Friedreich Ataxia

CHAPTER 66

Friedreich Ataxia

Introduction/Etiology/Epidemiology

• Friedreich ataxia (FRDA) is the most prevalent hereditary ataxia, with a prevalence ranging from 1 in 20,000 to 1 in 725,000 live births. It is most common in Western European populations. It is rarely reported in China, Japan, and the sub-Sahara region of Africa.

• This is a severe autosomal recessive disease of the central and peripheral nervous system.

• It is caused by mutations of the frataxin gene, FXN, on chromosome 9q13. About 96% of cases have 600 to 1,200 guanine-adenine-adenine (GAA) trinucleotide repeat expansions in the first intron of both alleles. This mutation results in reduced production of frataxin, a mitochondrial membrane protein important in iron-sulfur cluster biogenesis, storage, and transport.

• Longer lengths of GAA expansion result in lower frataxin production, earlier disease onset, and more severe symptoms, including loss of upper extremity deep tendon reflexes (DTR), a shorter time to loss of ambulation, and cardiomyopathy.

• Low levels of frataxin lead to intracellular oxidative stress and, ultimately, cell death resulting in damage to the brain, heart, and pancreas.

• Structural pathology of the central nervous system is most apparent in the spinal tracts and cerebellum.

— The dorsal root ganglia demonstrate hypoplasia of large and intermediate size neurons.

— Degeneration of the posterior (dorsal) columns of the spinal cord and the dorsal spinocerebellar fibers are typical.

— There is atrophy of the neurons in Clarke column and the gracile and cuneate nuclei.

— The main cerebellar abnormality is atrophy of the dentate nucleus and its efferent axons.

— Reduced cerebellar white and gray matter volume is associated with greater disease severity.

— Cerebral gray and white matter structural and functional aberrations have also been reported.

• The peripheral nervous system is affected, with loss of myelinated sensory nerves and secondary axonal degeneration, which progresses with age. This is most severe in the lower extremities.

• Pathology in the autonomic nervous system has also been described, which correlates with disease severity. Dysautonomia affects the gastrointestinal and genitourinary systems as well as thermoregulation and light sensitivity.

Signs and Symptoms

• Clinical manifestations usually begin between 10 and 15 years of age but may start as early as 2 years.

• Progressive trunk and limb ataxia is caused by cerebellar and spinocerebellar degeneration, sensory neuropathy, and vestibular nerve pathology. These are cardinal features leading to imbalance and frequent falls.

• Limb incoordination, intention tremor, and dysmetria progress steadily until patients lose fine motor skills and the ability to walk, stand, and, eventually, sit without support 10 to 15 years after disease onset.

• Degeneration of the corticospinal tracts in the spinal cord results in a loss of DTR and a positive Babinski sign in most patients. Muscle tone is usually decreased and sometimes normal but rarely increased.

• Progressive muscular weakness is common, especially affecting the lower extremities in those with earlier disease onset. Arm and hand weakness occur in later stages.

• Impaired vibration perception and proprioception occur from degeneration of the posterior columns of the spinal cord, especially in those with earlier disease onset. The dorsal root of the spinal nerve and the peripheral sensory nerves are also affected as the disease advances, but pain and temperature sensation are typically unaffected.

• Cerebellar dysarthria (slow, jerky speech with sudden utterances) characterized by velopharyngeal and laryngeal dysfunction is present in more than 90% of patients. This often appears 5 years after disease onset. Symptoms can be mild or more severe (as seen in those with longer disease duration).

• Abnormalities of eye movement are common, typically including fixation instability with frequent square wave jerks and ocular flutter. Optic atrophy may occur in up to 30% of patients. Loss of vision is noted less frequently.

• Although reduced hearing in the setting of background noise is common, sensorineural hearing loss affects only about 20% of patients with advanced disease.

• Autonomic nervous system dysfunction occurs later, causing cold and cyanotic legs and feet as well as reduced heart rate variability.

• The urinary system is affected in 40% of patients. Urinary retention, hesitance, and incontinence are typical features. This occurs in more severely affected individuals.

• Hypertrophic cardiomyopathy occurs in more than 90% of patients about 4 to 5 years after the onset of neurologic symptoms. It is the leading cause of death in FRDA, occurring in about 60% of patients.

— Typically, left ventricular hypertrophy develops, which progresses to myocardial fibrosis and, later, to ventricular thinning.

— Arrhythmias are common and can result in sudden death.

— Reduced systolic ejection fraction occurs in 20% of patients late in the disease; 30% die from end-stage congestive heart failure by 30 years of age.

— There is no effective treatment, although cardiac transplantation has shown promise.

• Sleep-disordered breathing may lead to daytime fatigue. This must be screened for when assessing patients with FRDA.

• Kyphoscoliosis is very common and can precede neurologic symptoms. Double major thoracic and lumbar curves are the predominant pattern. Scoliosis may cause back pain and cardiorespiratory compromise.

• Pes cavus is noted in 55% to 75% of patients but rarely causes problems. Pes equinovarus is also common and can cause morbidity. These foot deformities and hammer toes make ambulation more difficult.

• Carbohydrate intolerance is noted in about 20% of patients. This may relate to a combination of insulin resistance, decreased insulin secretion from pancreatic β-cell dysfunction, and mitochondrial dysfunction.

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