Pathogenesis and Pathophysiology. SCA5 is an autosomal dominant hereditary disorder that has been described in a large American ADCA-III family with an almost pure cerebellar phenotype. Using linkage analysis, the SCA5 locus has been mapped to chromosome 11cen. The SCA5 gene has not yet been cloned, and the mutation is unknown.
Epidemiology and Risk Factors. To date, SCA5 has been described in a single American ADCA-III family. Information on the incidence and prevalence of SCA5 is not available. In our experience, ADCA-III families account for less than 25 percent of all ADCA families. SCA5 is a genetically determined disorder with no known environmental risk or precipitation factors. Children from SCA5 patients have a 50 percent risk of developing the disease.
Clinical Features and Associated Disorders. SCA5 begins at any time between childhood and late adulthood with features of anticipation. The most dramatic examples of decreasing age at onset are observed with maternal transmission. On average, the disease starts at about the age of 30 years. The clinical syndrome is predominantly cerebellar and is marked by ataxia of gait and stance, ataxia of limb movements, dysarthria, and cerebellar oculomotor disturbances. Bulbar involvement has been noted in only two patients in whom the disease had an early onset. y
Differential Diagnosis and Evaluation. Since the SCA5 gene has not yet been isolated, a test that allows a molecular diagnosis of SCA5 in individual patients is not available. In appropriate families, a diagnosis of SCA5 can be made by linkage analysis with markers closely linked to the SCA5 locus on chromosome 11cen. Clinically, SCA5 can be distinguished from other types of ADCA by its predominantly cerebellar syndrome and its slower rate of progression.
Information about the electrophysiological characteristics of SCA5 is lacking. In patients with ADCA-III, nerve conduction and evoked potential studies produce normal results. MRI of SCA5 patients shows cerebellar atrophy with no evidence of brain stem involvement.
Management, Prognosis, and Future Perspectives. At present, there is no specific treatment for patients with SCA5. Symptomatic and palliative therapy is similar to that described for SCA1. Although SCA5 is disabling, the disease progresses slowly, and life expectancy is not shortened. Quantitative data about the rate of progression in SCA5 are not available. At present, the chromosomal localization of the SCA5 gene is known. To further understand the pathogenesis of SCA5 and to develop diagnostic tests, the SCA5 gene must be cloned and the mutation identified.
Other Degenerative Ataxias The ADCAs without retinal degeneration and with additional extracerebellar symptoms (ADCA-I) are a heterogeneous group of autosomal dominant diseases, some of which are due to mutations at the SCA1, SCA2, or SCA3 locus. An additional locus, SCA4, has been mapped to chromosome 16q in an American family characterized clinically by cerebellar ataxia, pyramidal tract signs, and sensory neuropathy. Detailed information about SCA4, however, is lacking.y The SCA6 locus maps to chromosome 19p. The mutation has been identified as a small CAG repeat expansion in a gene that codes for the alpha 1A voltage-dependent calcium channel subunit. Clinically, SCA6 families have an almost pure cerebellar phenotype.
AUTOSOMAL DOMINANT CEREBELLAR DISORDERS WITH RETINAL DEGENERATION
Pathogenesis and Pathophysiology. ADCA with retinal degeneration is an autosomal dominant disorder that is distinct from other types of ADCA in that it has the constant additional feature of retinal degeneration. ADCA with retinal degeneration has also been named ADCA-II. y The gene locus of ADCA-II, SCA7, has been mapped to chromosome 3p. y , y All available data suggest that ADCA-II is a genetically homogeneous disorder. Recently, a protein containing a polyglutamine expansion was detected in the brains of patients with SCA7, suggesting that SCA7 is caused by a CAG repeat expansion. y The clinical observation of marked anticipation in ADCA-II families also points toward an unstable mutation. Neuropathological examinations of ADCA-II patients have consistently revealed the presence of OPCA. All patients have primarily macular degeneration, which then spreads to involve the retina. There is often secondary atrophy of the optic nerve.
Epidemiology and Risk Factors. ADCA-II has been described in a small number of families. Information about the incidence and prevalence of ADCA-II is not available. ADCA-II is a genetically determined disorder with no known environmental risk or precipitation factors. Children
Figure 35-2 T1-weighted MRIs of infratentorial brain structures and cervical spinal cord in different types of degenerative ataxia. The images show the posterior fossa in the midsagittal uppeeleft) and axial slices at the level of the middle cerebellar peduncles (upper right), inferior olive complex lower left), and dens axis (ower right). A, Normal. B, SCA2. There is severe cerebellar and brain stem shrinkage, suggesting the presence of OPCA. In additiona, the cervical spinal cord is atroC, SCA3. There is only mild cerebellar vermal atrophy with additional involvement of the spinal c<D, IDCA-P/MSA. There is severe cerebellar and brain stem shrinkage, suggesting the presence of OPCA. The cervical spinal cord has normal size.
from ADCA-II patients have a 50 percent risk of developing the disease.
Clinical Features and Associated Disorders. ADCA-II begins at any time between childhood and late adulthood with features of anticipation. Anticipation is greater when the disease is transmitted by males. On average, ADCA-II begins around the age of 25 years. The clinical picture and the course of the disease depend on the age of onset. In patients with late disease onset (after the age of 40 years), cerebellar ataxia is always the first symptom. There are some exceptional patients who never develop visual problems. In most patients, however, ataxia is followed by progressive loss of vision. In about half the patients with late disease onset, there is no evidence of retinal degeneration
or optic atrophy, suggesting that retinopathy affects only the macula. All patients in whom the disease begins earlier (before the age of 40 years) have visual problems, starting either prior to or at the same time as the appearance of cerebellar ataxia. The majority of these patients have retinal degeneration, and some also have optic atrophy. Tendon reflexes are usually absent. A number of additional symptoms occur in less than half the patients and tend to be more frequent in patients with a long disease duration. These symptoms include gaze palsy, dysphagia, hearing loss, and muscle weakness. Dementia and basal ganglia symptoms are not typical features of ADCA-II. [d , y
Differential Diagnosis and Evaluation. The diagnosis of ADCA-II is based on the clinical observation of ataxia
in combination with progressive visual loss and a positive family history suggesting autosomal dominant inheritance. In selected families, the diagnosis can be further substantiated by demonstration of linkage to the SCA7 locus. Autosomal dominant retinitis pigmentosa is clearly distinct from ADCA-II in that ataxia is not a feature of this disorder. Sporadic cases involving ataxia and retinal degeneration may pose considerable diagnostic problems, particularly if reliable information about the family history is lacking. The differential diagnosis of these cases includes early-onset cerebellar ataxia with retinal degeneration (Hallgren's syndrome), Refsum's disease, abetalipoproteinemia, and neuronal ceroid lipofuscinosis.
MRI shows cerebellar and brain stem atrophy, suggesting the presence of OPCA. The electrophysiological features of ADCA-II have not been systematically studied. Electroretinography may be used to detect retinal degeneration early. There is no specific treatment for SCA7.
Prognosis and Future Perspectives. ADCA-II is a progressive disorder, and it progresses more rapidly in patients with early disease onset. On average, patients in whom the disease begins in childhood die 5 years after disease onset, whereas adult patients survive for about 15 years after onset. At present, the chromosomal localization of SCA7 is known. Immunocytochemical studies suggest that the mutation is an expanded CAG repeat. To further clarify the pathogenesis of SCA2 and to develop a diagnostic test for SCA7, the SCA7 gene must be cloned and the mutation identified.
Pathogenesis and Pathophysiology. DRPLA is an autosomal dominant disease that occurs mainly in Japan. The DRPLA gene is localized on chromosome 12p. DRPLA patients show an unstable expanded CAG repeat within a coding region of the gene. Whereas the repeat length in normals varies between 7 and 23 trinucleotides, in DRPLA patients there is one allele within a range of 49 to 79 repeat units. As in other trinucleotide repeat disorders, DRPLA alleles display intergenerational instability and show a tendency toward further expansion. Larger expansions frequently occur with paternal transmission. There is an inverse correlation between the length of the CAG repeat and the age of onset, the largest alleles occurring in patients with juvenile disease onset. Because of the intergenerational instability of expanded repeats, the age of onset varies with features of anticipation. y
DRPLA is also observed as an apparently sporadic disease. Molecular analysis in such patients has revealed expanded alleles of the DRPLA gene, showing that the molecular basis of inherited and sporadic DRPLA is the same. y The gene product encoded by the DRPLA gene, atrophin, is a 190-kD protein of unknown function that has been detected in various body tissues. In the brain, the DRPLA gene product is localized in the cytoplasm of neurons. An additional 205-kD protein has been found in DRPLA patients that probably represents the mutated protein with an elongated polyglutamine stretch. y
The degenerative pathological changes seen in DRPLA mainly affect the dentate nucleus with its projection to the red nucleus and the external pallidum with its projection to the subthalamic nucleus. Usually the dentatorubral system is more severely affected. Atrophy may also be seen in other basal ganglia nuclei, the thalamus, and the inferior olives. In several cases, degeneration of the posterior columns and spinocerebellar tracts has been described. Involvement of the pontine tegmentum has been found also, and this appears to correlate with oculomotor abnormalities.
Epidemiology and Risk Factors. DRPLA has been predominantly reported in Japan, but diseases with similar features have been occasionally observed in non-Japanese families. It has recently been shown that the Haw River syndrome, a hereditary disease occurring in an African-American family, is genetically identical with DRPLA.y In Japan, the prevalence rate of DRPLA has been estimated to be 0.1 per 100,000. y
Clinical Features and Associated Disorders. Onset of DRPLA occurs at any time from infancy to late adulthood with features of anticipation. On average, clinical features begin to appear at about the age of 30 years. The clinical picture of DRPLA is characterized by a wide range of manifestations, the precise nature of which depends on the age of onset and the length of the CAG repeat. The most constant clinical findings in DRPLA are cerebellar ataxia, dysarthria, and progressive dementia. These features are present in almost all patients regardless of age of onset and repeat length. Patients in whom the disease begins before the age of 21 years and who have large expansions show the clinical syndrome of progressive myoclonus epilepsy. Some of them have opsoclonus. In patients with a later disease onset and shorter expansions, myoclonus and seizures are less prominent. Instead, many of these patients have involuntary choreic or dystonic movements and psychiatric abnormalities including personality changes, hallucinations, and delusional ideas. Various oculomotor disturbances have been described including gaze-evoked nystagmus, broken-up smooth pursuit, square-wave jerks, and vertical gaze palsy. y
Differential Diagnosis and Evaluation. The diagnosis of DRPLA is made by demonstration of an expanded CAG repeat at the DRPLA locus. The differential diagnosis of juvenile-onset disease presenting with progressive myoclonus epilepsy includes Unverricht-Lundborg disease, mitochondrial encephalomyopathy with ragged red fibers (MERRF), neuronal ceroid-lipofuscinosis, Lafora body disease, and sialidosis. Adult-onset disease may be confused with Huntington's disease. Clinically, the presence of ataxia and seizures makes Huntington's disease unlikely and points to a diagnosis of DRPLA. DRPLA is distinct from ADCAs in that it has the clinical feature of dementia. A syndrome of ataxia, myoclonus, and rapid cognitive decline similar to that seen in DRPLA may occur in patients with Creutzfeldt-Jakob disease. Compared to DRPLA, however, Creutzfeldt-Jakob disease usually progresses faster. In exceptional cases, DRPLA may be mistaken for schizophrenia.
Molecular studies have shown that DRPLA and the Haw River syndrome are identical. Electroencephalographic (EEG) background activity is slowed in almost 80 percent of DRPLA patients. More than half have epileptiform EEG patterns, and EEG reveals photosensitivity in about one
third.y MRI of DRPLA patients shows atrophy of the superior cerebellar peduncles. In addition, T2-weighted images show high-intensity signals in the pallidum. y ,
Management. At present there is no specific treatment for DRPLA. DRPLA patients with epilepsy require standard antiepileptic treatment. Phenytoin should be avoided because it may worsen ataxia.
Prognosis and Future Perspectives. DRPLA is a progressive disorder. Quantitative data concerning the rate of progression in DRPLA are not available. As in Huntington's disease, SCA1, and SCA3, future research in DRPLA will focus on study of the mechanisms by which expanded CAG repeats lead to neurodegenerative cell death.
Episodic ataxia type 1 (EA-1) is an autosomal dominant disorder that is due to a missense mutation in the potassium channel gene, KCNA1, on chromosome 12p; the mutation leads to inefficient repolarization of the nerve cell membrane subsequent to an action potential. y EA-1 is a rare familial disorder. There is no information about the epidemiology of this disorder.
Onset of EA-1 occurs in early childhood. Clinically, EA-1 is characterized by brief attacks of ataxia and dysarthria. The attacks last for seconds to minutes and may occur several times per day. They are often provoked by movements and startle. Apart from ataxia, the attacks may have dystonic or choreic features. EA-1 is associated with interictal myokymia (i.e., twitching of the small muscles around the eyes or in the hands). Ataxia or gaze-evoked nystagmus is absent between attacks.y
A routine molecular genetic test for EA-1 is not available because different point mutations within the KCNA1 gene may lead to the disorder. Clinically, EA-1 can be differentiated from EA-2 by the shorter duration of the attacks, the presence of myokymia, and the absence of interictal ataxia and nystagmus. A number of rare metabolic defects of autosomal recessive inheritance may give rise to intermittent ataxia. These disorders include metabolic syndromes with hyperammonemia, aminoacidurias without hyperammonemia, and disorders of pyruvate and lactate metabolism. Interictal EMG of the muscles displaying myokymia shows spontaneous repetitive discharges that subside after nerve blockade. These abnormalities have also been termed neuromyotonia. y Neurographical and evoked potential studies do not reveal additional abnormalities. MRI of the head is normal.
Acetazolamide (250 mg 2 times a day) is beneficial in reducing attacks in some but not all kindreds. Anticonvulsants are used to reduce myokymia. EA-1 has a favorable prognosis in that the attacks tend to abate after early childhood. Electrophysiological studies of the abnormal potassium channels contribute to our understanding of the precise cellular mechanisms leading to intermittent ataxia and myokymia in EA-1, and improved understanding of the pathophysiology may lead to more effective therapies.
Episodic ataxia type 2 (EA-2) is an autosomal dominant disorder in which the responsible gene has been mapped to chromosome 19p. y The mutation causing EA-2 has been identified. The mutation affects the gene for the alpha 1A voltage-dependent calcium channel subunit and disrupts the reading frame. A CAG repeat expansion of the same gene is associated with a progressive form of ataxia, SCA6. The pathophysiology of EA-2 is poorly understood. A magnetic resonance spectroscopy study showed an abnormally elevated pH level in the cerebellum that was normalized by acetazolamide. y
EA-2 is a rare familial disorder, and information about its epidemiology is not available. Clinical onset of EA-2 usually occurs during childhood but may begin at any time from 6 weeks to 30 years of age. EA-2 is characterized clinically by recurrence of acute attacks of ataxia of gait and stance, limb ataxia, and dysarthria. The attacks last from several hours to a day or more. Emotional stress, exercise, and fatigue, but not movements or startle, may precipitate the attacks. The frequency of attacks varies widely, ranging from several times a day to less than once a month. Neurological examination between attacks discloses mild gait ataxia and gaze-evoked nystagmus. Some patients develop progressive ataxia and dysarthria. y , y
The differential diagnosis of EA-2 corresponds to that described for EA-1. In contrast to EA-1, however, EA-2 is often associated with MRI abnormalities. In particular, patients with progressive interictal ataxia show atrophy of the cerebellar vermis. y Electrophysiological investigations do not show consistent abnormalities.
Continued acetazolamide (250 mg 2 times a day) therapy completely abolishes episodes of ataxia in patients with EA-2. Cessation of acetazolamide usually prompts rapid recurrence of the attacks. y Experience with the first EA-2 family treated with acetazolamide suggests that acetazolamide remains effective in reducing attacks for up to 20 years. It is not clear whether acetazolamide is also effective in slowing the progressive ataxia that occurs in some family members. The clinical characteristics of EA-2 and its responsiveness to acetazolamide suggest that EA-2 is a channelopathy.
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