Friedreich Ataxia - Clinical Tree

Introduction

In 1863, Nicholaus Friedreich, professor of medicine in Heidelberg, Germany, wrote three articles “about a degenerative atrophy of the posterior columns of the spinal cord” causing progressive ataxia, sensory loss, and muscle weakness. The cause of what was called “Friedreich ataxia” (now abbreviated as FRDA) remained mysterious for more than 130 years thereafter. For many years, even the definition of this entity, as well as its inheritance, was somewhat blurred by confusing similarities with different inherited ataxias and neuropathies that were subsequently described. Landmark studies carried out in the late 1970s and early 1980s established the autosomal recessive pattern of inheritance and defined rigorous diagnostic criteria. These studies were key for the collection of clinically homogeneous families to be used for biochemical studies, and, after 1985, for molecular genetic studies. Eventually, the FRDA gene ( FXN ), and its major mutation, an intronic GAA triplet repeat expansion, were discovered in 1996. Thanks to this discovery, genetic testing, genotype-phenotype correlations, pathophysiological studies, and new approaches to treatment are becoming possible.

Epidemiology

In Caucasians, FRDA accounts for almost half of the cases of recessive ataxia. It has a prevalence of around 2×10 ⁻⁵ in Western Europe. This figure declines as one moves towards the East and North, likely because of a distant founder effect. Additionally, there are local clusters of FRDA due to a founder effect, such as those observed in Rimouski, in Québec, and in Kathikas-Arodhes, Cyprus. FRDA is almost nonexistent in Japan and possibly in all non-Caucasian populations (see below).

Pathology

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.

Case Example 49.1

History

The patient is a 14-year-old right-handed boy who has two older sisters with a similar disease. He was born at term after an uneventful pregnancy. Development was normal and he was healthy until approximately age 5, when he started to sway when walking. His gait worsened gradually. He is able to run, but has suffered minor injuries from falls. He does not have numbness or tingling. He is able to write and has no difficulties using his arms. There is no bowel or bladder incontinence and he has no difficulty with swallowing or with his speech. He is bothered most by feeling “dizzy” every 2 to 3 weeks, which at times requires him to sit. He has a poor appetite.

The patient has no history of medical or surgical illnesses and does not take any medication.

Physical Examination

The patient is a thin boy in apparent good general health. The general physical examination is negative except for mild kyphoscoliosis.

Neurological Examination

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.
Cranial Nerves II–XII: Speech is fluent without dysarthria. Extraocular movements are full; there is mild gaze-evoked nystagmus and fixation instability. The rest of the cranial nerve examination is normal.
Motor Examination : There is marked proximal and distal atrophy of all four extremities, especially the arms, without fasciculations. Strength is 5/5 proximally in the upper extremities with 5− grips bilaterally and 5/5 strength distally in the lower extremities. Tone is normal in the axial muscles and in all four extremities.
Reflexes : Absent proximally and distally in the upper and lower extremities. The plantar responses are flexor bilaterally.
Sensation : Intact to light touch, pinprick, proprioception, temperature and vibration.
Coordination : There is mild ataxia on heel-to-shin testing more than finger-to-nose testing. Mild dysdiadochokinesia. Writing and fine hand movements are normal.
Gait : Romberg sign is present. He is able to walk on his toes and heels, and there is good stride and arm swing. He has a slightly ataxic gait and has difficulty with tandem gait.

Nerve Conduction Studies

Mild slowing of MCV of right common peroneal nerve (36.5 m/sec), left common peroneal nerve (38.5 m/sec), left tibial nerve (37.9 m/sec). Absent SNAPs of the left median, ulnar, superficial peroneal, and bilateral sural nerves with absent left H-reflex.

MRI of the Brain and Spine

The upper cervical cord is slightly reduced in size without definite intrinsic signal abnormality. The posterior fossa and supratentorial compartment structures are normal.

EKG

Diffuse anomalies of repolarization with inverted T-waves in most derivations.

Echocardiography

Thickness of the left ventricular wall and of the interventricular septum are at the upper limit of normal. Heart mass is increased (132 g/m ² , normal <120).

Laboratory Tests

Routine laboratories, thyroid studies, anti-GM1, phytanic acid, vitamin E levels were normal. A FRDA molecular test revealed two expanded alleles corresponding to 700 and 900 GAA triplets.

Comment

This 14-year-old boy has a 9-year history of progressive gait difficulty, producing falls. Examination is significant for mild ataxic gait, the presence of a Romberg sign, fixation instability, moderate distal wasting of all four extremities, absent tendon reflexes, and mild appendicular ataxia greater in the legs than the arms. The case is typical of early-stage FRDA, except for a slower than usual progression. It illustrates well the usefulness and limitations of clinical diagnostic criteria, which if strictly applied would not have allowed a definite diagnosis. Onset at 5 years is well within the spectrum, and earlier than in most cases. A positive family history with two affected sisters, but healthy parents, suggests recessive inheritance of the condition. There is progressive truncal and limb ataxia, and tendon reflexes are absent in all four limbs. There are no cardiac symptoms, but EKG and echocardiography reveal repolarization abnormalities and moderate heart hypertrophy, typical findings in FRDA. However, the clinical course has so far been very slow, and the patient is still able to run, has flexor plantar responses, and has no dysarthria 9 years after onset. Also, there is no evident deep sensory loss, an unusual finding this late in the clinical course. Conversely, amyotrophy is more prominent than usual. Neurophysiological findings suggest the diagnosis of FRDA, particularly because SNAPs are absent and the H-reflex cannot be obtained, but MCVs are a little less than 40 m/sec. MRI, excluding cerebellar atrophy and showing some thinning of the cervical spinal cord, is highly suggestive of the diagnosis. All things considered, there is a very clear indication for ordering molecular testing, which confirmed the diagnosis.

Clinical Aspects

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.

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