CHAPTER 68 INHERITED ATAXIAS
The inherited ataxias are a heterogeneous group of neurodegenerative syndromes with a vast array of clinical signs and symptoms, both neurological and systemic. The clinical spectrum is wide and may range from “pure” cerebellar signs to constellations that include spinal cord syndromes, peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmological signs, psychiatric problems, and seizure disorders. Typically, inherited ataxias develop over years to decades; recessively inherited forms start in childhood and those dominantly inherited start in adulthood. Historically, these disorders were diagnosed with difficulty on the basis of clinical manifestations. Classification schemes, complicated by eponymous designations in the absence of genetically based information, further complicated the literature. Genetic advances, however, have aided in the classification and diagnosis of the inherited ataxias, identifying specific chromosomal defects or gene loci associated with a clinical phenotype in many instances.
BRIEF DESCRIPTION
The inherited ataxias are grouped (Table 68-1) by mode of inheritance: autosomal dominant, autosomal recessive, mitochondrial, and X-linked. More than 32 known autosomal dominant cerebellar ataxias (ADCAs) were known as of May 2006. The known ADCAs are designated as spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), episodic ataxia types 1 and 2, human spastic ataxia, and ataxia caused by mutations in the gene encoding fibroblast growth factor 14.1 These ataxias characteristically manifest symptomatically in adulthood. However, the phenomenon of anticipation occurs frequently because (1) many ADCAs occur on the basis of trinucleotide repeat expansion mutations, (2) the length of trinucleotide repeats may be correlated with symptomatic age-related onset, and (3) trinucleotide repeats may undergo further expansion in subsequent generations.
TABLE 68-1 Examples of Inherited Ataxias and Their Mode of Inheritance
| Mode of Inheritance | Inherited Ataxias |
|---|---|
| Autosomal recessive | Friedreich’s ataxia, late-onset Friedreich’s ataxia, FARR, AVED, ARSACS, Cayman’s ataxia, abetalipoproteinemia, ataxia telangiectasia, AOA, SCAN, xeroderma pigmentosum, Cockayne’s syndrome, trichothiodystrophy, Joubert’s syndrome, Gillespie’s syndrome, Behr’s disease, Marinesco-Sjögren syndrome, and metabolic ataxias (urea cycle defects, aminoacidurias, peroxisomal disorders, disorders of pyruvate and lactate, Wilson’s disease, hyperammonemic ataxia, Niemann-Pick disease type C, sialidosis, Refsum’s disease, ceroid lipofuscinosis, leukodystrophies, cholestanolosis, and gangliosidosis) |
| Autosomal dominant | Spinocerebellar ataxias, DRPLA, episodic ataxia types 1 and 2, HSA, and FGF14 |
| X-linked | Sideroblastic anemia and spinocerebellar ataxia, cerebellar ataxia 2 syndrome, ataxia syndrome with extrapyramidal involvement, Arts syndrome, ataxia with tremor and cognitive decline, and Pelizaeus-Merzbacher allelic variant |
| Mitochondrial | Leukodystrophy; MELAS; MERRF; NARP; Leigh’s syndrome; HAM; syndrome of ataxia, cataract, and diabetes mellitus; coenzyme Q10 deficiency; COX10 deficiency; cytochrome c oxidase I and II deficiency; pyruvate dehydrogenase disorders; and syndrome of sideroblastic anemia and spinocerebellar ataxia |
ADCA, autosomal dominant cerebellar ataxia; AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; AVED, ataxia with vitamin E deficiency; COX10, cytochrome oxidase 10; DRPLA, dentatorubral-pallidoluysian atrophy; FARR, Friedreich’s ataxia with retained reflexes; FGF14, fibroblast growth factor 14 (mutation causing disease); HAM, hearing loss, ataxia, and myoclonus; HSA, human spastic ataxia; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke; MERRF, myoclonic epilepsy and ragged red fibers; NARP, neuropathy, ataxia, and retinitis pigmentosa; SCAN, spinocerebellar ataxia with axonal neuropathy.
The autosomal recessive cerebellar ataxias (ARCAs) are less common than ADCAs. The two most common ARCAs are Friedreich’s ataxia and ataxia telangiectasia. Other less common ARCAs include ataxia with vitamin E deficiency (AVED), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), abetalipoproteinemia, Refsum’s disease, infantile-onset spinocerebellar ataxia, spinocerebellar ataxia with axonal neuropathy, Cayman’s ataxia, trichothiodystrophy, xeroderma pigmentosum, Cockayne’s syndrome, and ataxia with oculomotor apraxia.2,3 The ARCAs begin in infancy and early life.
Pathophysiological clues for many of the inherited ataxias are known. A few of the ARCAs have been genetically characterized with pathogenesis resulting from the loss of function of specific cellular proteins crucial in metabolic homeostasis, cell cycle, or DNA repair. For the ADCAs, the pathogenesis often appears related to the production of a toxic or harmful protein.2
EPIDEMIOLOGY AND RISK FACTORS
Estimates of the prevalence of the ADCAs are restricted to a few epidemiological studies hindered by founder effects in the isolated geographical populations studied. The population studies do indicate that the prevalence of the ADCA subtypes varies among ethnic and geographical populations.1 Although the prevalence is probably underestimated at three cases per 100,000 people, ADCAs are relatively uncommon disorders.4 In comparison, the prevalence of Huntington’s disease is 5 to 10 cases per 100,000 people. The most common ADCA worldwide is spinocerebellar ataxia type 3, followed by types 2 and 6, type 1, type 8, and type 7.5,6 The prevalence of DRPLA is 0.25% to 2% among patients with ADCA and is especially prevalent in Japan.7 The remaining subtypes are very rare.6
The exact prevalence of X-linked and mitochondrial inherited ataxias is unknown but believed to be extremely low. For example, the estimated prevalence of all mitochondrial disorders (with and/or without ataxia) is 11.5 cases per 100,000 individuals.8
The main risk factor for the inherited ataxias is a family history of ataxia. Spontaneous mutations are rarely identified.6 A patient with an ADCA, the proband, typically has a parent with the disease. However, this, too, is not a universal finding, because the mutant allele may have decreased penetrance in the parent, onset of the disease may be late in the parent but early in the proband secondary to anticipation, an affected parent may die before the disease manifests, the proband’s background may be unknown because of adoption or unknown lineage, or symptoms in a family member may go unrecognized.
Mitochondrial disorders can result either from mutations in mitochondrial DNA that are maternally transmitted or from mutations in nuclear DNA that may follow either an autosomal dominant or an autosomal recessive pattern of inheritance.8
CLINICAL FEATURES
The Autosomal Recessive Cerebellar Ataxias
The ARCAs are rare, with the exceptions of Friedreich’s ataxia and ataxia telangiectasia. For simplification, they can be grouped etiologically (Table 68-2) as those resulting from potentially increased oxidative stress, those resulting from problems in DNA repair, and those caused by metabolic derangements. The more frequently encountered ARCAs are discussed in the following section; the features that may aid in determining diagnosis are highlighted.
TABLE 68-2 Pathophysiology of Autosomal Recessive Cerebellar Ataxias
| Pathophysiology | Disease |
|---|---|
| Oxidative stress | Friedreich’s ataxia, late-onset Friedreich’s ataxia, FARR, AVED, ARSACS, Cayman’s ataxia, and abetalipoproteinemia |
| DNA repair failure | Ataxia telangiectasia, AOA, SCAN, xeroderma pigmentosum, Cockayne’s syndrome, trichothiodystrophy |
| Metabolic causes | Urea cycle defects, aminoacidurias, peroxisomal disorders, disorders of pyruvate and lactate, Wilson’s disease, hyperammonemic ataxia, Niemann-Pick disease type C, sialidosis, Refsum’s disease, ceroid lipofuscinosis, leukodystrophies, cholestanolosis, and gangliosidosis |
| Congenital ataxia syndromes | Joubert’s syndrome, Gillespie’s syndrome, Behr’s disease, Marinesco-Sjögren syndrome |
AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; AVED, ataxia with vitamin E deficiency; FARR, Friedreich’s ataxia with retained reflexes; SCAN, spinocerebellar ataxia with axonal neuropathy.
The ARCAs associated with oxidative stress include Friedreich’s ataxia and Friedreich’s ataxia–like syndromes, ataxias secondary to vitamin E deficiency, and Cayman’s ataxia. The most common of these is Friedreich’s ataxia. The classic clinical features include progressive gait and limb ataxia, dysarthria, absence of deep tendon reflexes, vibratory and proprioceptive sensory loss, and pyramidal weakness with a disease onset before 25 years of age.2 Symptomatic sensory loss typical of Friedreich’s ataxia helps to distinguish this ataxia from other spinocerebellar ataxias with severe reduction or loss of sensory action potentials without reduction of motor conduction velocities.9 About 25% of patients have an atypical manifestation after 25 years of age, called late-onset Friedreich’s ataxia, or with retained reflexes, known as Friedreich’s ataxia with retained reflexes, and/or slow disease progression. The skeletal, endocrine, and cardiovascular systems are affected; the disease manifests, respectively, as scoliosis and pes cavus, diabetes mellitus, and hypertrophic cardiomyopathy. Cardiomyopathy is a cardinal feature of Friedreich’s ataxia and detrimentally affects prognosis commonly, with early death secondary to heart failure or fatal arrhythmia. Optic neuropathy and sensorineural hearing may be present later in the disease. The pathogenesis of Friedreich’s ataxia involves a deficiency of a mitochondrial protein, frataxin, secondary to a guanine-adenine-adenine expansion. The genetic defect is believed to result in iron accumulation in mitochondria with oxygen-free radical production. The normal trinucleotide repeat range is estimated at 33 or fewer triplet repeats; pathological expansions range from 67 to 1000 triplets, with length inversely proportional to age at clinical onset, scoliosis, and cardiomyopathy.10 Unlike the ADCAs with trinucleotide repeats, Friedreich’s ataxia is not associated with anticipation. Patients with Friedreich’s ataxia become unable to walk within 11 years after disease onset and have a mean survival length of 36 years after onset of symptoms. Typically, more than two decades of life are spent in a debilitated motor state.11 To date, the size of the guanine-adenine-adenine pathological expansion has made development of transgenic animal models difficult.
AVED is a rare disorder with clinical manifestations similar to those of Friedreich’s ataxia. A patient with clinical features of Friedreich’s ataxia and negative genetic test results should be screened for AVED (with plasma vitamin E levels), especially because this syndrome is potentially treatable. Head titubation and dystonia are more common in AVED than in Friedreich’s ataxia; cardiomyopathy is a less frequent problem.2 The syndrome is caused by a defective transfer protein for α-tocopherol that prevents transfer of this most biologically active form of vitamin E to peripherally circulating lipoproteins.12 Oral vitamin E supplementation is the mainstay of treatment.
Cayman’s ataxia is an ARCA found in a population on Grand Cayman Island. It involves a mutation of the Caytaxin protein, found almost exclusively in the central nervous system, and is believed to bind a ligand with similar properties to vitamin E in the central nervous system.3 It is characterized by early-onset hypotonia, cerebellar ataxia, and psychomotor retardation.3
There are seven inherited ataxias caused by defective DNA repair: ataxia telangiectasia, ataxia with oculomotor apraxia, spinocerebellar ataxia with axonal neuropathy, ARSACS, xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy. The most common of these is ataxia telangiectasia. Ataxia telangiectasia is typified by neurological, dermatological, and immunological symptoms starting in infancy or early childhood, with death in early adulthood. Neurological manifestations include cerebellar ataxia, slowed horizontal saccades, dystonic posturing, chorea, tics or jerks, dysphagia and choking, and peripheral neuropathy. The dermatological signs include oculocutaneous telangiectasia, premature graying of hair, and premature senile keratosis.12 Patients with ataxia telangiectasia have recurrent sinopulmonary infections secondary to derangement of cellular and humoral immunity (deficient immunoglobulin A levels). Malignancy and neoplasia are common, especially those involving hematological cells. The mutations associated with ataxia telangiectasia in the ataxia telangiectasia mutation gene lead to mutations in nuclear protein, which normally repairs DNA. Consequently, individuals with ataxia telangiectasia have a sensitivity to ionizing radiation—a diagnostic hallmark of ataxia telangiectasia.3 Almost all persons with ataxia telangiectasia have an elevated α-fetoprotein level; however, this is a nonspecific finding. Ataxia with oculomotor apraxia may be a separate syndrome. It lacks the immunological features and sensitivity to ionizing radiation seen in classic ataxia telangiectasia.2,13 Survival of patients with ataxia telangiectasia after age 30 is rare. ARSACS is a rare ARCA secondary to defective DNA repair found in parts of Quebec.
Xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy are rare ARCAs characterized by extreme skin photosensitivity in combination with ataxia and possibly other neurological manifestations. Xeroderma pigmentosum is marked by the development of skin cancers, including squamous cell carcinomas and melanoma.12
