Check Your Diagnosis — Patient 25
Gholam K. Motamedi, M.D.
Patient #25 presented with progressive gait and limb ataxia, mild distal symmetrical sensory loss, diminished deep tendon reflexes, weakness of the gluteal muscles, and bilateral extensor plantar responses. These findings indicate cerebellar, peripheral nerve (or dorsal root ganglion), and corticospinal involvement and imply a multisystem degenerative disease. There was no evidence of autonomic dysfunction, and eye movements were left unaffected. Extrapyramidal involvement was not present arguing against one of the Multi-System Atrophies (MSAs), such as olivopontocerebellar atrophy (OPCA).
The most salient feature in this case is the patient's marked progressive ataxia. Ataxia may be due either to cerebellar or proprioceptive dysfunction, though it is rarely difficult to distinguish the two. However, when both are present, diagnostic difficulties arise. The findings in this case—gait and limb ataxia, titubation, loss of check response, and dysdiadochokinesia—point to an abnormality in the cerebellar system. This patient also had evidence of a peripheral neuropathy with involvement of the posterior columns evidenced by decreased position and vibratory sense. The degree of proprioceptive abnormality was not sufficient to explain the marked gait disturbance, however. While this patient exhibited dysfunction in both the cerebellar and proprioceptive systems, the cerebellar involvement was most impressive. The primary defect therefore lies somewhere in the connections to, from, or within the cerebellum.
We typically separate causes of cerebellar dysfunction by the age of onset and acuity of presentation. Typical causes of acute cerebellar dysfunction in childhood include drug ingestion, infection (cerebellitis), several genetic disorders, brain tumors (cerebellar astrocytomas, etc.), postinfectious immune syndromes, migraine, and cerebellar hemorrhage/stroke. In adults, acute causes of cerebellar dysfunction are largely restricted cerebellar stroke or hemorrhage. One must also consider demyelinating diseases, such as multiple sclerosis, and posterior fossa tumors. Postinfectious cerebellitis is an uncommon, but well-recognized cause in adults as well as children. Chronic or progressive ataxias in children are typically caused by posterior fossa tumors, structural abnormalities such as basilar impression, Chiari malformations, the Dandy-Walker malformation and other cerebellar aplasias, or a hereditary form of ataxia. Hereditary ataxias in childhood include the typical cerebellar degenerative diseases, such as Machado-Joseph disease, Olivopontocerebellar atrophy, Ramsay-Hunt syndrome, Friedreich's ataxia, and ataxia-telangiectasia among a host of metabolic disorders, such as abetalipoproteinemia, Hartnup disease, juvenile GM2 gangliosidosis, juvenile sulfatide lipidosis, maple syrup urine disease, Marinesco-Sjogren syndrome, Refsum disease, pyruvate dysmetabolism, and sea-blue histiocytosis. Adreoleukodystrophy and Leber optic atrophy may also cause cerebellar dysfunction. In adults, chronic ataxias are due usually to one of the spinocerebellar atrophies or toxin exposure (e.g., alcohol).
Given this bewildering array of possible diagnoses, one might consider it impossible to reach a final diagnosis. Ataxia is a common finding, so it, in itself, cannot be used to define a specific disease entity. One must consider other clinical information in arriving at a diagnosis. For instance, a history of intermittent ataxia and metabolic acidosis should raise the possibility of amino acid or organic acid dysmetabolism. Retinits pigmentosa, sensorineural deafness, neuropathy, and ataxia are very suggestive of Refsum disease. Cranial nerve dysfunction associated with signs of increased intracranial pressure and ataxia should prompt a search for a posterior fossa tumor. In this case, the constellation of posterior column signs, ataxia, diminished deep tendon reflexes, lower extremity weakness, and extensor plantar responses raise the possibility of Friedreich's ataxia, though the age of onset and absence of other supporting findings (kyphoscoliosis, pes cavus, deafness, etc.) makes this diagnosis less likely. Unfortunately, separating the causes of hereditary ataxia in adults is extremely difficult on purely clinical grounds. Most of the spinocerebellar degenerations have relatively late onsets (beyond the age of puberty), and most demonstrate some degree of cerebellar, pyramidal, and peripheral nerve involvement. However, most of these entities are also autosomal dominant, so a family history is often very instructive. In this case, there was no family history to suggest an autosomal dominant mode of inheritance. This may be due to a new mutation arising in this individual, or to an autosomal recessive inheritance pattern (as in Friedreich's ataxia), wherein neither parent would be affected.
The patient was found to carry the genetic defect responsible for Friedreich's ataxia, an unstable trinucleotide repeat (GAA) expansion in the first intron of the gene coding for frataxin. The triplet repeat expansion was only moderate, most likely accounting for the relatively late onset of the disease and mild symptomatology in this case. He was treated with physical therapy to assist in his gait. No other treatment options are available for this progressive disease. The patient was also told of the genetic nature of his disease.
Nicholaus Friedreich described the "degenerative atrophy of the posterior columns of the spinal cord" that now bears his name in 1863. The initial reports were met with skepticism, but the disease has since been well accepted. Until recently, controversy continued to surround this entity, largely because of the sizeable array of degenerative ataxias and difficulty in categorizing them. The Quebec Collaborative Group provided diagnostic criteria in 1976, and Anita Harding updated these criteria in the 1980's. The original description included an age of onset before 20 years, while Harding's categorization included an age of onset before 25 years. These differences reflect the well-recognized variability in disease severity and age of onset that is more common with Friedreich's ataxia than other recessive neurological diseases. Recent findings regarding the genetic underpinnings of this disease provide a more secure diagnostic test.
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that represents the most common hereditary ataxia (accounting for at least 50% of cases). The estimated prevalence of FRDA is 1-2/50,000 in North American and European populations. All races are affected and males and females are equally affected. Because it is autosomal recessive, parents are usually asymptomatic (in contradistinction to other adult onset hereditary ataxias which are dominantly inherited), though the consanguity rate is high. Transmission risk from affected parents to offspring is 1 in 220.
FRDA results from an unstable expansion of a polymorphic GAA repeat in the first intron of the X25 gene located on chromosome 9. The gene encodes a mitochondrial protein, frataxin, with unclear functions, but thought to regulate iron homeostasis. Yeast strains lacking a homologous protein develop mitochondrial dysfunction, resulting in excessive mitochondrial iron accumulation and defective oxidative metabolism. Patients with FRDA demonstrate similar abnormal mitochondrial iron deposition and pathological involvement of postmitotic tissues (though frataxin is not clearly recognized as a mitochondrial protein in humans).
All known cases of FRDA are caused by abnormalities resulting in decreased or absent transcription of the frataxin gene. Point mutations are a rare cause of FRDA, accounting for only 2% of recognized cases. Four different point mutations have been described, with all patients being heterozygous for the mutation. All result in a truncated form of frataxin. It is unknown whether homozygous point mutations have not been described because of their relative rarity, or if a homozygous mutation is lethal. The remainder of FRDA cases are due to the GAA expansion with 94% of cases homozygous for the expansion. In the vast majority of cases (98%), the GAA repeat expansion occurs in the first intron of the frataxin gene. FRDA, therefore, represents a novel genetic entity—it is the first disease recognized to result from a genetic abnormality within an uncoded region of DNA. In all other triplet repeat expansion diseases causing neurological dysfunction (myotonic dystrophy, Huntington's disease, Fragile X syndrome, Kennedy's syndrome, etc.), the defect has occurred within a coded region of DNA (an exon), generally resulting in a polyglutamine tail or other intervening stretch of abnormal amino acid sequences. This usually results in a gain of function (the altered protein may take on a new function) that results in the disease process. In FRDA, however, the abnormality results in decreased transcription, and hence translation, of frataxin. It is the decreased protein production, or loss of function, that is responsible for the disease phenotype. The exact mechanism by which this triplet repeat expansion within an intron results in decreased transcription of the gene is unknown. The sequence codes for a DNA segment with all purines on one strand and all pyrimidines on the other. This structure is thought to wind back down the major groove of the DNA helix and interfere with the transcriptional process, either by blocking the promoter region or by blocking transcriptional elongation. The expansion size is inversely correlated with transcriptional output. In patients with larger expansions, less frataxin mRNA is produced. This likely accounts for the observation that patients with larger expansion sizes show an earlier age of onset and more profound disabilities than those with smaller expansion sizes. Clinically, this poses a slight problem since patients with relatively small expansion sizes tend to present later in life, have a slower progression, are less likely to demonstrate evidence of a cardiomyopathy, and may retain deep tendon reflexes. These patients may be considered to have another of the late onset spinocerebellar degenerations unless FRDA is considered in the differential diagnosis.
Friedreich originally described this syndrome in nine members of three sibships with an age of onset near puberty. Ataxia and dysarthria were prominent; sensory loss and weakness were late findings in these cases. He also described nystgmus, scoliosis, foot deformity, and cardiac abnormalities in these patients. Erb later described loss of deep tendon reflexes in 1875.
Harding's diagnostic criteria include:
- Autosomal recessive inheritance
- Age of onset before 25 years
Within 5 years from onset
- Limb and trunk ataxia
- Absent tendon reflexes in the legs
- Extensor plantar responses
- Motor NCV > 40 m/s in upper limbs with small or absent SNAPs
After 5 years from onset
- Above plus dysarthria
Additional criteria, not essential for daignosis (present in 2/3)
- Pyramidal weakness of the legs
- Absent reflexes in the upper limbs
- Distal loss of joint and position sense in lower limbs
- Abnormal EKG
Other features, present in <50%
- Optic atrophy
- Distal weakness and wasting
- Pes cavus
- Diabetes mellitus
Symptoms usually begin between the ages of 8-15 years, but the range extends between 18 months and 25 years. Several reports describe families with later onset (between 20-30 years of age), but fulfilling all other diagnostic criteria. These families generally have smaller GAA repeat sizes and less severe disease courses. Gait ataxia is the most common first presenting symptom, although some patients fist evidence scoliosis or cardiac symptoms. Dysarthria, areflexia, pyramidal weakness of the legs, and distal loss of joint position sense are inconstant findings at presentation, but generally are present at some point during the course of the disease. Extensor plantar responses are present in 90% of patients.
Early childhood presentation differs slightly from the typical disease course. Children may be slow in learning how to walk, and, when they can ambulate, they do so in a clumsy and awkward manner. Early in the disease course children may demonstrate motor restlessness similar to chorea. Pseudoathetosis is also sometimes evident.
Flexor spasms are common, but muscle tone is usually normal (though some patients develop hypotonia later in the disease course). Muscle wasting, particularly in the upper limbs occurs in approximately 50% of patients. Symmetrical, slowly progressive weakness affects the lower extremities, particularly pelvic girdle muscles. In the majority of patients, the first significant weakness appears in the hip extensors, followed in a variable manner by weakness in other lower limb muscles. Upper extremity and trunk strength remain nearly normal until late stages of the disease.
The majority of cases show loss of vibration and position sense. Rhomberg's sign is usually present at the time of diagnosis. Decreased pain and touch perception may be present. Scoliosis is common and may be severe, especially in early onset cases. Nearly half of the patients have pes cavus and/or equinovarus deformity of the feet. Peripheral cyanosis of the lower limbs is common and most patients complain of cold feet. Optic atrophy is present in 25% of cases, but visual acuity is rarely severely reduced. Only 20% show evidence of nystamus. Extraocular movements are usually abnormal, with impaired saccadic and smooth pursuit movements (but frank ophtalmoplegia does not typically occur). Ten percent develop sensorineural deafness and one-third develop diabetes mellitus or a mild carbohydrate intolerance. At least 2/3 of patients with FRDA show evidence of cardiomyopathy. Symptoms are rare with the exception of exertional dyspnea. Angina and palpitations may occur but are rare. There may be clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds in asymptomatic patients. Cardiac failure and arrhythmias occur as a preterminal event. Nearly 65% of patients with FRDA have an abnormal ECG, most commonly showing evidence of ventricular hypertrophy or widespread T-wave inversion. Symmetric concentric hypertrophy is the most common finding by echocardiography.
Histologically, there is extensive degeneration, especially within the cervical spinal cord, of the posterior columns and the cell bodies (large neurons of the dorsal root ganglion and Clarke's column) supplying this region. There is also extensive sclerosis of the lateral columns (corticospinal tracts) and spinocerebellar tracts (especially in the lumbar spine). The brain, cerebellum, and brainstem are left relatively unaffected by this disease, with the exception of occasional patchy loss of Purkinje cells and mild degenerative changes in the brain stem nuclei and optic tract.
Electrophysiologically, the above pathology is reflected in the delayed, dispersed somatosensory evoked potentials recorded in the sensory cortex, and abnormal central motor conduction. Nerve conduction studies are helpful in differentiating FRDA from CMT. FRDA shows normal or minimally slow conduction velocities with absent or severely reduced sensory nerve action potential consistent with axonal degeneration in contradistinction to CMT which shows a typical demyelinating pattern. Visual evoked responses are usually reduced in amplitude and show delayed latencies.
Patients progress at variable rates. The mean age at which time a wheelchair becomes necessary is 18.2 years. Most patients are unable to walk by 20 years of age. Weakness is not the primary cause for lack of ambulation, but rather cerebellar dysfunction. Reported mean ages of death are variable and depend on age of presentation and rapidity of disease progression. Patients may survive into their seventh decade, though the mean age of death is typically around the mid 30s. Death generally occurs early in patients with significant cardiac disease and/or diabetes mellitus. There is no effective treatment for the disease.