Ataxia telangiectasia (AT) is the most common form of infantile-onset cerebellar ataxia, with a prevalence estimated at 1-2.5 per 100,000. In the classical form of AT progressive gait unsteadiness begins in the second year of life, soon after beginning to walk. Slurring of speech and hand incoordination follow soon afterward. There may be a history of mild mental delay. Head thrusting movements with voluntary gaze are sometimes seen, arising from a characteristic gaze apraxia. With progressive ataxia, patients are usually wheelchair-bound in childhood. Rarely, milder forms may have age of onset of cerebellar symptoms as late as 9 years of age, or may present with the gaze apraxia and resting tremor along with the systemic signs. AT is systemic condition in which the underlying cellular abnormality is related to defective DNA repair. AT patients have immunological incompetence, increased risk of malignancy, and progeric features. Patients often have a history of chronic sinusitis and bronchiectasis and cutaneous infections, such as impetigo, before the onset of neurological abnormalities. AT patients also have an increased frequency of lymphoreticular malignancy and germ cell tumors in childhood, and adenocarcinoma and other solid tumors as adults. First degree relatives, obligate carriers of the recessively inherited mutation also have an increased incidence of adenocarcinoma. There is often a delay in development of secondary sex characteristics, and a delayed or irregular menstrual cycle, indicating the presence of hypogonadism. There is no specific treatment for AT. Prevention and treatment of infections and early diagnosis and treatment of malignancies have the most significant impact on long-term survival. Because of the marked radiosensitivity of non malignant tissues in AT, tumors should not be treated with radiotherapy.
Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare form of autosomal recessive progressive ataxia with features similar to FRDA. Although most commonly arising before 20 years of age, the age at onset ranges from 3 to 62 years. Patients develop progressive gait unsteadiness and dysarthria that progresses to wheelchair confinement at a more variable (3-37 years) pace than that of Friedreich's ataxia. Examination usually reveals dysarthria, hand incoordination, gait unsteadiness, arreflexia, and vibratory/proprioceptive sense loss. More than 1/2 patients have extensor plantar responses. Diffuse muscle weakness most prominent distally may be present in 42% of patients. Retinopathy (9%) or dystonia/bradykinesia (13%) are found in minority of patients. Cardiomyopathy is also found in about 19% of patients. Skin may show xanthelasmata or tendon xanthomas.
The diagnosis of AVED is made by determination of serum vitamin E (alpha tocopherol) levels, which are severely reduced or totally absent, or by DNA testing. Treatment consists of supplementation with oral doses of vitamin E at a dose of 800 mg twice daily, along with supportive care.
ATAXIA LINKS
The autosomal dominant spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative disorders characterized by progressive motor incoordination often in association with other progressive neurological deficits. Patients with these conditions typically have an affected parent or can trace the condition in family members in earlier generations. Most affected patients have a similar onset of slowly progressive gait ataxia, dysarthria, and hand incoordination, rarely preceded for several years by symptoms of diplopia or vertigo. Patients may first notice trouble walking down stairs, on uneven terrain or in the dark, running, or with other activities requiring greater balance. These subtle changes may be accompanied by occasional slurring of speech. Eventually imbalance and dysarthria are more obvious and problems with upper limb incoordination and dysphagia develop. Symptoms may be more easily recognized when there are other affected family members.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a form originally identified in families originating in the Quebec region of Charlevoix-Saguenay 20 years ago. Patients with this condition have since been identified in Tunisia. In this disorder progressive gait unsteadiness, slurred speech and limb spasticity, followed by distal amyotrophy begins at age 3-20 years, although patients never walk normally. Fundoscopic examination reveals a unique diagnostic finding, myelinated fibers embedding retinal blood vessels. There is ankle arreflexia and knee hyperreflexia. Nystagmus, Babinski signs, and proprioceptive sensory loss are universally present. Some patients have amyotrophy of the lower limbs. Echocardiograms frequently show mitral valve prolapse, but no cardiomyopathy. Patients are confined to a wheelchair by the fifth decade. Recently the gene responsible for ARSACS was identified on chromosome 13q11-12, and the protein designated sacsin. Sacsin contains three large segments with sequence similarity to each other, and that are highly evolutionarily conserved.
Friedreich's ataxia (FRDA) which represents out 1/2 of all cases of hereditary ataxia has a prevalence of 2-4/100,000 and is the most common form of hereditary ataxia. The classic form has an age of onset between 2-25 years, and about 25% have an atypical presentation with milder phenotype and onset after 25 years. Typically, gait unsteadiness begins in childhood often simultaneous with spinal scoliosis. Gait ataxia progresses steadily, but worsening of both ataxia and scoliosis may seem greater during rapid growth in puberty. Dysarthria and hand incoordination usually develop in the next few years. Gait unsteadiness is particularly poor in darkness, due to prominent involvement of posterior columns. Optic nerve atrophy occurs in approximately 25% and sensorineural hearing loss in 10% of FRDA patients. Progression of the ataxia in the classic form is fairly uniform and patients are wheelchair bound 12 years after onset. Death may occur from the mid-thirties to the sixth and seventh decades, particularly with the milder variants (see below). Death is often related to cardiomyopathy, diabetes, or aspiration pneumonia. There is as yet no definitive treatment for FRDA, and management chiefly involves supportive care and avoidance of complications. As in all patients with ataxia, physical therapy and rest combine to allow patients to cope with increasing disability. Dysphagia and aspiration should be minimized. Spasticity may be managed with baclofen. Spinal scoliosis or kyphoscoliosis is present in over 90% of patients and may appear before the onset of imbalance. Intervention with bracing or surgical placement of stabilizing rods may be necessary to avoid deformities that reduce mobility and pulmonary function. Ten to twenty percent of patients with FRDA develop diabetes mellitus, an average of 15 years after onset of ataxic symptoms.
Infantile-onset spinocerebellar ataxia (IOSCA) is a rare, recessively inherited condition recognized in a single kindred in Finland. These patients develop clumsiness and lose their ability to walk between 1 and 2 years of age. By school age, they develop ophthalmoplegia and loss of hearing. They develop sensory neuropathy by adolescence. Neurological examination reveals ataxia, athetosis, and muscle hypotonia with loss of deep tendon reflexes. Unlike FRDA, magnetic resonance imaging reveals cerebellar atrophy. Sensory nerve action potentials are markedly diminished in amplitude. Female patients have hypergonadotrophic hypogonadism. The gene responsible for IOSCA.
Posterior column ataxia with retinitis pigmentosa (PCARP) is an infantile-onset syndrome described in a single Spanish family that has clinical overlap with the other spinocerebellar ataxias. This disorder has onset between 2 and 14 years of age. Initial symptoms are progressive sensory ataxia and visual loss. Patients may have scoliosis, camptodactyly, achalasia and gastrointestinal dysmotility. On examination of vision in older children ring scotomata can be appreciated. There is retinitis pigmentosa, generalized arreflexia and loss of position sensation. Rhomberg sign is present. Pain and temperature sensation and hearing appear intact. Imaging studies do not show cerebellar atrophy, but spinal MRI sometimes reveals T2 signal hyperintensity in the dorsal columns. There is no cardiomyopathy, foot deformity, ophthalmoplegia, pyramidal signs or amyotrophy. Sural nerve biopsy shows loss of large myelinated fibers and preservation of unmyelinated axons. Linkage analysis has revealed that the locus for this disorder, called AXPC1, is on chromosome 1 at 1q31-32. Until the gene is identified the diagnosis can only be suspected by demonstration of genetic linkage of a kindred to the defined AXPC1 locus using polymorphic microsatellite markers for this region.
Spinocerebellar Ataxia Type 1
Among SCA patients the proportion with SCA1 ranges from 3% in the Japan (0% in Korea and Portugal) to 40% in Russia and South Africa, and is found in about 6% of US SCA patients. SCA1 typically has an age of onset in the third or fourth decade, but severe forms of childhood- or juvenile-onset SCA1 have been documented that are known to be due to the more severely expanded alleles. Initial symptoms are gait unsteadiness, but increasing dysarthria and dysphagia soon follow. The rate of progression in adult-onset SCA1 may vary considerably, with confinement to wheelchair between 3 and 17 years after onset and death from ten to 30 years after onset. Death is often related to respiratory failure due to bulbar involvement. Patients with juvenile-onset disease (whose symptoms appear before age 13 years) have still more severe disease, having more widespread CNS involvement and being fatal before age 16.
SCA1 is caused by an expansion in CAG repeat in the SCA1 gene on 6p23 that leads to an elongated tract of glutamine residues within the protein ataxin-1. Ataxin-1 is a cytoplasmic and nuclear protein of unknown function. The diagnosis of SCA1 is established by the demonstration of expansion in one CAG repeat alleles in the SCA1 locus greater than 38 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 2
The proportion with SCA patients with SCA2 ranges from 4% in the Portugal (0% in Russia) to 47% in Italy, and is 15% for US SCA patients. The mean age of onset of SCA2 is in the 4th decade, but is more rapidly progressive when onset occurs before age 20. A form of infantile-onset SCA2 has been recognized associated with extreme expansions of SCA2 alleles, in which children have infantile spasms, severe hypotonia, pigmentary retinopathy, dysphagia, failure to thrive, and usually die before 2 years of age. In adult-onset SCA2 confinement to wheelchair may occur 10-20 years after onset, and death may occur 10-30 years after onset. Death may be due to respiratory or autonomic failure.
SCA2 is characterized by slowly progressive ataxia sometimes with leg stiffness and/or painful leg muscle cramps at night. Mild dementia has been reported, which appears to be predominantly an impairment of executive functions. Examination may reveal very mild dysarthria, slowed, hypometric or totally absent saccades, supranuclear ophthalmoplegia, fasiculations in the face and tongue, dystonia and chorea and segmental or total loss of reflexes. SCA2 is caused by an expansion in CAG repeat in the SCA2 gene on 12q23-24.1 that leads to an elongated tract of glutamine residues within a novel protein, ataxin-2. The diagnosis of SCA2 is established by the demonstration of an expansion in one CAG repeat alleles in the SCA2 locus greater than or equal to 34 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 3
a.k.a. Machado-Joseph Disease
SCA3 or Machado-Joseph disease is the most common recognized form of SCA in most populations. The proportion of SCA patients with SCA3 ranges from 7% in India (0% in South Africa and Italy) to 74% in Portugal, and is found in about 21% of US SCA patients. The age of onset of SCA3 usually the 2nd to the 4th decade. There are also reports of rare childhood-onset variants with severe disease, as well as variants with rigidity. Initial symptoms are usually unsteadiness or stiffness of gait, clumsiness, and slurred speech, but a significant proportion of patients develop diplopia before any gait difficulty. Typically the disease is slowly progressive, leading to the need for assistive devices including a wheelchair 10 to 15 years after onset. Death results from pulmonary complications and cachexia from 6 to 29 years after onset. SCA3/Machado Joseph disease (MJD) is due to an expansion of a CAG repeat expansion in the SCA3/MJD gene on 14q32.1 that leads to an elongated tract of glutamine residues within a novel, nucleocytoplasmic protein, ataxin-3. The diagnosis of SCA3 is established by the demonstration of an expansion in one CAG repeat alleles in the SCA3 locus greater than 55 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 5
Spinocerebellar ataxia type 5 (SCA5) was originally described in an American family of Anglo-Saxon origin descending from the grandparents of President Abraham Lincoln. The genetic locus was assigned to chromosome 11. Subsequently, a second SCA family of French origin was identified with a similar clinical presentation in which the responsible gene is located in the same region. Initial symptoms consist of slowly progressive gait unsteadiness and dysarthria. The age of onset was 10 to 68 years (14 to 40) usually in the third decade. The ataxia is very slowly progressive and some patients remain ambulatory for well after 10 years. Examination shows evidence of a pancerebellar syndrome with intact or increased reflexes, normal plantar reflexes and normal sensory examination. Facial myokymia is a prominent feature among the French kindred. Nystagmus is less prominent than in SCA6 or SCA8. MRI shows a marked global cerebellar atrophy with sparing of the brainstem. The gene for SCA5 chromosome 11p11-q11 encodes a beta spectrin protein that is expressed in Purkinje cells.
Spinocerebellar Ataxia Type 6
The proportion of SCA patients with SCA6 ranges from 2% in Italy (0% in China, Portugal, and Brazil) to 31% in Japan, and is found in about 15% of US SCA patients. The age of onset ranges from 19 to 71 years, with a mean age of onset in the fifth decade. Age of onset may vary between siblings with the same mutation by as much as 12 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance in about 90% of cases. The remainder of patients present with dysarthria. Symptoms progress slowly, and eventually all patients have gait ataxia, upper limb incoordination, intention tremor, and dysarthria. Patients with SCA6 occasionally manifest episodic ataxia or episodic vertigo. Diplopia occurs in about 50% of patients. Others experience visual disturbances related to difficulty fixating on moving objects. Dysphagia and choking are common. Lifespan is not shortened.
SCA6 is caused by an expansion in a CAG repeat in the gene CACNA1A, on 19p13.1 previously recognized to encode the alpha1A subunit, the main pore-forming subunit for the P/Q-type voltage-gated calcium channel. The diagnosis of SCA6 is established by the demonstration of an expansion in one CAG repeat alleles in the SCA6 locus greater than 19 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 7
SCA7 is a rare form of SCA in all populations. The proportion of SCA patients with SCA7 ranges from 0.5% in Germany and Russia (0% in Portugal, Korea, India and China) to 16% in some regions in Spain, and is found in about 4.5% of US SCA patients. The age of onset of the symptoms ranges widely, from infancy, to the fifth or sixth decade. SCA7 is characterized by abnormalities in color vision and central visual acuity, due to a macular pigmentary degeneration, and in adults visual symptoms often precede the cerebellar symptoms, or are detectable upon development of imbalance. Typical cerebellar signs of gait unsteadiness, incoordination and dysarthria develop soon afterward and progress to a bedridden state. Rate of progression depends on age of onset. In the infantile-onset form there is rapidly progressive cerebellar and brainstem degeneration and visual loss may be difficult to ascertain before death. Otherwise retinal degeneration is progressive and leads to blindness. When visual symptoms appear at or before adolescence, blindness can occur within a few years. Ataxia progresses to wheelchair confinement in 5-10 years. The retinal degenerative component distinguishes this hereditary ataxia from other forms of SCA. The diagnosis of SCA7 is established by the demonstration of an expansion in one CAG repeat alleles in the SCA7 locus greater than 36 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 8
SCA8 was originally described in association with a single large kindred of individuals suffering from adult-onset SCA having a dominant inheritance pattern with incomplete penetrance. In the original study there was clear distinction between normal and pathological alleles in a single family. Subsequent studies have reinforced the concept that some expanded alleles may not be pathogenic, and that the diagnosis of SCA should be confined to a narrower range of pathological alleles (see Table 3). Patients with pathological alleles have a characteristic presentation. Symptoms first appear between ages 18 and 65, with a mean of 39 years. Initial symptoms consist of gait ataxia, dysarthria, and dysphagia. Findings on examination include spastic and ataxic dysarthria, gaze-evoked nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sensation. Progression is generally fairly slow, but severely affected family members become confined to wheelchair by the fourth to fifth decades. SCA8 is associated with an expansion of a polymorphic CTA/CTG repeat in the 3-prime untranslated region of a gene located at 13q21. The length of the repeat present in the general population is 16 to 37 repeats in 99% of alleles. The repeat length that is likely to result in disease ranges from 107 to 127 CTG repeats. The diagnosis of SCA8 is suggested by the demonstration of expansion in one CTG repeat alleles in the SCA8 locus greater than 106 repeats and less than approximately 300 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 8
SCA8 was originally described in association with a single large kindred of individuals suffering from adult-onset SCA having a dominant inheritance pattern with incomplete penetrance. In the original study there was clear distinction between normal and pathological alleles in a single family. Subsequent studies have reinforced the concept that some expanded alleles may not be pathogenic, and that the diagnosis of SCA should be confined to a narrower range of pathological alleles (see Table 3). Patients with pathological alleles have a characteristic presentation. Symptoms first appear between ages 18 and 65, with a mean of 39 years. Initial symptoms consist of gait ataxia, dysarthria, and dysphagia. Findings on examination include spastic and ataxic dysarthria, gaze-evoked nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sensation. Progression is generally fairly slow, but severely affected family members become confined to wheelchair by the fourth to fifth decades. SCA8 is associated with an expansion of a polymorphic CTA/CTG repeat in the 3-prime untranslated region of a gene located at 13q21. The length of the repeat present in the general population is 16 to 37 repeats in 99% of alleles. The repeat length that is likely to result in disease ranges from 107 to 127 CTG repeats. The diagnosis of SCA8 is suggested by the demonstration of expansion in one CTG repeat alleles in the SCA8 locus greater than 106 repeats and less than approximately 300 repeats in an ataxia patient.
Spinocerebellar Ataxia Type 10
SCA10 is a form of autosomal dominant cerebellar ataxia that was recently described in several kindreds of Mexican origin. The age of onset ranges from 10-49 years. Initial symptoms of the disease are gait unsteadiness, clumsiness and dysarthria. In a significant number of patients generalized motor seizures develop within a few years after onset of the ataxia. Some patients have reduced IQ. Findings on examination include nystagmus, dysarthria, gait and limb ataxia and nystagmus, with normal reflexes and motor function. Seizures respond to anticonvulsants. MR brain scans demonstrate cerebellar atrophy. There have been no pathological studies to date.
SCA10 is due to expansion of a pentanucleotide (ATTCT) repeat in intron 9 of a novel gene on chromosome 22q13 of unknown function. Normal ATTCT repeats range from 10 to 22 ATTCT units. The expansions of the ATTCT repeat, which have not been accurately sized, are massive, up to 22.5 KB longer than the normal alleles. The diagnosis of SCA10 is established by the demonstration of expansion in one ATTCT repeat alleles in the SCA10 locus greater than 800 repeats in an ataxia patient. Patients with intermediate expansions of 30-799 repeats would also be candidates for a possible diagnosis of SCA10 and a more detailed examination of the kindred would be appropriate.
Spinocerebellar Ataxia Type 14
SCA14 was described in a single four-generation Japanese kindred with autosomal dominant cerebellar ataxia. The age of onset ranges from 3 to 42 years of age. Initial symptoms are ataxia of gait in may cases. However, in several individuals with an earlier onset initial signs include an irregular tremulousness of the neck and axial musculature, described as intermittent axial myoclonus, followed soon afterward by mild ataxia. Progression of disease is usually slow. Other findings on examination included gaze-evoked nystagmus, saccadic visual pursuits, upper and lower limb ataxia, dysarthria, and reduced Achilles reflexes. Neuroimaging studies reveal cerebellar atrophy. The gene for SCA14 encoded the protein kinase C gamma. The diagnosis is established by demonstration of one of several mutations indentified as pathogenic in this gene.
Sporadic Spinocerebellar Ataxia
About 1/3 of SCA patients do not appear to suffer from a form of familial SCA. Patients with sporadic ataxia usually have one of two clinical presentations. Approximately 1/3 of these patients develop a condition characterized by cerebellar ataxia alone, i.e., with little or involvement of other regions of the nervous system. These patients have a more slowly progressive form, may remain ambulatory for well beyond 5 years, and do not have a shortened life span. The remaining approximately 2/3 of sporadic ataxia patients develop a form of multiple system atrophy (MSA), characterized by ataxia associated with a combination of dementia, ophthalmoplegia, bulbar findings, tremor, bradykinesia or rigidity, autonomic dysfunction or other neurological abnormalities. These patients often have a more aggressive course leading to confinement to wheelchair by 5 years and in which frequent aspiration, reduced respiratory drive, or urinary retention lead to premature death by respiratory failure or sepsis. Conditions that may present as a form of sporadic SCA include Creutzfeldt-Jakob disease, subacute cerebellar degeneration, hypothyroidism, vitamin deficiency, chronic ethanol abuse, or a mitochondrial disorder. Sporadic ataxia has been associated with several different autoantibodies, although this finding is more typical of subacute cerebellar degeneration. Nevertheless, the majority of patients with sporadic ataxia have a truly idiopathic condition. After excluding a role for medical causes, such as diabetic polyneuropathy, hypothyroidism or vitamin deficiency, of ataxia in a given patient, consideration should be given to rare, but potentially identifiable conditions. Included among these are ataxia associated with antibodies, and ataxic variants of prion disease.
eles in the SCA2 locus greater than or equal to 34 repeats in an ataxia patient.
X-linked Sideroblastic Anemia and Ataxia
Several forms of congenital or progressive ataxia have an X-linked pattern of inheritance. The gene for one form of progressive ataxia, X-linked sideroblastic anemia and ataxia (XLSA/A) has been identified (Table 2). XLSA/A is an infantile-onset gait disorder affecting male children beginning with delayed motor milestones and followed by onset of slowly progressive ataxia between 40 and 50 years of age. The disorder may lead to confinement to wheelchair after at least 10 years of disease progression. Examination of adults shows dysarthria, ataxia of upper limbs and gait, ophthalmoparesis, hypometric saccades, saccadic pursuit, nystagmus, occasional perioral fasciculations, normal to increased deep tendon reflexes and normal plantar reflexes, sensory examination and negative Rhomberg sign. The gene responsible for XLSA/A is located on Xq13 and encodes the human ATP-binding cassette (ABC) transporter ABC7.