SPINOCEREBELLAR DEGENERATION DISEASES
Friedreich's ataxia is a spinocerebellar degeneration syndrome with the onset of symptoms before age 20 years. This autosomal-recessive condition has been linked in one subtype to chromosome 9ql3-21.1 (FRDA) with the protein implicated being termed "frataxin." A second subtype referred to as FRDA2 is linked to chromosome 9p23-pll.
The incidence of Friedreich's ataxia is 1 in 25,000 to 50,000. Carrier frequency is 1 in 60 to 110. The age of onset is usually less than 20 years, typically around puberty with a range from 2 to 25 years. Obligate signs and symptoms include progressive ataxic gait, cerebellar dysfunction with tremor and dysmetria, dysarthria, decreased proprioception or vibratory sense (or both), muscle weakness, and absent DTRs. Other common signs include cavus foot deformity, cardiomyopathy, scoliosis, and upper motor neuron signs, such as a Babinski sign and spasticity. Weakness is progressive, and it affects lower extremities and small muscles in hands and feet. Sensory loss is typical and especially affects vibration and joint position sensation. Tendon reflexes are often absent. An occasional patient may have chorea without ataxia. With electrodiagnostic studies, sensory nerve potentials may be absent or reduced. Progression is slow, and the mean time to wheel chair is 15 years of age and death from cardiomyopathy ranges from the third to the seventh decade.
The prevalence of scoliosis approaches 100% but some cases have more severe progressive spinal deformity than others. Those Friedreich's ataxia cases with onset of disease before the age of 10 years generally have more severe progressive scoliosis. Those with the onset of disease during or after puberty have later-onset spinal deformity which may not require surgical intervention.
Frataxin is a mitochondrial protein located on the inner mitochondrial membrane. It is likely required for maintenance of mitochondrial genome and it is involved in iron homeostasis and iron transport into mitochondria. Idebenone is a power antioxidant and a synthetic analogue of coenzyme Q. It may improve iron homeostasis and mitochondrial function in Friedreich's ataxia. In randomized clinical trials, longer term idebenone treatment has been shown to prevent progression of cardiomyopathy and cardiac hypertrophy in both pediatric and adult patients with Friedreich's ataxia. Its stabilizing effect on neurologic dysfunction has been shown to be present only in the pediatric population, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may be an important factor in the effectiveness of the therapy (191). The findings of the open-label IONIA-E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurologic function and improving fine motor skills and speech (192,193).
Other Hereditary Ataxias
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The genetic forms of ataxia are diagnosed by family history, physical examination, and neuroimaging. Molecular genetic tests are available for the diagnosis of many but not all spinocerebellar ataxias (SCA). At least 28 genetically distinct autosomal-dominant SCA subtypes and four other autosomal-dominant hereditary ataxias have been identified. Childhood onset has been found commonly in SCA7, SCA13, SCA17, and SCA21 and more rarely in SCA1, SCA2, SCA3, SCA5, and SCA22. Other pedigrees of SCA with childhood onset have been identified in only single families. Autosomal-dominant episodic ataxia 1 (EA1) with episodic attacks of myokymia and ataxia and linkage to chromosome 12pl3.3 has onset in the first decade. At least seven autosomal-recessive ataxias in addition to Friedreich's ataxia have been identified, most of which have childhood onset. The most common of these is ataxia telangiectasia, with linkage to chromosome llq22.3, which presents in the first decade with ataxia, dysarthria, ocular telangiectasias, immune deficiency, and risk of cancers.