardiomyopathy). Musculoskeletal disorders (so-called Friedreich’s foot and severe kyphoscoliosis) are observed in 80% of patients (Figure 213). Finally, diabetes is common (10% of patients).
Friedreich’s ataxia tragically ends in death at the end of the fourth decade, most often due to cardiac reasons.
The above description is a description of the so-called typical Friedreich’s ataxia, but with the possibility of making an accurate diagnosis through genetic testing, it was seen that at least a quarter of patients exhibit an “atypical” clinical picture (onset after the age of 25, preservation of muscle reflexes and/or deep positional sensitivity, etc.). Therefore, it is a clinical recommendation that every ataxic patient with the onset of the disease after the age of 25 and without other explanations for ataxia be genetically tested for this disease.
Diagnostic procedures. An electrocardiogram can indicate a heart disorder. EMNG documents the loss of large sensory axons in peripheral nerves. With the use of CT or NMR, we do not find disorders of the cerebellum, but atrophy of the cervical part of the spinal cord can be observed. Precise diagnosis is made possible by genetic testing.
Genetic basis and pathogenesis of Friedreich’s ataxia. The gene whose mutation causes Friedreich’s ataxia is located on the short arm of chromosome 9. It is an unstable expansion of the number of trinucleotide repeats (GAA) in the first intron of this gene. Namely, while the majority of healthy individuals have between 7 and 22 GAA repeats, the mutation is an increase in the number of these trinucleotide repeats (pathogenic mutations for Friedreich’s ataxia contain 66-1000 GAA repeats). Since the disease is inherited recessively, both copies of the gene must be mutated. In about 95% of patients, this GAA expansion exists in both alleles (homozygous expansion). Only 5% of patients have an expansion on one allele (heterozygous expansion), but there is a point mutation in the other. The number of repeats affects some features of the disease: (a) diabetes and cardiomyopathy mostly occur in patients with a higher number of GAA repeats (> 650-700) and (b) there is an inverse correlation between the number of repeats and the age at the onset of the disease (the higher number of repeats, the disease is likely to start earlier).
The gene codes for a mitochondrial protein, frataxin, and a pathogenic mutation for Friedreich’s ataxia causes a partial deficiency of this protein. Frataxin plays a role in iron metabolism in mitochondria, so its partial deficiency causes accumulation of iron in mitochondria, which in turn promotes oxidative stress and damage to cellular structures.
Therapy. The essence of the effort should be based on adequate rehabilitation and preservation of mobility as long as possible, as well as monitoring and trying to treat cardiomyopathy, diabetes and skeletal deformities. Idebenone, an analog of coenzyme Q, has a certain positive effect on hypertrophic cardiomyopathy, which reduces oxidative damage triggered by iron accumulation in mitochondria.