What are the most common autosomal recessive ataxias?
Autosomal recessive cerebellar ataxias are heterogeneous, often multisystem neurodegenerative diseases that tend to manifest in children and young adults, and should be suspected in anyone under the age of 30 with insidious and progressive ataxia, hypotonia, or clumsiness.
Friedreich’s ataxia (FA)
Friedreich’s ataxia is the most frequent and presents between 7 and 25 years of age.
A repeat expansion in frataxin, a mitochondrial protein involved in cellular iron homeostasis, leads to dysfunction in the respiratory chain and Krebs cycle.
FA manifests with progressive gait and limb ataxia, dysarthria, sensory neuropathy, and pyramidal signs.
Patients are generally areflexic but exhibit extensor plantar responses. Scoliosis, square wave jerks, left ventricular hypertrophy (60% of patients), and diabetes mellitus (15%) or carbohydrate intolerance (25%) may also be present. Nystagmus and cerebellar atrophy are not prominent.
Progression includes significant difficulties with activities of daily living, loss of ambulation, dysarthria, and dysphagia.
Ataxia telangiectasia (AT):
Ataxia telangiectasia is the second most frequent and often starts before age 5 years.
Progressive hypotonia and clumsiness are accompanied by conjunctival telangiectasias, oculomotor apraxia, dysarthria, chorea ± dystonia, and sensorimotor axonal neuropathy.
Mutations of the ATM gene, a member of the phosphatidylinositol-3 kinase family of proteins involved in repair of DNA damage, cause a predilection for lymphoid malignancies and recurrent infections.
Loss of ambulation occurs within 10 years. Severe cerebellar atrophy develops over time.
Elevated serum alpha-fetoprotein levels can assist with diagnosis.
Anheim M, Tranchant C, Koenig M: The autosomal recessive cerebellar ataxias. N Engl J Med 366:636-646, 2012. Vermeer S, van de Warrenburg BP, Willemsen MA, Cluitmans M, Scheffer H, Kremer BP, Knoers NV: Autosomal recessive cerebellar ataxias: the current state of affairs. J Med Genet 48:651-659, 2011.