Friedreich’s Ataxia (Freidreich’s Ataxia; Spinocerebellar Ataxia – OMIM 229300)

Friedreich ataxia is one of the most common hereditary ataxias, with a prevalence of approximately 1–2 per 100,000 in the general population [Harding, 1984]. Caucasians are affected more often than other racial groups, with a prevalence closer to 1 per 50,000 [Cossee et al., 1997]. Clinically, the disease is signaled by the presence of ataxia and corticospinal tract dysfunction. Other associated features include nystagmus, kyphoscoliosis, and an unusual cardiomyopathy. The disease was originally reported by Friedreich [Friedreich, 1863], who believed it was associated only with spinal cord abnormalities, subsequent findings demonstrated involvement of the medulla, peripheral nerves, and cerebral cortex in some cases.

Clinical manifestations

Symptoms typically begin around puberty, although onset might be detected at age 2 years or may be delayed until the second decade. The initial presentation is usually progressive gait ataxia and slowing. The gait pattern can seem wild, with a reeling or lurching quality. Both legs are commonly involved, although asymmetries are sometimes present. Bladder dysfunction may manifest at any time during the disease course; symptoms of spastic bladder are common. The upper extremities tend to be affected only late in the disease course. Although muscle strength is fairly preserved, patients typically require a wheelchair for mobility about 15 years after symptom onset.

Loss of cells in cranial nerves VII, X, and XII causes facial weakness, with cerebellar dysarthria and dysphagia. Lateral or horizontal nystagmus may be prominent, and visual pursuit is punctuated with small jerks. Impairment of pupillary responsivity and limited extraocular movements are also common. Additional ophthalmologic abnormalities include cataracts, retinitis pigmentosa, and optic atrophy. Auditory dysfunction is common [Cassandro et al., 1986], and is documented by abnormal brainstem auditory-evoked potentials that are likely the result of impairment of both central and peripheral acoustic pathways [Knezevic and Stewart-Wynne, 1985]. The degree of hearing compromise is variable; in addition, some patients experience vertigo. Although higher cortical function appears intact by clinical measures, some studies suggest a decrease in information processing speed [Hart et al., 1985].

The lower limbs typically show loss of deep tendon reflexes, but reflexes may be preserved for a longer period in young children [Salih et al., 1990], and patients with late-onset disease can be spastic with hyperreflexia. Bilateral extensor toe signs are easily elicited. Cremasteric and abdominal reflexes may be lost. The masseter reflex remains intact [Auger, 1992]. Occasionally, weakness, muscle atrophy, and profound hypotonia may be evident, usually associated with spinal nerve disintegration. Virtually all facets of cerebellar function are involved, and both gross and fine coordination are affected. Position sense, vibration sense, and other skills requiring normal posterior column function are grossly impaired. Autonomic innervation of superficial layers of skin may be involved. Pain, touch, and temperature sensation are usually intact, but diminish over the course of the illness. Evidence of axonal sensory neuropathy, indicated by electrodiagnostic studies, is invariably present. Somatosensory-evoked potentials are abnormal, as is central motor function, as determined by magnetic stimulation [Claus et al., 1988].

Patients with Friedreich’s ataxia often develop talipes equinovarus or pes cavus. Deformities of the hand can also occur. Flexor spasms can become a great source of pain. Many patients suffer from kyphoscoliosis [Labelle et al., 1986], and may be unable to walk secondary to poor balance and an abnormally shifted center of gravity (Figure 67-4). Surgical intervention can correct the abnormal spinal curvature, and this is likely to help with ventilation and autonomic functions, even if it does not restore ambulation.

Fig. 67-4 Friedreich’s ataxia and moderate scoliosis in a 13-year-old boy who is unable to walk independently.

Cardiomyopathies are the most common accompanying cardiac abnormalities, although congenital heart disease has been described on occasion. The cardiomyopathy is often progressive, and is documented even before clinical manifestations by the presence of electrocardiogram (EKG) abnormalities (e.g., deep Q waves, low-wave QRS complexes, S-T segment changes, T-wave inversion) [Harding and Hewer, 1983; Child et al., 1986]. Arrhythmias may be particularly worrisome and life-threatening. EKG and vector cardiographic changes are demonstrable in more than 90 percent of patients [Child et al., 1986]. Left ventricular hypertrophy or symmetric ventricular hypertrophy is frequently evident on echocardiography [Pentland and Fox, 1983]. Hypertrophic cardiomyopathy is the leading cause of death in Friedreich’s ataxia patients.

Diabetes mellitus is associated with Friedreich’s ataxia; even in its absence, the glucose tolerance curve may be abnormal. Insulin resistance appears to be the explanation [Khan et al., 1986]. Unaffected relatives may also manifest insulin resistance. Episodic hypothermia, intermittent vomiting, and ventilatory dysfunction have also been reported [Thoren, 1962].

Imaging studies show both structural and functional changes that correlate with pathologic progression. MRI studies document atrophy of the upper cervical spinal cord and cerebellum [Wessel et al., 1989]. PET imaging demonstrates a widespread increase in cerebral metabolic rate for glucose in the brain of ambulatory patients with Friedreich’s ataxia. As the disease progresses, glucose metabolism decreases in a regionally specific manner; only the caudate and lenticular nuclei have increased metabolic rate in nonambulatory patients [Gilman et al., 1990].

Diagnosis is suggested by the presence of the expected clinical manifestations and sometimes by family history. Distinct diagnostic criteria for Friedreich’s ataxia were advanced by Geoffroy and colleagues [Geoffroy et al., 1976]: autosomal-recessive inheritance, onset before 10 years of age, gait ataxia, dysarthria, absent deep tendon reflexes, dorsal column signs, and weakness. The presence of an abnormal 5-hour glucose tolerance curve is corroborative. Spinal fluid findings may include elevated protein content and mild pleocytosis.

Friedreich’s Ataxia 2 (OMIM 601992)

Other families with a Friedreich’s ataxia disease phenotype, but without point mutations or GAA expansions in the X25 gene, have been described [Kostrzewa et al., 1997; Christodoulou et al., 2001]. In one family, linkage to a locus on chromosome 9p23–p11 has been found [Christodoulou et al., 2001]. The biological basis for the genocopy is not known, but it has been proposed that mutations in genes that lie in the iron metabolism pathway may be responsible.

Vitamin E Deficiency and Related Syndromes

Ataxia with isolated vitamin E deficiency (AVED – OMIM 277460) is a rare but important – and treatable – cause of early-onset ataxia. The clinical presentation closely resembles that of Friedreich’s ataxia (ataxia, dysarthria, loss of lower limb reflexes, and peripheral neuropathy appearing between the ages of 4 and 18), except that cardiac involvement is rare, diabetes is not part of the clinical constellation, and AVED patients are more likely to display head titubation and reduced visual acuity. (Some develop retinitis pigmentosa.) Similar features can be seen in individuals with malabsorption syndromes, chronic steatorrhea, abetalipoproteinemia (Bassen–Kornzweig disease), or primary vitamin E deficiency; these individuals should be identified by their risk factors.

Numerous mutations have been identified in the tocopherol transfer protein gene (TTP1), which encodes the α-tocopherol transfer protein (TTPA) [Ouahchi et al., 1995; Cavalier et al., 1998]. TTPA is expressed in the liver and is responsible for the incorporation of tocopherol (vitamin E) into very-low-density lipoprotein (VLDL) [Traber et al., 1990]. Mutated TTPA proteins fail to facilitate the secretion of vitamin E from cells, and the severity of the AVED pathology corresponds to the degree of impairment associated with each mutation [Qian et al., 2006].

Because this disease is treatable, all patients with a phenotype reminiscent of Friedreich’s ataxia should be evaluated for vitamin E deficiency. Supplementation rapidly normalizes plasma vitamin E levels and halts disease progression; mental deterioration and ataxia symptoms can be reversed, if treated early enough. In older patients, deficits in proprioception and gait unsteadiness are likely to remain.

Ataxia-Telangiectasia (AT; Louis-Bar Syndrome – OMIM 208900)*

Ataxia-telangiectasia (AT) is one of the most common inherited causes of early childhood-onset ataxia in most countries, with a prevalence of 1 in 40,000–100,000 live births in the United States. The disease is characterized by progressive cerebellar ataxia, ocular apraxia, oculocutaneous telangiectasias, choreoathetosis, proclivity to sinopulmonary infections, and lymphoreticular neoplasia. Death often occurs by the fourth or fifth decade of life, typically resulting from sinopulmonary disease, neoplasms, or from neurologic deterioration.

The initial clinical description of this disease was reported by Syllaba and Henner [1926], who called it congenital double athetosis-aconjunctival vascular plexus syndrome. Louis-Bar [1941] reported a 9-year-old male with associated ataxia and oculocutaneous telangiectasias, classifying the case as a previously unrecognized phakomatosis. Two additional independent reports subsequently appeared in the literature [Biemond, 1957; Boder and Sedgwick, 1957], and Boder and Sedgewick named the condition ataxia-telangiectasia.

Clinical manifestations

Early motor development appears to be normal until around the time that the child starts walking, when ataxia is noted. The ataxia is progressive and ultimately leads to an inability to ambulate by the beginning of the second decade. Choreoathetosis and dystonia occur in up to 90 percent of patients, and these motor findings become more prominent with increasing age. Facial weakness leads to the characteristic impassive faces, as well as drooling and dysarthria. While strength is initially normal, many patients in their 20s and 30s develop progressive spinal muscular atrophy, predominantly affecting the hands and feet [Gatti et al., 1991]. Peripheral neuropathy in the form of diminished deep tendon reflexes and loss of large fiber sensation is also seen. Mental function is well preserved, although deficits in short-term memory can occur in the third and fourth decades [Gatti et al., 1991].

Oculomotor apraxia is a distinguishing feature of the disease. The apraxia commonly presents before the appearance of conjunctival telangiectasias and is characterized by defects of initiating voluntary saccades, hypometric voluntary saccades accompanied by compensatory eye-blinking and/or head-thrusting movements, and disrupted smooth pursuit movements [Smith and Cogan, 1959; Baloh et al., 1978]. Involuntary saccade initiation and optokinetic nystagmus may be impaired as well, and oculovestibular reflexes may be increased.

Telangiectasias are usually first observed in patients between the ages of 2 and 4 years, although they can occur as early as birth and as late as 14 years of age [Centerwall and Miller, 1958; McFarlin et al., 1972] (Figure 67-5). In addition to the conjunctivae, they appear on exposed areas of the skin, particularly areas of friction and trauma, such as the auricle, nasal bridge, and antecubital and popliteal spaces. Exposure to sun enhances their appearance. Premature aging of hair and skin is frequent, as are skin infections, including chronic blepharitis. Other skin changes, consisting of vitiligo and café-au-lait spots, can be seen. Rarely, scleroderma-like lesions occur.

Fig. 67-5 Characteristic conjunctival telangiectasias observed in a 12-year-old with ataxia-telangiectasia.

Recurrent sinopulmonary infections are common, affecting 90 percent of patients, and usually result in chronic bronchitis, bronchiectasis, or both. The impairment of cellular immunity is also manifest by abnormally developed or absent adenoids, tonsils, lymphoid tissue, and thymus gland. Patients have an impaired delayed hypersensitivity response to skin-sensitizing antigens and a delayed homograft-rejection response [McFarlin and Oppenheim, 1969].

Patients with AT are prone to develop tumors and are more likely than the general population to have Hodgkin’s disease, leukemia, lymphoma, and lymphosarcoma. Other associated neoplasms include brain tumors, gastric adenocarcinomas, ovarian dysgerminomas, gonadoblastomas, cystic adenofibromas, uterine leiomyomas, and thyroid adenomas [Miller and Chatten, 1967; Gatti and Good, 1971].

Hypogonadism is frequent in both genders, and growth retardation is notable’ despite normal levels of growth hormone. Insulin-resistant diabetes is also occasionally seen as part of the clinical constellation.

Patients with less severe variant forms of AT have been described [Gilad et al., 1998; Saviozzi et al., 2002]. Immunodeficiency, telangiectasias, cancer, and sinopulmonary infections may be absent or reduced, but the neurological manifestations still occur. These individuals have a later onset and slower progression of neurological signs, longer life spans, and decreased chromosomal instability and cellular radiosensitivity.

Ataxia-Telangiectasia-Like Disorder (ATLD – OMIM 604391)

ATLD patients have been described with clinical presentations including cerebellar ataxia and oculomotor apraxia, which are essentially identical to that of ataxia-telangiectasia except that telangiectasias are absent [Klein et al., 1996; Fernet et al., 2005]. Two of the patients, who were brothers, presented first with chorea that later progressed to ataxia [Klein et al., 1996]. In 2005, Fernet et al. described ten ATLD patients from three unrelated Saudi Arabian families. These patients had slowly progressive ataxia and ocular apraxia, but they did not develop tumors. Furthermore, they did not have telangiectasia, raised AFP, or reduced immunoglobulin levels [Fernet et al., 2005].

Increased susceptibility to DNA damage was noted in all four patients. Stewart et al. [1999] showed that the disorder maps to chromosome 11q21 in all four patients. Loss-of-function mutations in the hMRE11A gene are causative. Like ATM, MRE11A is important for DNA repair, and may act as a sensor of DNA damage. Stewart et al. estimate that approximately 6 percent of AT patients may in fact have ATLD [Stewart et al., 1999].

Ataxia-Oculomotor Apraxia 1 (AOA1; Early-Onset Ataxia with Ocular Motor Apraxia and Hypoalbuminemia – OMIM 208920)

This autosomal-recessive ataxia was initially described in Japanese families but has subsequently been described in other areas of the world as well [Tranchant et al., 2003]. It is the most frequent cause of autosomal-recessive cerebellar ataxia in Japan, and the second most common cause in Portugal. The presentation is nearly identical to that of AT without the non-neurological features [Aicardi et al., 1988], and accounts for up to 10 percent of autosomal-recessive cerebellar ataxias. Gait imbalance and dysarthria are the typical presenting features, although chorea can sometimes be the presenting symptom. Ocular apraxia typically occurs a few years after symptom onset; with time, progressive ophthalmoplegia occurs as well. Areflexia, dystonia, choreoathetosis, sensory and motor neuropathy, cognitive impairment, and retinal/macular lesions seen on funduscopy can also be part of the presentation. Life span is not affected.

Laboratory studies reveal hypoalbuminemia and hypercholesterolemia in the majority of cases as a later manifestation of the disease. Neuroimaging demonstrates cerebellar and sometimes brainstem atrophy. Pathology studies show loss of Purkinje cells in the cerebellum, and degeneration of the posterior columns, spinocerebellar tracts, and anterior horn cells of the spinal cord [Sekijima et al., 1998].

The gene, APTX, maps to chromosome 9p13.3 and is expressed in all body tissues [Date et al., 2001; Moreira et al., 2001]. Several mutations have been described, as have compound heterozygotes; frameshift and nonsense mutations result in more severe phenotypes than missense mutations. The APTX gene product, aprataxin, has domains that suggest a potential role in single-strand DNA repair, and has been shown to interact with another protein implicated in this process [Sano et al., 2004]. CoQ₁₀ is often low in patients with AOA1 [Le Ber et al., 2007], and this deficiency responds to CoQ₁₀ supplementation [Quinzii et al., 2005].

Spinocerebellar Ataxia, Autosomal-Recessive 1 (SCAR1 – OMIM 606002); Ataxia-Oculomotor Apraxia 2 (AOA2)

A second AT-like spinocerebellar ataxia with slightly different features than AOA1 has been described in families of several different ethnic backgrounds. The clinical features of AOA2 include gait ataxia, sensorimotor neuropathy, and ocular apraxia, the latter occurring about 50 percent of the time. While overall cognitive function is normal, subtle changes in executive function can be seen on neuropsychologic testing [Le Ber et al., 2004]. Neuroimaging demonstrates cerebellar atrophy. AOA2 is distinguished from AOA1 by the later age of onset, less common ocular apraxia, high levels of serum AFP, and normal serum albumin. The functional prognosis is also better in AOA2. The gene (SETX) maps to chromosome 9q34 [Nemeth et al., 2000]. Mutations cause premature termination of the senataxin protein, which is a member of the helicase family and is involved in RNA maturation and termination [Moreira et al., 2004]. Recently, Suraweera et al. [2009] have proposed a role for senataxin in the regulation/modulation of transcription.

Interestingly, other mutations in senataxin are transmitted in an autosomal-dominant manner and cause juvenile amyotrophic lateral sclerosis (ALS4) [Chen et al., 2004a]; the basis for the dramatic phenotypic difference between the two diseases is unknown.

Spinocerebellar Ataxia, Autosomal-Recessive 2 (SCAR2 – OMIM 213200); Cerebellar Hypoplasia, Nonprogressive Norman Type

Norman [1940] described three siblings in one family and two siblings in another who had had cerebellar ataxia and mental deficiency since early life. Postmortem examinations showed severe cerebellar granule cell loss. One child showed delayed motor development and mental deficiency in infancy. Other features included small head, cataracts, increased knee jerks, and intention tremor [Norman, 1940]. The disease locus was assigned on chromosome 9q34–qter [Delague et al., 2001]. It is not certain if SCAR2 is distinct from the disorder called cerebellar hypoplasia (OMIM 213000).

Spinocerebellar Ataxia, Autosomal-Recessive 3 (SCAR3 – OMIM 271250); Spinocerebellar Ataxia with Blindness and Deafness (SCABD)

This recessively inherited spinocerbellar ataxia accompanies optic and cochlear degeneration, leading to blindness and deafness [Spoendlin, 1974; van Bogaert and Martin, 1974]. Bomont et al. [2000] described an Israeli man and his niece, who were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. They demonstrated its linkage to the chromosome 6p23–p21.

Spinocerebellar Ataxia, Autosomal-Recessive 4 (SCAR4 – OMIM 607317); Spinocerebellar Ataxia with Saccadic Intrusions (SCASI)

Five of 14 siblings of a family of Slovenian descent have been described with progressive ataxia, gait unsteadiness, and difficulty reading starting in the third decade. All patients developed gait, trunk, and limb ataxia, as well as pyramidal tract signs. They eventually required walking aids by the sixth decade (ages 49–56 years). Moreover, patients had myoclonic jerks, fasciculations, impaired joint position sense, cerebellar dysarthria, and mild pes cavus. There was also striking disturbance of eye movements, with horizontal macrosaccadic oscillations of a high velocity that were induced with each gaze shift. By genome-wide linkage analysis a candidate locus on chromosome 1p36 was identified [Swartz et al., 2003].

Spinocerebellar Ataxia, Autosomal-Recessive 5 (SCAR5 – OMIM 606937); Nonprogressive Congenital Cerebellar Ataxia with Mental Retardation, Optic Atrophy, and Skin Abnormalities (CAMOS)

Megarbane et al. [2001] described five children from a large inbred Lebanese Druze family, with a new form of nonprogressive autosomal-recessive congenital ataxia associated with optic atrophy, severe mental retardation, short stature, speech defect, abnormal osmiophilic pattern of skin vessels, and cerebellar atrophy. There was no evidence of metabolic disease, and analysis of respiratory chain complex abnormalities was unremarkable [Megarbane et al., 2001]. The disease locus has been mapped to a 3.6-cM interval on chromosome 15q24–q26 using identity by descent and DNA pooling [Delague et al., 2002].

Spinocerebellar Ataxia, Autosomal-Recessive 6 (SCAR6 – OMIM 608029); Norwegian Nonprogressive Infantile Cerebellar Ataxia (CLA3)

SCAR6 was first described in seven consanguineous patients, four adults and three children from a large inbred Norwegian family, ranging in age from 4 years to 59 years. All patients showed a nonprogressive cerebellar ataxia manifesting in early childhood. The phenotype of this disorder includes defects in motor coordination of limbs, slow speech, poor eye movement coordination, slight spastic signs, short stature, but normal intelligence [Kvistad et al., 1985]. The disease locus has been mapped to a 19.5-cM interval on chromosome 20q11–q13 [Tranebjaerg et al., 2003].

Spinocerebellar Ataxia, Autosomal-Recessive 7 (SCAR7 – OMIM 609270)

Breedveld et al. [2004] identified a nonconsanguineous Dutch family with slowly progressive spinocerebellar ataxia, nystagmus, saccadic pursuit eye movements, a postural tremor, hyperreflexia, extensor plantar responses, and absence of other (non)neurological features. All patients with this childhood-onset disease were studied as adults, from 46 to 64 years of age, but the severity of symptoms and progression of the disease within this family were remarkably variable. Using a systematic genome-wide scan, the responsible gene for SCAR7 was mapped to a 5.9 cM interval on chromosome 11p15 [Breedveld et al., 2004].

Spinocerebellar Ataxia, Autosomal-Recessive 8 (SCAR8 – OMIM 610743); Cerebellar Ataxia, Autosomal-Recessive, Type 1 (ARCA1); Recessive Ataxia of Beauce

SCAR8 is identified in 26 French Canadian families, including 53 affected members, mostly from the Beauce and Bas-St-Laurent regions of the province of Quebec in Canada and mapped on the chromosome 11p15. SCAR8 is a fairly pure cerebellar ataxia that is caused by various mutations in SYNE1 [Gros-Louis et al., 2007]. This autosomal-recessive disease starts at 17–46 years of age. Various mutations produce a fairly homogeneous phenotype among patients. A splice-site mutation was the most common mutation, occurring at a frequency of 50.8 percent among 124 patients [Dupre et al., 2007]. SCAR8 shows slow progression and causes moderate disability. Affected individuals have significant dysarthria, mild oculomotor abnormalities, occasional brisk reflexes in the lower extremities, normal nerve conduction studies, and diffuse cerebellar atrophy on imaging [Dupre et al., 2007].

SYNE1 encodes a very large protein with 8797 amino acid residues. The protein contains two N-terminal actin-binding regions that comprise tandem-paired calponin-homology domains, a transmembrane domain, multiple spectrin repeats, and a C-terminal klarsicht domain (KASH). It is highly expressed in Purkinje cells and neuromuscular junctions. SYNE1 is a part of the spectrin family, a group of structural proteins that share a common function of linking the plasma membrane to the actin cytoskeleton [Gros-Louis et al., 2007].

Spinocerebellar Ataxia, Autosomal-Recessive 9 (SCAR9 – OMIM 612016); Cerebellar Ataxia, Autosomal-Recessive, Type 2 (ARCA2)

SCAR9 has been described in four patients from a consanguineous Algerian family and in three other sporadic patients with slowly progressive childhood-onset gait ataxia and cerebellar atrophy. Five patients had pes cavus, 4 had brisk reflexes, 2 had Huffmann’s sign, 3 had mild psychomotor retardation, 3 had exercise intolerance and elevated serum lactate, and 1 patient had mild axonal degeneration of the sural nerve. Single nucleotide polymorphism (SNP)-based genome-wide scanning revealed a locus for autosomal-recessive ataxia at chromosome 1q41, and further sequencing led to the identification of the causative mutation as a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for muscle coenzyme Q₁₀ (CoQ₁₀ or ubiquinone) biosynthesis [Lagier-Tourenne et al., 2008].

CoQ₁₀ deficiency has been reported in some patients with childhood-onset cerebellar ataxia [Lamperti et al., 2003]. CoQ₁₀ deficiency causes mitochondrial dysfunction because CoQ₁₀ carries electrons from complex I and complex II to complex III in the mitochondrial respiratory chain. Most of the SCAR9 patients showed a decreased level of CoQ₁₀ [Lagier-Tourenne et al., 2008]. CoQ₁₀ supplementation might be beneficial for SCAR9 patients, as well as for others with mitochondrial respiratory chain dysfunction-related ataxias.

Cerebellar Ataxia, Cayman Type (ATCAY – OMIM 601238)

Cerebellar ataxia, Cayman type, is a recessive disorder described in an isolated population from Grand Cayman Islands, mapping to chromosome 19q13.3 [Johnson et al., 1978; Brown et al., 1984; Nystuen et al., 1996]. The disorder causes hypotonia from birth, followed by psychomotor retardation, nystagmus, intention tremor, dysarthria, and ataxic gait. The cerebellar findings are typically nonprogressive. Brain imaging shows isolated cerebellar atrophy. The ATCAY gene is expressed only in neurons in the brain and in components of the spinal cord and peripheral nervous system. Two nucleotide substitutions, one in exon 9 that results in a serine to arginine substitution, and one in intron 9 that interferes with splicing, have been identified as causative [Bomar et al., 2003]. ATCAY codes for the caytaxin protein, a protein that shares a conserved domain with TTPA (see Vitamin E deficiency syndromes, above). However, it does not appear that caytaxin binds vitamin E, and its function is currently unknown.

Infantile-Onset Spinocerebellar Ataxia (IOSCA – OMIM 271245)

IOSCA, the second most common inherited ataxia in Finland with a population carrier frequency of more than 1:230, maps to chromosome 10q24 [Nikali et al., 2005]. Dysfunction starts at 9–18 months of age, with muscle hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural hearing deficit, sensory axonal neuropathy, epileptic encephalopathy, and female hypogonadism [Koskinen et al., 1994; Nikali et al., 2005]. Sensory axonal neuropathy and progressive atrophy of the cerebellum, brainstem, and spinal cord are neuropathological characteristics of IOSCA [Koskinen et al., 1994]. The disease results from a recessive mutation in C10Orf2, which encodes Twinkle (Y508C), a mitochondrial (mt)DNA-specific helicase [Nikali et al., 2005]. Different mutations in this same gene cause autosomal-dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions (OMIM 606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA [Nikali et al., 2005]. The depletion of mtDNA has been shown in IOSCA patients’ brains. This finding categorizes IOSCA as a new member of the mtDNA depletion syndrome family [Hakonen et al., 2008].

Ramsay Hunt Syndrome: Progressive Myoclonic Ataxia and Progressive Myoclonic Epilepsy (Baltic Myoclonus, Mediterranean Myoclonus, Unverricht–Lundborg Syndrome)

Ramsay Hunt syndrome is a heterogeneous group of disorders whose clinical hallmarks are cerebellar ataxia and myoclonus [Hunt, 1922]. The presentation and severity are variable, and the differential diagnosis includes myoclonic epilepsy with ragged red fibers (MERRF), sialidosis, and progressive myoclonic epilepsy. These disorders are described in other chapters in this text.

Progressive myoclonic epilepsy (OMIM 254800) was first described in families from Estonia and Eastern Sweden, but is most common in Finland. The disease typically presents with generalized tonic-clonic seizures and myoclonus, with ataxia seen later in the course. Dodecamer repeats in the promoter region of the cystatin B gene are the most frequent cause [Lafreniere et al., 1997; Virtaneva et al., 1997].

Other Childhood-Onset Ataxias

Other early-onset ataxias with associated deafness and varying degrees of mental retardation have been reported. In Behr’s syndrome, mental retardation, ataxia, sensory neuropathy, spasticity, and optic atrophy are the predominant findings [Thomas et al., 1984]. Marinesco–Sjögren syndrome is characterized by mental retardation, ataxia, cataracts, short stature, and limited sexual maturation.

Other conditions have been associated with atypical findings of dementia, muscular atrophy, ichthyosis, and familial spastic paralysis. Both autosomal-dominant and X-linked transmission have been described in these patients [Spira et al., 1979; Farlow et al., 1987].

Spinocerebellar Ataxia Type 1 (SCA1 – OMIM 164400)

SCA1 is characterized by progressive loss of balance and coordination, mild cognitive impairments, oculomotor deficits (including gaze palsy and slowing of saccades), dysarthria, dysphagia, and eventual respiratory failure. The primary sites of neurodegeneration in SCA1 include cerebellar Purkinje cells, brainstem cranial nerve nuclei, the inferior olive, and spinocerebellar tracts [Zoghbi and Orr, 2000]. Onset is typically in the third or fourth decade of life, but patients presenting as young as 4 years of age and as late as 60 years of age have been reported [Zoghbi and Orr, 2000]. The disorder has been described in many ethnic groups, including whites, blacks, Asians and Iakuts [Ranum et al., 1994a].

The SCA1 gene was mapped to chromosome 6p22–23 and the mutation identified using a positional cloning approach [Orr et al., 1993; Banfi et al., 1994]. A highly polymorphic CAG repeat encoding a polyglutamine tract was found to be unstable and expanded in all individuals with SCA1 [Orr et al., 1993]. The number of CAG repeats ranges from 6 to 44 on normal chromosomes, and from 39 to 82 on SCA1 chromosomes [Servadio et al., 1995]. The distinction between disease-causing and “normal” alleles in the range of overlap is made on the basis of the fact that the repeat tract on normal chromosomes is interrupted by 1–4 CAT trinucleotides in alleles with 20 or more repeats, whereas SCA1 chromosomes contain a “pure,” uninterrupted CAG tract [Chung et al., 1993]. This observation led to the hypothesis that loss of the CAT interruption rendered the SCA1 CAG repeat unstable and more likely to expand [Chung et al., 1993].

There is a strong inverse correlation between repeat size and age of onset; individuals with 70 or more CAG repeats have childhood onset, a rapidly deteriorating course, and death within 4–5 years, whereas adult-onset patients have fewer than 70 repeats and typically live 10–20 years after symptoms appear [Zoghbi and Orr, 2000]. Genetic anticipation, or the tendency of affected individuals in each successive generation of a kindred to show earlier and earlier disease onset, is a prominent feature of all polyglutamine repeat diseases. The mechanism involves progressive expansion of the polyglutamine repeats in disease alleles, particularly those that are paternally transmitted [Orr et al., 1993].

The SCA1 CAG repeat falls within the open reading frame of a transcript that is widely expressed and whose size is approximately 11.5 kb [Orr et al., 1993]. The CAG repeat codes for polyglutamine within ataxin-1, a protein predicted to contain 792–830 amino acids, depending on the size of the repeat [Banfi et al., 1994]. Ataxin-1 is predominantly nuclear in neurons and cytoplasmic in peripheral cells; neurons might shuttle the protein between the two compartments [Servadio et al., 1995]. A 120-residue region of the protein (563–694 in alleles containing 30 glutamines) shares significant sequence similarity with the HMG-box transcription factor HBP1 and has been implicated in protein–protein interactions and possibly in protein–RNA interactions [Chen et al., 2004b].

The exact cellular functions of ataxin-1 are currently unknown. Mice lacking ataxin-1 have spatial and motor learning deficiencies, as well as impairment of short-term plasticity [Matilla et al., 1998], but do not display ataxia or neuronal degeneration. These findings show that loss of function of ataxin-1 cannot explain SCA1 pathogenesis. Support for a gain-of-function pathogenic mechanism first came from mice overexpressing a mutant SCA1 cDNA with 82 glutamines (82Q), specifically in Purkinje cells. These mice developed progressive ataxia and Purkinje cell degeneration [Burright et al., 1995]. The mutant ataxin-1 accumulates in nuclear inclusions (NIs), along with components of the proteasome, suggesting that mutant ataxin-1 might misfold and resist degradation [Cummings et al., 1998]. Similarly, fruitflies that overexpress human ataxin-1 (82Q) also developed progressive neuronal degeneration and ataxin-1-containing NIs that co-localized with chaperones and ubiquitin. To characterize the effects of the SCA1 mutation on all ataxin-1-expressing neurons, an expanded CAG tract of 154 repeats was targeted in place of the typical two CAGs present in the endogenous mouse locus. Sca1^154Q/+ mice reproduced all features of human SCA1, including ataxia, brainstem dysfunction, Purkinje cell degeneration, and premature death [Watase et al., 2002]. Consistent with the in vivo data, cellular and in vitro studies demonstrated that ataxin-1 is ubiquitinated, that the expanded polyglutamine tract retards its degradation, and that inhibition of the proteasome enhances its accumulation [Cummings et al., 1998, 1999]. Chaperone overexpression, which presumably aids in the folding and/or elimination of the expanded protein, improved motor coordination and suppressed Purkinje cell degeneration in SCA1 (82Q) transgenic mice [Cummings et al., 2001]. The important roles of protein misfolding and degradation have also been demonstrated in several other polyglutamine diseases [Opal and Zoghbi, 2002].

Ataxin-1 is phosphorylated at serine 776 (S776); when this serine is mutated to alanine (S776A), mutant ataxin-1 does not accumulate when overexpressed in cultured cells. Moreover, mice that express ataxin-1 (82Q) with an alanine at position 776 do not develop ataxia or pathology, in spite of the long glutamine tract. These data show that:

Furthermore, neuropathogenesis of ataxin-1 depends on native, not novel, protein interactions [Lam et al., 2006]. Lim et al. [2008] proposed a two-pronged model of SCA1 neurodegeneration, in which increased function of a particular stable endogenous protein complex is combined with a simultaneous loss of function of other stable endogenous protein complexes.

Continuous expression of mutant ataxin-1 is necessary for progression of SCA1 pathogenesis. Given the reversibility of the symptoms and cell pathology in an SCA1 mouse model, there is a window of opportunity when therapies can ameliorate this disease [Zu et al., 2004]. No treatment is currently available for SCA1. Patients experience progressive limitations in their activities, lose the ability to walk, and eventually become bedridden. Based on the studies in SCA1 animal models, it appears that lithium and neural stem cell transplantation in the cerebellum could be viable therapeutic approaches for SCA1 patients [Watase et al., 2007; Chintawar et al., 2009].

Spinocerebellar Ataxia Type 2 (SCA2 – OMIM 183090)

In 1989, Orozco et al. described a form of dominantly inherited spinocerebellar ataxia that occurs at an estimated frequency of 41 per 100,000 in the province of Holguín, Cuba [Orozco et al., 1989]. Age of onset varies from 2 to 65 years, with 40 percent of the patients presenting with symptoms before 25 years of age. Onset before the age of 20 years correlates with a more aggressive disease course. The clinical features include ataxia, dysarthria, tremor, and extremely slow saccades. Hyporeflexia of the upper limbs and ophthalmoparesis are seen in over half the patients. Dementia occurs in a significant minority of patients. The locus was termed SCA2 and mapped to chromosome 12q24 [Gispert et al., 1993]. Families with this disorder from other regions of the world have also been described [Lopes-Cendes et al., 1994].

Pathology specimens show severe loss of Purkinje cells and of neurons in the substantia nigra and basis pontis. Mild to moderate neuronal loss is seen in the inferior and accessory olives; dentate, arcuate, gracile, and accessory cuneate nuclei; internal granule cell layer of the cerebellum; and the anterior horns of the spinal cord. Axonal loss from the dorsal roots and posterior columns, the dorsal spinocerebellar tract, and often the anterior spinal roots is also found. Reactive gliosis can be seen in the globus pallidus, thalamus, subthalamus, and periaqueductal regions [Koeppen, 1998; Huynh et al., 1999].

Using three different approaches, the SCA2 gene was identified, and the mutation was determined to involve an expansion of a CAG trinucleotide repeat that lies within the coding region of a novel protein termed ataxin-2 [Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996]. Normal ataxin-2 alleles contain 15–24 CAG repeats (with 22 repeats found 94 percent of the time), while disease alleles have 35–59 repeats. The range of pathogenic alleles in SCA2 is shifted toward shorter repeats compared with other SCAs, suggesting that the expanded repeat within ataxin-2 is more deleterious to neurons. The CAG repeat in the SCA2 gene is interrupted by 1–3 CAA units only on normal alleles, suggesting that, as in SCA1, interruption of CAG repeats confers stability. Finally, there is a strong inverse correlation between the size of the repeat and the age of symptom onset.

The SCA2 gene, ataxin-2, contains 25 exons and spans approximately 130 kb of genomic DNA. Two alternately spliced forms of messenger (m)RNAs are generated, one of which results in a protein that is truncated by 70 amino acids [Sahba et al., 1998]. Ataxin-2 mRNA is found in multiple tissues and in all regions of the CNS [Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996], where it is present predominantly in neurons and is highly expressed in Purkinje cells [Huynh et al., 1999]. Ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, a stress granule component and a key factor for translational control [Nonhoff et al., 2007]. Ataxin-2 is associated with rough endoplasmic reticulum in a complex that is RNA, salt, and phosphorylation-dependent [van de Loo et al., 2009]. Ataxin-2 associates with polyribosomes under normal conditions and is recruited to stress granules upon environmental stress. Mutant ataxin-2 sensitizes Purkinje cells to glutamate-induced apoptosis. Glutamate-induced cell death of 58Q PC (Purkinje cell) cultures was attenuated by dantrolene, a clinically relevant ryanodine receptor (an intracellular calcium channel) inhibitor and Ca² stabilizer. Thus, neuronal Ca² signaling may play an important role in SCA2 pathology and the ryanodine receptor could be a potential therapeutic target for treatment of SCA2 patients [Liu et al., 2009].

Machado–Joseph Disease (SCA3 – OMIM 109150)

SCA3, also known as Machado–Joseph disease (MJD), was first described in families with Azorean-Portuguese origin and is the predominate form of autosomal-dominant SCA in Europe, Japan, and the United States (reviewed in Riess et al. [2008]). The clinical features of MJD include progressive ataxia, areflexia, peripheral amyotrophy, external ophthalmoplegia, bulging eyes, facial and lingual fasciculations, muscle atrophy, parkinsonian features, dystonia, and spasticity. Age of onset varies from 5 to 75 years of age, and correlates inversely with the CAG repeat length [Riess et al., 2008]. Early attempts to categorize this disorder into different clinical subtypes were thwarted by the variability in presentation and the tendency of individuals to “evolve” from one subtype to another [Rosenberg et al., 1976; Coutinho and Andrade, 1978; Barbeau et al., 1984].

The MJD gene, which encodes ataxin-3, was mapped to the long arm of chromosome 14 (14q24.3–q32) [Takiyama et al., 1993]. Subsequently, Stevanin et al. [1994] mapped the gene in a family with a dominantly inherited spinocerebellar ataxia to chromosome 14q24.3–qter. Normal MJD1 alleles contain from 13 to 47 CAG repeats, while expanded alleles contain 45–84 repeats [Riess et al., 2008].

Several ataxin-3 isoforms have been described. It is the smallest of the polyglutamine proteins with a ubiquitin interaction motif (UIM) situated near the polyglutamine domain. Ataxin-3 interacts with Rad23 and valosin-containing protein (VCP) [Doss-Pepe et al., 2003]. Rad23, a member of the proteasomal protein degradation machinery, in turn interacts with the proteasome subunit S5a, suggesting a role of the protein complex in “protein shuttling” for translocating proteins to the proteasome for degradation. VCP, also called CDC48, is an ATPase associated with various activities and has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (reviewed in Riess et al. [2008]. Mutation of VCP causes inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD – OMIM 167320). Most interestingly, Parkin, the E3 ubiquitin ligase that is frequently mutated in early-onset autosomal-recessive Parkinson’s disease, promotes ubiquitination and degradation of ataxin-3 [Tsai et al., 2003].

The pathogenesis of MJD/SCA3 is still poorly understood. The introduction of ataxin-3 with an expanded polyglutamine tract into cultured cells induces apoptosis, suggesting that the mutant protein is either directly or indirectly involved with a cellular suicide pathway [Ikeda et al., 1996]. Other studies suggest that protein misfolding, presumably initiated by the expanded polyglutamine tract, leads to ubiquitination and subsequent formation of intranuclear inclusions [Chai et al., 1999]. This is a common pathway in polyglutamine expansion diseases. How this leads to cell dysfunction and death, and why the clinical time course takes so long to evolve, remain unknown.

Spinocerebellar Ataxia Type 4 (OMIM 600223)

Seven kindreds (one from Utah and six from Japan) have been described thus far [Gardner et al., 1994; Nagaoka et al., 2000]. Clinically, affected individuals in the Japanese families have a pure cerebellar ataxia, while those in the Utah kindred also have dysarthria and sensory axonal neuropathy [Flanigan et al., 1996]. Detailed genetic mapping studies show that the gene involved in SCA4 maps to the long arm of human chromosome 16. Anticipation does not occur.

Spinocerebellar Ataxia Type 5 (OMIM 600224)

The locus for SCA5 was localized to the centromeric region of human chromosome 11, based on detailed mapping studies of two major branches of a family descended from the paternal grandparents of President Abraham Lincoln [Ranum et al., 1994b]. Ikeda et al. [2006] found that SCA5 is caused by mutations in SPTBN2, which encodes beta-3 spectrin. Beta-3 spectrin is highly expressed in Purkinje cells and stabilizes the glutamate transporter EAAT4. The phenotype is that of pure cerebellar ataxia and dysarthria. The disease is milder than that observed in other SCAs, without substantial effects on life span.

Spinocerebellar Ataxia Type 6 (SCA6 – OMIM 183086)

SCA6 accounts for 1–13 percent of ADCA families from European centers, 6–31 percent from Japanese centers, and up to 11 percent in Chinese series [Schols et al., 1998] (see review in Mantuano et al. [2003]). The mutation is occasionally found in sporadic cases as well. The clinical features consist predominantly of mild but slowly progressive cerebellar ataxia of the limbs, gait ataxia, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss. Cognitive function is not affected. Patients often have acute episodes of ataxia or vertigo that are responsive to acetazolamide. Onset is later than the other dominantly inherited SCAs, typically occurring in the third decade at the earliest. Brain imaging reveals atrophy of the cerebellum.

Pathology specimens demonstrate loss of Purkinje and granule cells, with proliferation of Bergmann glia, that is more prominent in the vermis than in the hemispheres [Gomez et al., 1997; Tsuchiya et al., 1998; Takahashi et al., 2004]. Loss of inferior olive neurons also occurs, but may be secondary to the cerebellar changes.

The genetic locus was mapped to chromosome 19q13, where a CAG repeat expansion in exon 47 at the 3′ region of the CACNA1A gene was identified as the causative mutation [Zhuchenko et al., 1997]. CACNA1A codes for the brain-specific, voltage-sensitive α_1A (Ca_v2.1) subunit of the P/Q-type calcium channel, which is highly expressed in Purkinje cells [Ishikawa et al., 1999]. Alternative splicing leads to six isoforms, three of which contain the polyglutamine sequence. Repeat expansions are the smallest of the triplet repeat diseases, with 21 or more repeats being pathogenic. Individuals who are homozygous for expanded repeats show no phenotypic or age-of-onset differences [Takiyama et al., 1998]. Phenotypic severity is inversely correlated with the number of CAG repeats, as is the age of onset [Takahashi et al., 2004]. Clinical anticipation has been observed, but does not always appear to stem from CAG repeat instability. No CAA interruptions are present in the repeats.

Proteins with the expanded repeat aggregate specifically in the cytoplasm of Purkinje cells [Ishikawa et al., 1999]. These inclusions are not ubiquitinated and lack several other components found in the inclusions of other CAG repeat disorders. It is not clear whether SCA6 is caused by a “gain-of-function” mechanism similar to that in other polyglutamine diseases, or by a channelopathy that alters calcium homeostasis. As will be discussed later (see “Episodic Ataxias” later in this chapter), point mutations and deletions in the CACNA1A coding sequence cause episodic ataxia type 2 and familial hemiplegic migraine type 1. Families with significant phenotypic overlap have been identified, leading some to postulate that the three disorders represent a spectrum of disease, rather than truly separate entities. The identification of small triplet expansions (20 and 23 repeats) in two kindreds whose members presented with episodic ataxia type 2, and the identification of a point mutation leading to early hemiplegic migraine and later progressive ataxia, are supportive of this interpretation [Jodice et al., 1997; Alonso et al., 2003]. Gabapentin, which interacts with the α2δ subunit of the P/Q-type voltage-dependent calcium channel, demonstrated clinical benefit in a small trial on SCA6 patients [Nakamura et al., 2006]; establishing the efficacy of gabapantin will require further controlled trials.

Spinocerebellar Ataxia Type 7 (SCA7 – OMIM 164500)

SCA7 is distinguished clinically from the other SCAs by the presence of macular dystrophy leading to pigmentary retinal degeneration (reviewed in Michalik et al. [2004]). The retinal changes in SCA7 start in a central location and move peripherally as the disease progresses, thus distinguishing the eye findings from those in retinitis pigmentosa. Progressive ataxia/dysmetria, pyramidal tract signs, supranuclear ophthalmoplegia, and dysarthria/dysphagia are also present, and occasionally dementia and deafness are seen as well [Benton et al., 1998]. Either ataxia or visual changes can be the presenting symptom, depending upon the number of CAG repeats in the expanded allele (see below). Brain imaging in all cases typically demonstrates cerebellar atrophy; ventricular dilatation and delayed myelination can be found in infantile cases. Brain pathological specimens show atrophy of the cerebellum, with loss of dentate neurons and Purkinje cells, and loss of inferior olivary neurons in the brainstem; posterior column, and dorsal and ventral spinocerebellar tract loss in the spinal cord; and macular degeneration with loss of photoreceptive cells in the retina.

An extremely aggressive infantile-onset form of SCA7 has been described [Enevoldson et al., 1994; Benton et al., 1998]. It presents with hypotonia, dysphagia, myoclonic seizures, and visual disturbances that typically lead to rapid mental deterioration and severe physical disability, culminating in death by age 3 or earlier. The infantile-onset form is also associated with cardiac abnormalities, particularly patent ductus arteriosus [Benton et al., 1998; Johansson et al., 1998; van de Warrenburg et al., 2001]. Childhood-onset SCA7 is less aggressive than the infantile-onset form but more progressive than the adult-onset form.

SCA7 maps to the short arm of chromosome 3 [Benomar et al., 1995; Gouw et al., 1995; Holmberg et al., 1998]. By using an antibody that selectively detects proteins containing an expanded polyglutamine tract, it was demonstrated that the mutational mechanism in SCA7 is expansion of a CAG repeat [Trottier et al., 1995]. SCA7 encodes a novel protein, ataxin-7, with a polyglutamine tract at the amino-terminus [David et al., 1997]. The SCA7 CAG repeat ranges in size from 4 to 35 repeats in normal alleles, and from 37 to 306 repeats in expanded alleles. Typically, larger expansions are paternally inherited and result from significant intergenerational repeat instability. An inverse correlation exists between repeat length and age of onset, and repeat expansions of over 59 repeats tend to develop visual impairment prior to ataxia [Johansson et al., 1998]. Alleles ranging in size from 34 to 36 repeats have been observed in individuals who are at risk but asymptomatic at the time of evaluation [David et al., 1997; Benton et al., 1998; Holmberg et al., 1998; Johansson et al., 1998].

Mouse models of SCA7 have provided some insight into the pathogenesis of the disease. Expression of the expanded ataxin-7 protein in transgenic mice leads to the development of intranuclear inclusions and the degeneration of rod photoreceptors and Purkinje cells, findings that are consistent with the human phenotype [Yvert et al., 2000]. In retinal photoreceptor cells, the expression of expanded ataxin-7 is associated with alterations in gene expression that predate photoreceptor degeneration [La Spada et al., 2001; Yoo et al., 2003]. Another interesting finding is that the speed of ataxin-7 accumulation varies in different neuronal populations, suggesting that intrinsic differences in the ability to clear mutant protein may explain the variable susceptibility of different cell types in this and other polyglutamine diseases [Yoo et al., 2003]. Cellular dysfunction predates the appearance of neuronal inclusions, suggesting that, while they are part of the pathogenesis, inclusions in and of themselves are not the primary cause of dysfunction [Yoo et al., 2003].

Recently, it has been shown that ataxin-7 is a core component of a transcriptional co-activator complex called STAGA (reviewed in Garden and La Spada [2008]). STAGA is the mammalian equivalent of a yeast transcriptional co-activator named SAGA, which contains histone acetyltransferase (HAT) activity, mediated by the Gcn5 enzyme. Sgf73, the yeast homolog of ataxin-7, is a component of the SAGA complex with essential function in yeast [Sanders et al., 2002]. Two independent groups have shown that ataxin-7 is indeed a core component of STAGA complex in mammals [Helmlinger et al., 2004; Palhan et al., 2005], but why, in spite of ubiquitous expression of the STAGA complex, neurodegeneration happens only in specific group of neurons remains to be understood. The answer might underlie identification of STAGA-dependent transcription factors whose functional impairment underlies the production of the SCA7 phenotype.

Spinocerebellar Ataxia Type 8 (SCA8 – OMIM 608768)

Described predominantly in Caucasian families from the United States and Canada, the clinical presentation of SCA8 is similar to that of the other slowly progressive SCAs. Ataxic dysarthria, nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sense are present [Koob et al., 1999]. MRI of the brain demonstrates cerebellar atrophy. SCA8 was mapped to chromosome 13q21, and the vast majority of disease alleles in individuals of European descent share a common haplotype [Ikeda et al., 2004].

Unlike other repeat disorders caused by polyglutamine expansions, SCA8 is caused by a CTG repeat in a noncoding gene; that is, no open reading frame is present in the gene, suggesting that it is transcribed into mRNA but not translated into protein [Koob et al., 1999]. This is only one of several unusual characteristics of SCA8. There is high variability in the repeat length of wild-type alleles; more than 99 percent of unaffected individuals have repeat lengths less than 74, but a few unaffected individuals have 800 repeats, by far the largest number of normal repeats of any SCA. This remarkable overlap of repeat size in pathogenic and nonpathogenic alleles is unique among the SCAs. Furthermore, homozygosity for an expanded allele does not appear to exacerbate the disease phenotype, as it does in SCA1 and dentatorubral-pallidoluysian atrophy. Repeat lengths contract with paternal transmission and expand with maternal transmission, another unusual finding of this disease. Further confusing the picture is the coexistence of SCA8 expansions with those of SCA1 or SCA6 in some kindreds [Izumi et al., 2003; Sulek et al., 2003]. SCA8 expansions have also been found in patients with Alzheimer’s disease, Parkinson’s disease, and an individual with vitamin E deficiency heterozygous for the TTPA mutation [Sobrido et al., 2001; Cellini et al., 2002; Izumi et al., 2003]. How these factors influence the pathogenesis of the disease is unknown, and has led some authors to question the pathogenesis of the expansion itself [Stevanin et al., 2000; Worth et al., 2000; Schols et al., 2003].

The genomic arrangement of the SCA8 locus suggests a potential function of the gene. The SCA8 gene lies in a reverse orientation to and partially overlaps the locus of another gene (KLHL1). It has been suggested that the SCA8 mRNA functions as an endogenous inhibitory RNA for KLHL1, or as a regulator of RNA-binding proteins [Mutsuddi et al., 2004].

Although a relationship between repeat size and clinical signs was demonstrated in the initial report, other families with this disorder have shown greater variability in penetrance [Ikeda et al., 2004]. Sequence interruptions of the CTG expansion and the size of the CTA tract that precedes the CTG expansion are among the multiple factors that may influence SCA8 disease penetrance. A similar RNA gain of function to that seen in myotonic dystrophy types 1 and 2 (DM1, OMIM 160900; DM2, OMIM 602668) has been suggested for SCA8 pathogenesis. Recent evidence suggests that SCA8 CUG^exp transcripts form hallmark ribonuclear inclusions that co-localize with MBNL1 in humans and mice, and that genetic loss of Mbnl1 enhances motor coordination deficits in SCA8 BAC-EXP mice [Daughters et al., 2009]. Furthermore, ATXN8OS CUG^exp transcripts dysregulate MBNL1-CUGBP1 pathways in the CNS and trigger downstream molecular changes in gamma-aminobutyric acid (GABA)_A transporter 4 (Gabt4) regulation through an RNA gain-of-function mechanism. Unlike DMPK and ZNF9 (the genes responsible for DM1 and DM2, respectively), which have broad expression patterns, SCA8 is almost exclusively expressed in the CNS; the spatial and temporal expression differences between SCA8, DMPK, and ZNF9 could explain the phenotypic differences between these three diseases (reviewed in Dick et al. [2006]).

Spinocerebellar Ataxia Type 10 (SCA10 – OMIM 603516)

Grewal et al. [1998] described a dominantly inherited SCA in a single four-generation Mexican kindred. The locus was independently mapped to chromosome 22q13 by two different groups [Matsuura et al., 1999; Zu et al., 1999]. SCA10 is the second most common form of dominantly inherited ataxia after SCA2 in people of Mexican descent and MJD in southern Brazil; this fact, coupled with the rarity of expanded alleles in other populations, has led to the hypothesis that the mutation arose in the New World [Matsuura et al., 2002]. The phenotype consists of ataxia, dysarthria, nystagmus, extrapyramidal signs, and epilepsy. Mood disorders and polyneuropathy diagnosed by nerve conduction studies can also be seen. A pentanucleotide (ATTCT) repeat in intron 9 of the ataxin-10 gene is responsible for the phenotype; instability of the repeat region can lead to as many as 4500 repeats [Matsuura et al., 2000]. There is an inverse correlation between expansion size and the age of onset, and genetic anticipation is present. The repeats are highly unstable when transmitted paternally, while maternal transmission results in more stable repeats. Brain imaging reveals cerebellar atrophy.

Ataxin-10 is a protein that is widely expressed throughout the brain and in several other tissues [Marz et al., 2004]. It is localized to the cytosol and perinuclear region in neurons. Whether the disease phenotype stems from genomic disruption, RNA gain of function, or ataxin-10 loss of function is unknown, although decreased ataxin-10 RNA levels in primary cerebellar and cortical neuronal culture result in increased apoptosis, suggesting that loss of function may be the pathogenetic mechanism [Marz et al., 2004].

Spinocerebellar Ataxia Type 11 (SCA11 – OMIM 604432)

Worth et al. [1999] described a single eight-generation family with 34 affected individuals, suffering from a benign, slowly progressive, pure cerebellar syndrome linked to chromosome 15. Mean age of onset was about 25 years; genetic anticipation did not appear to be present. The most prevalent symptoms were gait, truncal, and limb ataxia, dysarthria, nystagmus, and hyperreflexia in the lower limbs [Edener et al., 2009]. In 2007, truncation mutations in the tau tubulin kinase 2 gene (TTBK2) were described as being associated with spinocerebellar ataxia type 11: a one-base insertion in a British pedigree and a deletion of a dinucleotide in a family of Pakistani ancestry [Houlden et al., 2007]. Neuropathological examination did not reveal neuronal inclusions using hematoxylin and eosin, p62, ubiquitin or 1C2 immunohistochemistry, but neurofibrillary tangles, neuropil threads, and tau-positive neuritis were visible in the medullary tegmentum, nigra, midbrain tegmentum and tectum, and putamen. The cerebellum showed cell loss but no other visible pathology, perhaps due to the high resistance of the cerebellum to forming tangles [Houlden et al., 2007].

Spinocerebellar Ataxia Type 12 (SCA12 – OMIM 604326)

Identified in a family of German descent [Holmes et al., 1999], SCA12 is unique, in that action tremor is the most distinguishing clinical feature and is typically the initial symptom. Slow progression over several decades leads to head tremor, gait ataxia, dysmetria, dysarthria, hyperreflexia, parkinsonian signs, abnormal eye movements, and occasionally dementia. Two patients in the initial kindred were reported with childhood-onset symptoms; one had nystagmus from birth, while the other had lower-extremity dystonia that developed in childhood [O’Hearn et al., 2001]. Brain imaging reveals both cortical and cerebellar atrophy. Pathology is available only on a single brain, and revealed diffuse atrophy of cerebral and cerebellar cortices, and specifically loss of Purkinje cells. SCA12 is rare, except in India, where it is the third most common SCA [Srivastava et al., 2001; Holmes et al., 2003].

Genetic analysis revealed a triplet CAG expansion on chromosome 5q31–q33. No apparent relationship exists between repeat size and age of onset. Unlike other SCAs with CAG expansions, the expanded allele does not lead to a polyglutamine tract. Rather, the CAG expansion is found 133 nucleotides upstream of the transcription start site for PPP2R2B. The SCA12 gene product is a brain-specific regulatory subunit of protein phosphatase 2A that regulates neuronal survival through mitochondrial fission/fusion balance [Dagda et al., 2008].

Spinocerebellar Ataxia Type 13 (SCA13 – OMIM 605259)

SCA13, initially described in a four-generation French family [Herman-Bert et al., 2000], has also been characterized in a large Filipino pedigree [Waters et al., 2005]. The SCA13 gene maps to chromosome 19q13, and mutations in the voltage-gated potassium channel KCNC3 are causative for the disease [Waters et al., 2005]. Sequence analysis of KCNC3 revealed mutations 1554 G→A (R420H) in the Filipino family and 1639C→A (F448L) in the French pedigrees. Both mutations alter KCNC3 function in a Xenopus laevis oocyte expression system. The F448L mutation would be expected to be more severe because it alters key gating properties of KCNC3 channels. In contrast, R420H would be expected to reduce channel activity without changing the functional properties of the residual current [Waters et al., 2006]. This is consistent with the childhood onset with concurrent mental retardation (IQ = 62–76) and seizures in members of the French pedigree and their absence in the Filipino patients. These mutations are expected to change the output characteristics of fast-spiking cerebellar neurons, where KCNC channels confer capacity for high-frequency repetitive firing.

Spinocerebellar Ataxia Type 14 (SCA14 – OMIM 605361)

Three families (one Japanese, one Dutch, and one English/Dutch) have been described, all with a locus mapping to 19q13.4 telomeric to the locus for SCA13 [Yamashita et al., 2000; Brkanac et al., 2002a; van de Warrenburg et al., 2003]. The phenotype varies from family to family, and within families as well. In the Japanese kindred, subjects with onset of symptoms before 27 years of age presented with axial myoclonus prior to the development of ataxia, while those with onset after age 39 presented with a pure cerebellar ataxia. Gait ataxia, dysarthria, horizontal gaze nystagmus, abnormal smooth pursuit movements, hyper- and hyporeflexia, and peripheral neuropathy were described in all of the families [Yamashita et al., 2000; Brkanac et al., 2002a; van de Warrenburg et al., 2003]. Imaging reveals atrophy of the cerebellar vermis and/or hemispheres. Life span does not appear to be affected in any of the kindreds, and ataxia displays a slowly progressive course. Genetic anticipation occurs. Limited pathologic specimens suggest a primary Purkinje cell defect [Brkanac et al., 2002b].

Molecular studies reveal that missense point mutations in exon 4 of the protein kinase C gamma (PRKCG) gene are responsible. PRKCG is a member of a serine/threonine kinase family that is involved in cell proliferation and signal transduction processes. The mechanism of pathogenesis remains unknown [Chen et al., 2003; van de Warrenburg et al., 2003; Yabe et al., 2003].

Spinocerebellar Ataxia Types 15 and 16 (SCA15 – OMIM 606658 and 606364)

Spinocerebellar ataxia type 15 (SCA15) is characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. Additional clinical features include mild titubation and postural or action tremor. The locus for SCA15 was first mapped to 3p24.2–3pter in an Australian family [Storey et al., 2001]. Hara et al. mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk. The first family had partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase-modifying factor 1 (SUMF1) genes. and the second family had only a point mutation in ITPR1 (P1059L). The proline was highly conserved and the mutation was absent in 234 chromosomes in Japanese controls [Hara et al., 2008]. These results suggest that ITPR1 but not SUMF1 is the causative gene for SCA15. On the other hand, Iwaki et al. showed that haploinsufficiency in ITPR1 alone is the cause of what had been thought to be a different disease, SCA16 (OMIM 606364) [Iwaki et al., 2008]. Since these discoveries, SCA16 has been considered a “vacant SCA” and families in Iwaki et al. are regarded as actually having SCA15.

Spinocerebellar Ataxia Type 17 (SCA17 – OMIM 607136)

This SCA variably presents with predominant symptoms of cerebellar ataxia associated with dysarthria and extrapyramidal symptoms (e.g., parkinsonism and dystonia), with mental deterioration/dementia and psychiatric symptoms such as depression and hallucinations, or as a Huntington’s disease phenocopy with chorea as the major manifestation (reviewed in Stevanin and Brice [2008]). Different individuals in the same family can have dramatically different presenting phenotypes and, as the disease progresses, symptoms from each of the subtypes can occur in the same individual. Neuroimaging demonstrates diffuse cortical and cerebellar atrophy that is most pronounced in the vermis. Pathologic specimens reveal neuronal loss in many brain areas, including loss of Purkinje cells [Nakamura et al., 2001; Rolfs et al., 2003].

SCA17 is caused by CAG repeat expansions in the TATA-binding protein (TBP) gene on chromosome 6q27 [Nakamura et al., 2001]. Like other SCAs, short CAA tracts interrupt the CAG repeats; however, both the CAG and CAA tracts are replicated in the expansions, distinguishing this SCA. Marked anticipation was observed in an Italian kindred, with the youngest family member in the fourth generation presenting with dysarthria and ataxia at age 3 [Maltecca et al., 2003]. Repeat sizes of 42–48 repeats show variable penetrance. Like other expansion diseases, an inverse correlation exists between repeat size and age of onset.

TBP is the DNA binding subunit of the RNA polymerase II transcription factor D complex, which is important in general gene transcription [Tsuji, 2004]. Immunostaining for ubiquitin, TBP, and polyglutamine tracts demonstrates their presence in intranuclear inclusions in several neuronal cell types, including Purkinje cells [Nakamura et al., 2001; Rolfs et al., 2003].

Spinocerebellar Ataxia Type 18 (SCA18; Sensory/Motor Neuropathy with Ataxia – OMIM 607458)

SCA18, or sensorimotor neuropathy with ataxia (SMNA), was described in a five-generation American family of Irish descent [Brkanac et al., 2002b]. Clinically, affected individuals present first with gait instability in the dark, followed by limb ataxia, nystagmus, decreased vibratory and position sense, decreased deep tendon reflexes, and proximal or distal muscle weakness and atrophy. Upgoing plantar responses and pes cavus are occasionally seen. Neuroimaging is either normal or demonstrates mild cerebellar atrophy. Electromyography/nerve conduction velocity studies show evidence of denervation and axonal sensory neuropathy. Thus, the overall picture is one of a mixed cerebellar degeneration and peripheral neuropathy. The disorder was mapped to chromosome 7q31–32. Interferon-related developmental regulator gene 1 (IFRD1) has been proposed as a candidate gene [Brkanac et al., 2009].

Spinocerebellar Ataxia Type 19 (SCA19 – OMIM 607346)

A single Dutch family with ataxia, cognitive impairment, irregular postural tremor, myoclonus and poor performance on the Wisconsin Card Sorting Test has been described. Imaging shows atrophy of the cerebellar hemispheres or vermis [Schelhaas and van de Warrenburg, 2005]. The genetic locus maps to chromosome 1p21–q21, where it overlaps with the locus for SCA22 (see below).

Spinocerebellar Ataxia Type 20 (SCA20 – OMIM 608687)

A dominantly inherited cerebellar ataxia associated with palatal tremor and a characteristic dysphonia has been described in a single Anglo-Celtic kindred [Knight et al., 2004]. Imaging shows mild to moderate cerebellar atrophy and the unique finding of dentate calcification in the absence of basal ganglia calcification. The genetic locus overlaps with that of SCA5, so the separate identity of this SCA remains to be established.

Spinocerebellar Ataxia Type 21 (SCA21 – OMIM 607454)

This SCA was described in a single French kindred with gait ataxia, extrapyramidal signs such as tremor, akinesia and cogwheeling, and mental impairment mapping to chromosome 7p21.3–p15.1 [Devos et al., 2001; Vuillaume et al., 2002]. Eye movements are normal, and disease progression is slow. Anticipation is suggested. Brain imaging shows marked atrophy of the cerebellum. The responsible gene has not yet been identified.

Spinocerebellar Ataxia Type 22 (SCA22)

Chung et al. [2003] reported a pure cerebellar ataxia syndrome consisting of gait and limb ataxia, dysarthria, and nystagmus in a single Chinese kindred, mapping to chromosome 1p21–q23. Neuroimaging showed diffuse involvement of the cerebellum. Anticipation is suggested. Based on their chromosomal loci, it has been suggested that SCA19 and SCA22 might be the same disorder [Schelhaas and van de Warrenburg, 2005]; identification of the responsible gene(s) should answer this question.

Spinocerebellar Ataxia Type 23 (SCA23)

A single, three-generation Dutch family with a late onset (>40 years), slowly progressive SCA was identified with locus linkage at 20p13–p12.2 [Verbeek et al., 2004]. The clinical presentation includes gait and limb ataxia, disturbance of oculomotor control, dysarthria, and hyperreflexia. Neuroimaging demonstrates severe cerebellar atrophy. Pathology in a single individual who died at 80 years of age showed loss of Purkinje cells, neurons in the dentate nuclei and inferior olives; thinning of the cerebellopontine tracts; demyelination of the posterior and lateral columns in the spinal cord; and ubiquitin-positive, polyglutamine-negative intranuclear inclusions in nigral neurons that resembled Marinesco bodies. The pathogenic significance of this last finding is uncertain. A candidate gene approach has thus far failed to identify the responsible gene.

Spinocerebellar Ataxia Type 25 (SCA25 – OMIM 608703)

Stevanin et al. [2004] reported a single French kindred with cerebellar ataxia and peripheral sensory neuropathy manifest as loss of vibratory, light touch, and pain sensation. Initial symptoms often include vomiting and gastrointestinal features. No evidence of anticipation was found. Brain imaging shows global cerebellar atrophy. A candidate gene search failed to identify the affected gene.

Spinocerebellar Ataxia Type 26 (SCA26 – OMIM 609306)

Yu et al. [2005] studied a six-generation kindred of Norwegian ancestry with pure cerebellar ataxia signs, including slowly progressive gait ataxia, trunk and limbs ataxia, dysarthria, and irregular visual pursuit movements. Age at onset ranged from 26 to 60 years. Genome-wide linkage analysis identified the disease locus as chromosome 19p13.3, close to SCA6 (OMIM 183086). Genetic analysis, however, showed that these patients have wild-type CACNA1A alleles [Yu et al., 2005]. The region consists of approximately 100 known and predicted genes, and the responsible gene for SCA26 has not been identified.

Spinocerebellar Ataxia Type 27 (SCA27 – OMIM 609307); Fibroblast Growth Factor 14-SCA

Van Swieten et al. described a large Dutch family with early-onset hand tremor, dyskinesia, and slowly progressive cerebellar ataxia. Limb ataxia develops between the ages of 15 and 20 years. Ataxia, dysmetric saccades and smooth pursuit movements, nystagmus, small-amplitude hand tremor, psychiatric symptoms, and decreased cognitive performance are part of SCA27. Brain imaging is normal or shows cerebellar atrophy. The disease is associated with an F145S mutation in the fibroblast growth factor 14 (FGF14), a gene on chromosome 13q34 [van Swieten et al., 2003]. FGF14 knockout mice show ataxia and paroxysmal dyskinesia [Wang et al., 2002]. FGF14 regulates the intrinsic excitability of Purkinje cells [Shakkottai et al., 2009]. Other patients with a truncating mutation or a chromosome translocation have been reported to have similar phenotypes to SCA27.

Spinocerebellar Ataxia Type 28 (SCA28 – OMIM 610246)

SCA28 has been described in 13 patients in two Italian families with a juvenile-onset, slowly progressive ataxia. The mean age at onset for balance and gait abnormalities was 19.6 years (range 12–36). Other features included limb ataxia, dysarthria, and lower limb hyperreflexia [Cagnoli et al., 2006; Mariotti et al., 2008]. The disease locus was found on chromosome 18p11.22–q11.2. Two different missense mutations have been found in the AFG3L2 (ATPase family gene 3-like 2) protein [Mariotti et al., 2008]. AFG3L2 and paraplegin are nuclear-encoded mitochondrial proteins that form a hetero-oligomer. These ubiquitous proteins are m-AAA proteases and their complex ensures protein quality control in the inner mitochondrial membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Mutations in paraplegin are responsible for a recessive form of hereditary spastic paraplegia (SPG7 – OMIM 607259), whereas mutant forms of AFG3L2 cause dominantly inherited SCA28. Mice haploinsufficient for AFG3L2 recapitulate important pathophysiological features of the human disease. Respiratory chain dysfunction and increased production of reactive oxygen species might explain the pathophysiology of SCA28 [Maltecca et al., 2009].

Spinocerebellar Ataxia Type 30 (SCA30)

Storey et al. [2009] have described an Australian family with slowly progressive ataxia in middle to late decades of life, with only minor pyramidal signs. MRI studies revealed cerebellar atrophy with preservation of the nodulus/uvula and brainstem. The patients did not have nystagmus or neuropathy. Linkage analysis identified chromosome 4q34.3–q35.1 as the locus, which is distinct from previously reported loci [Storey et al., 2009].

Spinocerebellar Ataxia Type 31 (SCA31 – OMIM 117210)

Nagaoka et al. [2000] reported 28 affected individuals from six Japanese families with cerebellar dysarthria, limb ataxia, decreased muscle tone, and horizontal gaze nystagmus. The disease starts at 45–72 years of age. The disease locus mapped to chromosome 16q22.1, the same locus as in SCA4. But these patients, unlike SCA4 patients, did not have any sign of pyramidal tract involvement, such as exaggerated tendon reflexes, Babinski signs, or spasticity [Nagaoka et al., 2000]. Recently, Sato et al. [2009] studied 160 affected individuals from 98 SCA31 families and 430 control subjects, including 5 SCA4 patients. They found an insertion, from 2.5–3.8 kb long, consisting of complex pentanucleotide repeats, including a long (TGGAA)n stretch. In controls, shorter (1.5–2.0 kb) insertions lacking (TGGAA)n were found only rarely. One family showed anticipation, and the length of the repeat inversely correlated with age of onset; an expansion was documented in a single family showing anticipation. The repeat insertion was located in introns of TK2 and BEAN (brain expressed, associated with Nedd4) expressed in the brain and formed RNA foci in Purkinje cell nuclei. They also found a single-nucleotide change in an intron of the thymidine kinase 2 gene (TK2). However, this did not appear to affect splicing or expression patterns [Sato et al., 2009].

Episodic Ataxias

There are seven episodic ataxias, all of which are rare dominant disorders characterized by intermittent ataxia. EA1, EA2, and EA5 are caused by channelopathies, EA6 is caused by mutation of a glutamate receptor, and the pathogenesis of EA3, EA4, and EA7 is unknown.

Episodic ataxia type 1 (EA1 – OMIM 160120), also known as episodic ataxia with myokymia, is characterized by intermittent episodes of ataxia that can occur spontaneously but are often precipitated by exercise, fever, stress, or even sudden movement. The attacks can last seconds to minutes and may occur several times per day. Myokymia, a rippling movement of muscle, is usually observed in the periorbital and small hand muscles and persists between ataxic attacks. EA1 maps to human chromosome 12p13, and the disease is caused by point mutations in the potassium channel gene, KCNA1 (Kv1.1) [Browne et al., 1994; Comu et al., 1996]. All affected individuals are heterozygous.

Episodic ataxia type 2 (EA2 – OMIM 108500), also known as hereditary paroxysmal cerebellar ataxia, is characterized by intermittent attacks of ataxia and dysarthria lasting from a few minutes to a few days. Nausea, migraine, weakness, vertigo, diplopia, oscillopsia, and/or dystonia may accompany an attack. Attacks are often followed by a period of fatigue. Interictal neurologic findings include nystagmus (either gaze-evoked or downbeat), mild cerebellar ataxia, and occasionally epilepsy. A progressive cerebellar ataxia is seen in some kindreds. The ataxia and number of attacks typically decrease with acetazolamide treatment; 4-aminopyridine may be a useful alternative if acetazolamide fails or loses effectiveness [Strupp et al., 2004].

The gene locus for this disease was mapped to the short arm of chromosome 19 in a position that overlaps the locus for familial hemiplegic migraine (FHM) [Vahedi et al., 1995; von Brederlow et al., 1995]. Ophoff et al. subsequently demonstrated that both EA2 and FHM are caused by mutations in the CACNA1A gene [Ophoff et al., 1996]. Thus, EA2, FHM, and SCA6 are allelic disorders. CACNA1A codes for the brain-specific, voltage-sensitive α_1A (Ca_v2.1) subunit of the P/Q-type calcium channel, which is highly expressed in Purkinje cells [Ishikawa et al., 1999]. Several different missense and nonsense mutations in the gene are associated with EA2 [Jen et al., 2004]. Although there initially appeared to be a clear genotype–phenotype relationship, further studies have demonstrated that the nature of the mutation in the gene is not predictive of whether an individual will clinically present with EA2 or FHM.

EA3 (OMIM 606554), also called periodic vestibulocerebellar ataxia, was described in a large Canadian kindred [Steckley et al., 2001]. Clinical attacks consist of vertigo, incoordination, imbalance, tinnitus, diplopia, and/or visual blurring lasting for 1 minute to 6 hours. Interictal myokymia and/or ataxia are also present. Attacks often occur 1–2 times per day, followed by a refractory period. Generalized seizures occur in some members of the kindred, suggesting that a channelopathy might be responsible. Acetazolamide was useful for reducing the frequency of attacks in one patient. EA1 and EA2 loci were excluded by mapping studies. By a genome-wide screen Cader et al. [2005] found linkage to a 4-cM region on chromosome 1q42 in the family reported by Steckley et al. [2001]. Although Steckley et al. [2001] referred to periodic vestibulocerebellar ataxia (PATX) as episodic ataxia-3 (EA3) and the disorder in OMIM 606554 as EA4, the same group [Cader et al., 2005] later referred to the disorder described by Steckley et al. [2001] in OMIM 606554 as EA3. Thus episodic ataxia 4 (EA4) is designated for PATX [Steckley et al., 2001; Cader et al., 2005].

EA4, or periodic vestibulocerebellar ataxia (PATX – OMIM 606552), has been described in two white families from North Carolina [Farmer and Mustian, 1963; Vance et al., 1984]. Clinically, the disorder consists of episodic attacks of vertigo, nausea, tinnitus, horizontal nystagmus, oscillopsia, and ataxia that begin in the third decade and may evolve into a constant condition. The visual sensation of objects moving past the patient, such as occurs while riding in a car, can exacerbate attacks, while lying quietly for 15–30 minutes can alleviate an attack. Acetazolamide is not therapeutic, although antihistamines have been anecdotally reported to decrease the frequency and severity of attacks in at least some individuals [Farmer and Mustian, 1963]. Neuroimaging and pathology studies have not been done. Several SCA loci, as well as EA1 and EA2, have been eliminated as causative [Damji et al., 1996]. The causative gene locus is not known.

EA5 (OMIM 601949) was identified when a series of families with episodic ataxia were screened for mutations in the calcium channel b4 subunit CACNB4 on chromosome 2q [Escayg et al., 2000]. This family had clinical features similar to EA2 but no mutation was found in CACNA1A. The episodes last for hours. Complicating matters, the same mutation was found in a German family with generalized epilepsy (but no ataxia) and functional studies showed only subtle changes in calcium channel function (reviewed in Jen et al. [2007]).

EA6 (OMIM 612656) was identified in a single child with episodic and progressive ataxia, episodes of seizures, and hemiplegia that lasted from hours to days. Through a candidate gene approach, a de novo mutation was identified from a screen of the candidate gene SLC1A3 on chromosome 5p13, a glutamate transporter localized to astrocytes [Jen et al., 2005]. De Vries et al. [2009] reported a Dutch family in which three individuals had a milder version of this type of episodic ataxia. The mutation altered a strictly conserved amino acid residue, and functional studies of the mutated protein showed an almost complete loss of function with a dominant negative effect on the wild-type allele.

In the case of EA7 (OMIM 611907), Kerber et al. [2007] described seven patients with episodic ataxia from a four-generation family. Symptoms started before 20 years of age; attacks lasted hours to days and were associated with weakness and dysarthria. Exercise and excitement were triggers. Two affected family members reported vertigo during attacks. The frequency ranged from monthly to yearly and tended to decrease with age. By genome-wide linkage and haplotype analysis, chromosome 19q13 has been identified as the EA7 gene locus [Kerber et al., 2007].

Dentatorubral-Pallidoluysian Atrophy (DRPLA – OMIM 125370)

DRPLA is a rare autosomal-dominant, neurodegenerative disorder characterized by progressive ataxia, myoclonus, epilepsy, chorea, athetosis, and dementia [Smith et al., 1958]. The hereditary nature of the disease was confirmed through detailed clinical, genetic, and neuropathologic studies of five Japanese families with familial myoclonic epilepsy and choreoathetosis [Naito and Oyanagi, 1982]. Clinically, age of onset is linked to disease phenotype. Early onset cases (<20 years of age) tend to present with a progressive myoclonic epilepsy syndrome consisting of epilepsy, myoclonus, cerebellar ataxia, and mental retardation, while adult-onset cases (>20 years of age) tend to present with cerebellar ataxia, choreoatheotosis, and/or dementia. The phenotypic diversity within and among families is striking, as is the overlap with the clinical presentation of Huntington’s chorea.

Imaging studies demonstrate cerebellar, tegmental, and cerebral atrophy, as well as signal changes in the white matter. In late-onset cases, signal change can also be found in the pons, midbrain, thalamus, and globus pallidus (reviewed in Kanazawa [1998]). Pathologic findings in DRPLA include neuronal loss in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus. There is also diffuse loss of myelin staining in the cerebral white matter [Kanazawa, 1998; Munoz et al., 2004]. The disorder is very rare, except in Japan, where it accounts for a significant proportion of autosomal-dominant spinocerebellar ataxias [Watanabe et al., 1998].

By using a candidate gene approach, the mutation causing DRPLA was identified by two research groups [Koide et al., 1994; Nagafuchi et al., 1994]. They both found linkage to chromosome 12 and identified a CAG repeat as responsible for the disorder. An inverse correlation exists between the number of repeat units and the age of onset. Anticipation has been demonstrated in both paternal and maternal transmission of the disease allele, and extreme expansions (>90 repeats) can lead to infantile disease [Shimojo et al., 2001]. Gene dosage also plays a role in severity of phenotype, with homozygosity for a pathogenic allele causing more severe clinical manifestations than would otherwise be predicted based on repeat length [Sato et al., 1995].

The clinical heterogeneity of DRPLA belies its genetic cause. Haw River syndrome shares many clinical and neuropathologic features with DRPLA, Huntington’s disease, and the SCAs. However, this clinical entity differs from DRPLA in the absence of myoclonic epilepsy, as well as the presence of basal ganglia calcifications and neuroaxonal dystrophy. Despite these phenotypic differences, the DRPLA expansion was detected in an African American family with Haw River syndrome [Burke et al., 1994]. Similarly, Warner et al. [1994] reported the CAG repeat expansion in a family of Maltese origin with variable clinical features that included dementia and seizures in younger patients, and dementia, psychosis, ataxia, and chorea in older patients. The neuropathologic findings in this family were not consistent with DRPLA. These examples illustrate the wide phenotypic diversity encountered in DRPLA. Genetic testing for the disorder is therefore indicated in patients with an autosomal-dominant disorder causing dementia, ataxia, seizures, psychiatric symptoms, dystonia, chorea, or myoclonus. Also, patients with features of Huntington’s disease but no evidence of expansion of the Huntington’s disease CAG repeat should be evaluated for the CAG repeat at the DRPLA locus.

The pathogenesis of DRPLA remains a mystery. The number of CAG repeats varies in different tissues and tends to be larger in the brain, suggesting somatic instability of the repeat [Ueno et al., 1995]. However, the degree of expansion does not seem to parallel neuropathologic involvement. Intranuclear inclusions are found in both neurons and glia; their presence in oligodendrocytes may cause the white-matter lesions that are sometimes seen [Hayashi et al., 1998]. Atrophin-1, the DRPLA gene product, is expressed ubiquitously in human tissue. Several proteins proposed to interact with atrophin-1 have been identified using a yeast two-hybrid screen [Wood et al., 1998]. Recent evidence suggests that the wild-type atrophin-1 protein is involved in regulation of transcription, both positively and negatively [Shimohata et al., 2000; Zhang et al., 2002]. Therapeutically, hypoactivation of histone H₃ in brain tissue of Atro-118Q mice, a transgenic DRPLA mouse model, as well as administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice [Ying et al., 2006].

Hereditary Spastic Ataxia (HSA)

The hereditary spastic ataxias are a heterogeneous group of disorders that combine the features of hereditary spastic paralysis and spinocerebellar ataxia. They typically present first with lower limb spasticity, followed by ataxia, dysarthria, and gait disturbance. Autosomal-dominant, recessive, and X-linked forms have been described.

Spastic Paraplegia, Ataxia, and Mental Retardation (SPAR – OMIM 607565)

Hedera et al. [2002] identified a single kindred whose older members presented with uncomplicated spastic paraplegia, while later generations had either spastic paraplegia and ataxia, or spastic paraplegia, ataxia, and mental retardation [Hedera et al., 2002]. Multiple SCAs and hereditary spastic paraplegias were excluded by gene tests and linkage analysis, demonstrating that SPAR is a distinct disorder. Neuroimaging demonstrates dorsal column atrophy in all three types, while only the latter two had cerebellar atrophy. Pathologic studies are not available. Genetic anticipation, both in age of onset and disease severity, was suggested. The causative gene is unknown.