Central Nervous System

Friedreich considered the degeneration of the posterior columns of the spinal cord as the hallmark of the disease. The appearance of the posterior columns is shrunken, grayish, and translucent. Atrophy is most severe for the fibers originating more caudally, therefore affecting the Goll more than the Burdach tract. Clarke’s column, which receives afferents from collaterals of axons in the dorsal columns, shows profound neuronal loss. Spinocerebellar tracts, which originate from Clarke’s column, also are atrophic, dorsal elements more than ventral. This finding may be the only known example of trans-synaptic degeneration in humans. The sensory system involvement continues rostrally into the brainstem, with atrophy of the gracilis and cuneate nuclei and of the medial lemnisci, particularly in the ventral portion deriving from the gracile nuclei. Atrophy extends to the cranial nerve sensory nuclei and the entering roots of cranial nerves V, IX, and X, the descending trigeminal tracts, and the solitary tracts. The accessory cuneate nuclei, corresponding to Clarke’s column in the spinal cord, are markedly atrophic. Therefore, the sensory systems providing information to the cerebrum and cerebellum regarding the position and speed of body segments, particularly the lower limbs, are severely compromised in FRDA.

In the motor system, the long crossed and uncrossed corticospinal motor tracts are atrophic, suggesting a “dying back” process because atrophy is more severe distally. Loss of pyramidal neurons in the motor cortex is variable, while motor neurons in the brainstem and in the ventral horns are preserved.

In the cerebellum, atrophy of the dentate nuclei and the superior cerebellar pedunculi is most prominent, whereas cortical atrophy tends to occur late and be mild. Quantitative analysis of synaptic terminals suggests a loss of contacts over Purkinje cell bodies and proximal dendrites. Neuropathology studies in subjects affected with FRDA who died at different ages indicate that sensory system involvement occurs very early and may even be developmental, while the dentate nucleus and pyramidal tracts are affected later as disease progresses.

Areas of variable involvement include the auditory system and the optic nerves and tracts. The basal ganglia may show moderate cell loss in the external pallidus and subthalamic nuclei in some cases. The thalamus, striatum, and substantia nigra do not appear to be directly involved by the disease. Finally, because many patients with FRDA die as a consequence of heart disease, widespread hypoxic changes and focal infarcts are often found in the central nervous system.

In the peripheral nervous system, the major finding is the loss of large primary sensory neurons in the dorsal root ganglia (DRG). Peripheral nerves show loss of large myelinated sensory fibers, while the fine, unmyelinated fibers are well preserved. Interstitial connective tissue is increased. This sensory axonal neuropathy is an early event in the course of the disease and is scarcely progressive.

In summary, FRDA causes a profound loss of large dorsal root ganglia neurons, leading to degeneration of the central and peripheral branches of their axons, and probably to trans-synaptic degeneration of Clarke’s column with consequent atrophy of the spinocerebellar tracts. Primary sensory neurons in cranial nerves are sometimes atrophic as well, typically in the acoustic nerve where atrophy leads to sensorineural hearing loss. In addition, the dentate nucleus and the distal portion of the corticospinal motor tracts undergo progressive atrophy. Therefore, patients with FRDA have a deficit of deep sensory input to the cerebrum and the cerebellum as well as a deficient cerebellar output, producing a mixed cerebellar and sensory ataxia. The simultaneous presence of axonal sensory neuropathy and pyramidal tract degeneration leads to the typical combination of absent tendon reflexes and extensor plantar responses.

Heart

Heart pathology in FRDA typically consists of hypertrophic cardiomyopathy with thickening of ventricular walls and interventricular septum, evolving into a dilatative cardiomyopathy in the late stage of the disease. Hypertrophic and normal-appearing cardiomyocytes intermingle with atrophic, degenerating, even necrotic fibers. Connective tissue is increased, and diffuse and focal inflammatory cell infiltration may be observed. A variable number of cardiomyocytes, from less than 1% to more than 10%, have intracellular iron deposits but do not necessarily show morphological changes indicative of degeneration. This finding is specific to FRDA and may reflect the basic biochemical defect.

Other Organs

Kyphoscoliosis is observed in more than three-quarters of the patients, mostly as a double thoracolumbar curve resembling the idiopathic form of scoliosis (see Case Example 49.1 ). Pes cavus, pes equinovarus, and clawing of the toes are found in about half the cases and thought to be secondary to nerve degeneration. Late in the disease, patients show a loss of islet cells without the signs of autoimmune inflammatory reaction found in type 1 diabetes.

Onset

The onset of FRDA occurs most commonly around puberty, but may occur earlier as well as in adult life. Molecular genetic studies have shown that late-onset patients (LOFA) carry mutations in the same gene as in typical FRDA cases. Large variations in age of onset within a sibship are occasionally observed, and are now explained at least in part by the dynamic nature of the mutation.

The typical patient at onset is a child who recently started to sway when walking and who falls easily. As in many degenerative diseases, an acute illness or injury may precede the appearance of the symptoms. Sometimes the child was active in sports and there were no clues of the impending neurological illness. More commonly the child had been considered “clumsy” for some time before the overt appearance of symptoms. Presentations with gait instability or generalized clumsiness are most common, but non-neurological manifestations such as scoliosis (often considered to be idiopathic) or cardiomyopathy (5%) may precede the onset of ataxia. Rarely, patients are diagnosed with idiopathic hypertrophic cardiomyopathy and treated for up to 2–3 years before neurological symptoms appear.

Neurological Signs and Symptoms

Ataxia with mixed cerebellar and sensory features is the hallmark of the disease, usually beginning as truncal ataxia causing swaying, reduced balance, and occasional falls. The gait abnormality is initially subtle and may reveal itself only as difficulty in tandem gait. Subsequently, the ataxic gait becomes evident with irregular steps, veering, and difficulty in turning. Inability to stand on one foot progresses to instability when standing with feet close together worsened by eye closure (positive Romberg sign). With further progression, gait becomes more and more ataxic and broad-based, with frequent losses of balance that requires intermittent support (furniture, walls, an accompanying person’s arm). Patients become completely unable to stand with feet close together, and then need support even when standing with their feet apart. A cane and then a walker become necessary. Finally, 10 to 15 years after onset, most individuals with FRDA lose the ability to walk, stand, and sit without support. Variability is remarkable, however; some patients are wheelchair dependent in their early teens while others are able to walk until their thirties and occasionally later.

After trunk ataxia, limb incoordination with dysmetria and intention tremor appear. Fine motor skills become impaired, with increasing difficulty in activities such as writing, dressing, and handling utensils. Ataxia is progressive and there are no remissions, although at the beginning of the illness periods of stability are frequently observed. Within five years from clinical onset, a progressive dysarthria appears, consisting of slow, jerky speech with sudden utterances. Speech deteriorates over years until it becomes almost unintelligible. Swallowing difficulties, particularly with liquids, commonly appear with advancing disease. Patients with very advanced disease frequently choke and may require modified foods and eventually a nasogastric tube or gastrostomy feedings.

Higher functions are well preserved; intellectual and learning disabilities do not seem to be more common in patients with FRDA than in the general population. However, subtle neuropsychological abnormalities do occur, mostly consisting of slowed information processing speed as well as altered motor planning. If not properly managed FRDA may have a substantial impact on academic, professional, and personal development.

The neurological examination shows a characteristic pattern of abnormal findings. Axonal sensory neuropathy results in sensory loss and loss of deep tendon reflexes. Loss of position and vibration sense may not be evident at onset but is invariably found within a few years of onset. Perception of light touch, pain, and temperature is initially normal and tends to decrease with advancing disease. Loss of tendon reflexes at least in the lower limbs is a typical feature of the disease, but a minority of patients with FRDA retain tendon reflexes and sometimes have brisk reflexes with spasticity; this group of patients is referred to as FRDA with retained tendon reflexes (FARR). Some patients with retained reflexes eventually lose them with disease progression, but many retain reflexes late in the course of the disease. Pyramidal involvement causes progressive muscular weakness that becomes severe only late in the progression of the disease. In fact, ataxia and not weakness is the primary cause for loss of ambulation; even when patients become wheelchair dependent, they maintain on average 70% of their normal strength in the lower limbs. Pyramidal involvement also results in extensor plantar responses, but exceptions to this rule are well known. Sensory neuropathy and pyramidal tract degeneration result most often in the typical mixed picture of areflexia associated with extensor plantar responses, but sometimes one component obscures the other. Such partial pictures are usually observed in milder cases of the disease.

Muscle tone is often normal at onset. However, with advancing pyramidal involvement and particularly when ambulation becomes severely impaired, many patients complain of spasms in the lower limbs, mostly occurring at night. When patients are wheelchair dependent, disuse atrophy occurs.

The typical oculomotor abnormality of FRDA is fixation instability with square-wave jerks, which may be seen early in the course of the disease. Various combinations of cerebellar, vestibular and brain-stem oculomotor signs may be observed, but nystagmus (gaze-evoked) is uncommon and ophthalmoparesis does not occur. Optic atrophy with or without visual impairment is detected in about 30% of patients, more as the disease advances. Sensorineural hearing loss affects about 20% of patients. However, sophisticated studies of auditory function revealed abnormalities in patients with normal tonal audiometry, even early in the course of the disease, which correlate with overall clinical progression. Auditory neuropathy and dysfunction of auditory pathways result in impaired speech perception.

Heart Disease

In most patients with FRDA heart disease remains asymptomatic, but in a significant minority, particularly in patients with earlier age of onset, it contributes to disability and may cause premature death. Cardiac mortality is excessive among FRDA patients, particularly before the age of 40, after which causes of death are more commonly related to advanced neurological disability. The most common cardiac symptoms are shortness of breath (40%) and palpitations (11%). The electrocardiogram (EKG) shows T-wave inversions, signs of ventricular hypertrophy, conduction disturbances in about 10% of patients, supraventricular ectopic beats, and atrial fibrillation. The latter is a negative prognostic sign. The frequency of EKG changes may be underestimated because studies vary over time and include occasional normal recordings. Repeated EKG recordings are the most sensitive test for FRDA-related cardiomyopathy. Echocardiography and Doppler echocardiography demonstrate concentric hypertrophy of the ventricles (62%) or asymmetric septal hypertrophy (29%), with diastolic function abnormalities.

Diabetes Mellitus

About 10% of FRDA patients develop diabetes mellitus and 20% have carbohydrate intolerance. Beta-cell dysfunction as well as peripheral insulin resistance occurs. Although some cases may be initially controlled by oral hypoglycemic drugs, insulin dependence is eventually the rule. FRDA patients should be checked regularly for the development of diabetes because it may increase the burden of disease, complicate the neurological picture, and even promote potentially fatal complications.

Other Clinical Manifestations

Kyphoscoliosis may cause pain and cardio-respiratory problems. Pes cavus and pes equinovarus may render ambulation even more difficult. Autonomic disturbances, most commonly cold and cyanotic legs and feet, increase in frequency as the disease advances. Parasympathetic abnormalities such as decreased heart rate variability have been reported. Urgency of micturition is relatively common and incontinence may occur.

Biochemical Investigations

Commonly tested biochemical parameters in blood, urine, and cerebrospinal fluid are normal in FRDA. There is an ongoing search for biomarkers of disease status, progression, and response to treatments. Measures of iron metabolism and oxidative stress have been investigated first. Blood iron, iron binding capacity, and ferritin are normal, but there is an increase in circulating transferrin receptors. Several markers of oxidative stress have been reported to be increased, including urinary 8-hydroxy-2′-deoxyguanosine (8OH2′dG), a marker of oxidative DNA damage and plasma malondialdehyde, a marker of lipid peroxidation. However, measuring oxidative stress markers has proven difficult in clinical practice, and an attempt to use 8OH2′dG as an endpoint in a clinical trial has failed. Proteomic studies of plasma and urine are under-way. Gene expression profiling in peripheral blood mononuclear cells (PBMCs) has detected a set of genes whose expression is significantly and consistently different in FRDA patients versus carriers and controls. In ex vivo experiments, some of these genes respond to treatments that normalize frataxin levels.

Neuroimaging

Thinning of the cervical spinal cord with signal abnormalities in the posterior and lateral columns can be detected on sagittal and axial magnetic resonance (MRI) images in almost all FRDA patients. Brainstem, cerebellum, and cerebrum are less severely affected, but they tend to be smaller in FRDA patients compared with healthy controls. The extent of this diffuse atrophy correlates with clinical severity. Mild vermian and lobar cerebellar atrophy occurs in more severe and more advanced cases.

More recently, advanced imaging techniques have been used to detect structural changes in FRDA, which have been confirmed to extend beyond the cerebellum and spinal cord. Diffusion-based MRI studies showed significantly lower fractional anisotropy, higher mean diffusivity and increased radial diffusivity in dentato-rubral, dentato-thalamic, and thalamo-cortical tracts, correlating with clinical severity. Altered cerebello-cerebral white matter connectivity, as shown by diffusion MRI and tractography, is the likely basis of abnormalities detected by functional imaging studies, in particular decreased brain activation during specific cognitive tasks.

Metabolic imaging studies have also revealed widespread abnormalities. Fluorodeoxyglucose (FDG) PET scan showed increased metabolism in the brain of FRDA patients who are still ambulatory. As disease progresses and the patients lose their ability to walk, glucose consumption decreases and eventually becomes subnormal. Although not yet fully explained, this abnormality may relate to mitochondrial dysfunction.

Neurophysiological Investigations

Electromyography and nerve conduction studies reveal the underlying axonal sensory neuropathy, with sensory nerve action potentials (SNAPs) lost or severely reduced and motor and sensory nerve conduction velocities (NCVs) within or just below the normal range. These findings clearly distinguish an early case of FRDA from a case of hereditary demyelinating sensorimotor neuropathy. The severity of the neurophysiological abnormalities related to the axonal sensory neuropathy does not correlate with disease duration, indicating that the atrophy of sensory neurons is nonprogressive. Degeneration of both peripheral and central sensory fibers also results in dispersion and delay of somatosensory evoked potentials (SEPs). Brainstem auditory evoked potentials (BAEPs), beginning from the most rostral component, wave V, progressively deteriorate in all patients. Visual evoked potentials (VEPs) are commonly (50–90%) reduced in amplitude with normal P 100 latency. In all cases, central motor conduction is slower than normal; in contrast to the sensory involvement, this slowing becomes more severe with increasing disease duration.

Variant Phenotypes: The Role of Molecular Testing

When direct molecular testing for FRDA became available, positive results were obtained in up to 10% of patients with recessive or sporadic ataxia who did not fulfill the diagnostic criteria for FRDA. No one clinical finding or combination of findings exclusively characterizes positive cases or is necessarily present. Even neurophysiological evidence of axonal sensory neuropathy is occasionally absent in patients with a proven molecular diagnosis. However, presence of the “classical” features of FRDA, including cardiomyopathy, is highly predictive of a positive test, although a few negative cases have been reported. Absence of cardiomyopathy and moderate or severe cerebellar cortical atrophy, demonstrated by MRI, appear to be the best predictors of a negative test.

Specific variant phenotypes have been shown to be due to the same genetic mutation causing typical FRDA (GAA repeat expansion), including LOFA, FARR, and Acadian ataxia. LOFA patients have onset after age 25 years and exhibit an overall milder, slowly evolving disease with fewer skeletal abnormalities. The frequency of cardiomyopathy may be lower in LOFA than in typical FRDA. FARR patients have retained deep tendon reflexes in the lower limbs after the onset of neurological symptoms. They also tend to be mild cases with later onset and slower course than typical FRDA patients. Acadian ataxia is found among the descendants of French colonizers who settled in Eastern Canada during the seventeenth century and were expelled by the British in the eighteenth century. Many moved to Louisiana, where they became known as “Cajuns” (a corruption of “Acadians”), and some later returned to the Canadian Atlantic provinces. The disease was introduced into this population by very few individuals, possibly a single couple, a founder effect. Acadian ataxia is milder and evolves more slowly than typical FRDA, with less severe cardiomyopathy.

Prognosis

On average, FRDA patients lose their ability to walk 15 years after onset, but variability is very wide. Early onset and left ventricular hypertrophy appear to be predictors of a faster rate of progression of the disease. The burden of neurological impairment, cardiomyopathy, and occasionally diabetes shortens life expectancy. In a retrospective study of FRDA patients to determine cause of death, followed by a case-control analysis comparing characteristics of deceased patients with living, age- and sex-matched FRDA controls, cardiac dysfunction was the most frequent cause of death, most commonly congestive heart failure or arrhythmia. In this study, median age of death due to cardiac cause was 17 years, while median age of death due to noncardiac cause was 29 years. However, survival may be significantly prolonged with treatment of cardiac symptoms, treatment of diabetes, and prevention and control of complications resulting from prolonged disability. Carefully managed patients may live several more decades. Currently no treatments affect the degenerative process, but emerging knowledge from characterization of the FRDA gene product may change this picture in the future.

Vitamin E Deficiency

Patients with ataxia and isolated vitamin E deficiency (AVED ; OMIM 277460), a cause of ataxia with sensory neuronopathy similar to that found in FRDA, may show a phenotype that closely resembles typical FRDA, but more commonly have atypical features (see Case Example 49.2 ). Head titubation and dystonia, frequent in AVED, are unusual in FRDA. AVED patients may retain lower limb reflexes. Peripheral nerve conduction studies may be normal. Somatosensory evoked potentials show normal peripheral and delayed central conduction, indicating a disproportionate involvement of the central versus the peripheral axonal branch of primary sensory neurons. Serum vitamin E levels are markedly reduced in all patients and represent the diagnostic test. The disease is caused by mutations in the gene encoding alpha-tocopherol transfer protein, the liver enzyme that loads alpha-tocopherol onto lipoproteins. The disease is treatable with high oral doses of vitamin E.

Case Example 49.2

History

The patient is a 17-year-old right-handed boy from Sicily who has an older sister with a similar disease and whose parents are second-degree cousins. He was born at term after an uneventful pregnancy. Development was normal. Since childhood, the patient has been considered clumsy and never participated in sports in school. At age 7, a mild kyphoscoliosis was diagnosed, which then showed very limited progression. At around the same age, the presence of bilateral genu recurvatum was noticed. No other major health problem was evident until approximately age 13, when the patient started to have balance problems, to sway when walking, and occasionally to fall. His gait has gradually worsened and he now requires support to prevent falling. In the last year, the mild dysarthria has been noticed. A nodding head tremor has also appeared during the last year.

The patient goes to a technical school; he is able to write without difficulty and to use his hands in skilled activities. There is no dysphasia and no bowel or bladder incontinence. The patient has a regular diet and does not drink or smoke. There is no history of major medical or surgical illnesses and he does not take any medications.

Physical Examination

The patient is an average-size adolescent in apparent good general health. The general physical examination reveals a mild kyphoscoliosis and a bilateral genu recurvatum. The rest of the examination is negative.

Neurological Examination

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  Mental status : The patient is well oriented. He can write a sentence and prints his name without difficulty. He recalls 3 out of 3 objects at 0 and 3 minutes.

  
  
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  Cranial Nerves II–XII: Speech is mildly dysarthric but easy to understand. There is a continuous nodding tremor of the head at a frequency of about 2–3 Hz. There is a mild bilateral eyelid retraction. Extraocular movements are full. There is mild gaze-evoked nystagmus. The rest of the cranial nerve examination is normal.

  
  
• 
  

  Motor examination : Muscle bulk and strength are normal in the four limbs. The muscles of all four extremities are markedly hypotonic.

  
  
• 
  

  Reflexes : Absent proximally and distantly in the upper and lower extremities. The plantar response is extensor bilaterally.

  
  
• 
  

  Sensation : Intact to light touch, pin prick, and temperature. Loss of vibration sense at the malleoli bilaterally and severe impairment at the knees bilaterally. Joint position sense is impaired to the ankles bilaterally.

  
  
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  Coordination : Finger to nose testing is within normal limits. Rapid alternating movements are very mildly impaired. Writing and fine movements of the hand appear normal. Mild ataxia at heel-to-shin testing.

  
  
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  Gait : Romberg is positive. Gait is moderately ataxic with polydirectional swaying, enlarged base, and irregular steps.

Nerve Conduction Studies

MCV is normal in the right common peroneal nerve, left common peroneal nerve, and left tibial nerve. SNAP is decreased in the left median nerve (3.1 μV); SCV is normal in the left median nerve.

MRI of the Brain and Spine

The upper cervical cord is slightly reduced in size. There is moderate diffuse atrophy of the cerebellum and of the cerebral hemispheres with mild increase in size of the ventricular system and dilatation of the sulci. There is no definite signal abnormality.

EKG

Sinus tachycardia (120 beats per second); no other EKG abnormality.

Echocardiography

Normal.

Laboratory Tests

Routine laboratory testing, including thyroid status and lipoproteins, was normal. An FRDA molecular test was negative. Plasma vitamin E level, determined by HPLC, was undetectable.

Comment

This young man is the offspring of consanguineous parents and has a similarly affected sister, indicating the recessive nature of his ailment. He presents with a 3-year history of gait instability, loss of balance, and occasional falls. More recently a mild dysarthria and head tremor were added to the clinical picture. There is deep sensory loss in the lower limbs, absent tendon reflexes in the four limbs, and bilateral extensor plantar responses. SNAPs are reduced but still measurable; MCV and SCV velocities are normal. There is no evidence of cardiomyopathy other than sinus tachycardia, in particular no repolarization abnormalities in the EKG and no heart hypertrophy. Overall, the clinical picture resembles an early case of FRDA. However, a few findings are unusual in this case: coordination is surprisingly well preserved in the upper limbs, and there is a continuous nodding head tremor and also eyelid retraction. Kyphoscoliosis is frequent in FRDA, but genu recurvatum is not typical and pes cavus foot deformities are absent. The molecular test for FRDA turned out to be negative. Plasma vitamin E measurement demonstrated profound deficiency of this vitamin, not accompanied by plasma lipid or lipoprotein abnormalities, as found in ataxia with isolated vitamin E deficiency (AVED). Mutation analysis of the tocopherol-transfer protein gene revealed that this patient and his sister are both homozygous for a common AVED mutation found in North Africa and Sicily.

The clinical features of this patient more commonly seen in AVED than in FRDA include the nodding tremor of the head, the minimal upper limb ataxia, the lack of hypertrophic cardiomyopathy, and the preservation of SNAPs. In this regard, vitamin E deficiency affects the central branch of the T-shaped axon of primary sensory neurons more than peripheral branch, while FRDA affects both branches equally. Genu recurvatum, eyelid retraction, and the diffuse mild cerebellar and cerebral atrophy on MRI are not typical of AVED and represent peculiar features of this patient.

The patient was treated with 500 mg of alpha-tocopherol daily. Plasma vitamin E measurement, repeated after two months, was normal. The patient has remained on treatment for several years and not only has there been no further deterioration of the neurological symptoms, but there have been some improvements of his dysarthria and of his gait.

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