Huntington Disease Involves Degeneration of the Striatum
Huntington disease usually strikes in early or middle adulthood and affects 5 to 10 people per 100,000. The clinical presentation includes loss of motor control, cognitive impairment, and affective disturbance. Motor-control problems most commonly manifest themselves early as chorea, involuntary jerky movement that involves the small joints at first but then gradually creates instability of gait as the trunk and legs are affected. Fast, fluid movements are replaced by rigidity and bradykinesia (difficulty initiating action and unusually slow movements).
Cognitive impairment—such as difficulty in planning and executing complex functions—typically appears along with the involuntary movements but may be detected by formal neuropsychological testing even prior to motor dysfunction. Affective disturbances (psychiatric and behavioral features) include depression, irritability, social withdrawal, and disordered sleep. Hypomania and increased energy occur in 10% of the patients, whereas frank psychosis with delusions occurs in a smaller subset.
In adult patients the disease progresses inexorably to death some 17 to 20 years after onset. Juvenile-onset cases suffer a more rapid course of the disease and within only a few years typically develop bradykinesia, dystonia (spasm of the neck, shoulders, and trunk), rigidity (resistance to the passive motion of a limb), seizures, and severe dementia.
The pathological hallmark of Huntington disease is degeneration of the striatum, with the caudate nucleus being more affected than the putamen. Loss of a class of inhibitory interneurons in the striatum, the medium spiny neurons, reduces inhibition of neurons in the external pallidum (see Chapter 43). The resulting excessive activity of the pallidal neurons inhibits the subthalamic nucleus, which could account for the choreiform movements. As the disease progresses and striatal neurons projecting to the internal pallidum degenerate, rigidity replaces chorea. Abnormalities in corticostriatal projections are thought to contribute to pathogenesis. Juvenile cases suffer a more severe and generalized pathology that often includes cerebellar Purkinje cells.
Huntington disease is an autosomal dominant disorder and one of the first human diseases to have its gene mapped using polymorphic DNA markers. It is caused by expansion of a translated CAG repeat that encodes a glutamine tract in the huntingtin protein. Normal or wild-type alleles have 6 to 34 repeats, whereas disease-associated alleles typically have 36 or more repeats and are quite unstable when transmitted from one generation to the next, especially through paternal germ cells.
The dynamic nature of the mutation, expanding in successive generations, accounts for the greater severity of the disease in juvenile-onset cases, a phenomenon known as anticipation. The length of the repeat correlates inversely with the age of onset, one of the many common features of neurodegenerative diseases caused by CAG-repeat expansions (Figure 44–1). Huntington disease-like 2 (HDL2), a rare neurodegenerative disorder that is clinically similar to Huntington disease, is caused by CTG expansion in junctophilin 3.
The length of the CAG repeat and age of onset in spinocerebellar ataxia are inversely correlated.
The longer the CAG tract, the earlier the onset for a given disease. Specific repeat lengths, however, have different results depending on the host protein. For example, a 52-repeat of CAG causes juvenile onset of symptoms in spinocerebellar ataxia type 2 (SCA2), adult onset in spinocerebellar ataxia type 1 (SCA1), and no disease in spinocerebellar ataxia type 3 (SCA3).
Huntington disease appears to be a true dominant disease in that patients homozygous for the condition do not differ significantly from their heterozygous siblings. The expanded glutamine tract causes the huntingtin protein to gain toxic function in addition to its normal function. Huntingtin is expressed throughout the brain in the cytoplasm, where it associates with microtubules, with a minor fraction present in cell nuclei. Although its precise functions are unknown, huntingtin is an essential protein in normal embryonic development as shown by mouse knock-out studies; it is also essential for neuronal integrity in the postnatal brain.
Spinobulbar Muscular Atrophy Is Due to Abnormal Function of the Androgen Receptor
Spinobulbar muscular atrophy (Kennedy disease), the only X-linked disorder among the neurodegenerative diseases discussed in this chapter, is caused by expansion of a translated CAG repeat in the androgen receptor protein, a member of the steroid hormone receptor family. Only males manifest symptoms; the mutant androgen receptor is toxic when in the nucleus, and such localization requires the male hormone androgen. Proximal muscle weakness is usually the presenting symptom; eventually the distal and facial muscles weaken as well. Muscle wasting is prominent, secondary to degeneration of motor neurons.
Bulbar dysfunction results from loss of brain stem motor neurons. Many patients also develop gynecomastia, late hypogonadism, and sterility, indicating the loss of androgen receptor function. Individuals lacking androgen receptor function without expansion of CAG repeats do not, however, develop motor neuron degeneration. It thus appears that the glutamine expansion causes a partial loss of function that accounts for the secondary sexual characteristics and a partial gain of function that affects neurons and produces the neurological phenotype.
Hereditary Spinocerebellar Ataxias Include Several Diseases with Similar Symptoms but Distinct Etiologies
The spinocerebellar ataxias and dentatorubropallidoluysian atrophy are dominantly inherited neurodegenerative diseases that, for all their heterogeneity, are characterized predominantly by dysfunction of the cerebellum, spinal tracts, and various brain stem nuclei. The basal ganglia, cerebral cortex, and peripheral nervous system are also affected in some subtypes or in isolated cases (Table 44–1).
Table 44–1Pattern of Inheritance and Main Clinical Features of Neurodegenerative Diseases Caused by Unstable Trinucleotide Repeats ||Download (.pdf) Table 44–1 Pattern of Inheritance and Main Clinical Features of Neurodegenerative Diseases Caused by Unstable Trinucleotide Repeats
|Disease ||Inheritance ||Typical presenting features ||Principal regions affected |
|SBMA ||X-linked recessive ||Muscle cramps, weakness, gynecomastia ||Lower motor neurons and anterior horn cells |
|Huntington ||AD ||Cognitive impairment, chorea, depression, irritability ||Striatum, cortex |
|Huntington-like 2 ||AD ||Cognitive impairment, chorea, depression, irritability ||Striatum, cortex |
|SCA1 ||AD ||Hypermetric saccades, ataxia, dysarthria, ophthalmoparesis ||Purkinje cells, dentate nucleus, inferior olive |
|SCA2 ||AD ||Ataxia, hyporeflexia, slow saccades ||Purkinje cells, granule cells, inferior olive |
|SCA3 ||AD ||Ataxia, gaze-evoked nystagmus, bulging eyes, dystonia, spasticity ||Pontine neurons, substantia nigra, anterior horn cells |
|SCA6 ||AD ||Ataxia, late onset (>50 years of age) ||Purkinje cells, granule cells |
|SCA7 ||AD ||Ataxia, visual loss due to retinal degeneration, hearing loss ||Purkinje cells, retina (cone and rod degeneration) |
|SCA8 ||AD ||Scanning dysarthria, ataxia ||Purkinje cells |
|SCA10 ||AD ||Ataxia and seizures ||Purkinje cells |
|SCA12 ||AD ||Early arm tremor, hyperreflexia, ataxia ||Purkinje cells (cortical and cerebellar atrophy) |
|SCA17 ||AD ||Dysphagia, intellectual deterioration, ataxia, absence seizures ||Purkinje cells, granule layer, upper motor neurons |
|DRPLA ||AD ||Dementia, ataxia, choreoathetosis ||Dentate nucleus, red nucleus, globus pallidus, subthalamic nucleus, cerebellar cortex, cortex |
The two clinical features common to all the spinocerebellar ataxias are ataxia and dysarthria. These typically appear in mid-adulthood and gradually worsen, making walking impossible and speech incomprehensible. The brain stem dysfunction manifests itself through difficulties in swallowing and breathing and eventually causes death.
Features such as chorea or dementia are associated more strongly with one spinocerebellar ataxia than others, but these symptoms are so variable that they cannot be reliably used to refine the diagnosis. Even individuals within the same family can present a quite different clinical picture. Thus, although the spinocerebellar ataxias are single-gene Mendelian disorders, individual genetic makeup and environmental influences clearly affect the clinical-pathological situation.
For example, Machado-Joseph disease and spinocerebellar ataxia type 3 (SCA3) had been regarded clinically as distinct diseases before it was discovered that they are caused by mutations in the same gene. The clinical confusion arose by historical accident. The most prominent features of the Portuguese families first studied by Machado and Joseph were bulging eyes, faciolingual fasciculations, parkinsonism, and dystonia, whereas the first SCA3 patients had features more reminiscent of SCA1 (hypermetric saccades and brisk reflexes in addition to the characteristic ataxia and dysarthria). We now know that these apparent clinical differences are at least partially attributable to differences in length of the CAG repeats. Nonetheless, differences in the activity of other proteins caused by genetic variations are probably also at play.
Although the age of onset within each type of ataxia depends on the number of CAG repeats in the gene (Figure 44–1), the toxicity of the abnormally long glutamine tract in the protein product depends on the protein: Expanded glutamine tracts have different effects in different proteins. For example, very short repeat lengths that are detrimental to Purkinje cells in SCA6 are nonpathogenic in other SCAs. In fact, the CAG expansion in SCA6 is the shortest of all the spinocerebellar ataxias: 21 to 33 repeats in mutants compared to fewer than 18 in normal alleles. In contrast, the gene responsible for SCA7 normally tolerates a few dozen CAG repeats, and in the disease state undergoes some of the largest expansions seen in any spinocerebellar ataxia (hundreds of CAGs). (Table 44–2.)
Table 44–2Hereditary Ataxias Caused by Expansion of Unstable Trinucleotide Repeats ||Download (.pdf) Table 44–2 Hereditary Ataxias Caused by Expansion of Unstable Trinucleotide Repeats
| || || || || ||Repeat lengths |
|Disease ||Gene ||Locus ||Protein ||Mutation ||Normal ||Disease |
|SCA1 ||SCA1 ||6p23 ||Ataxin-1 ||CAG repeat in coding region ||6–44* ||36–121 |
|SCA2 ||SCA2 ||12q24.1 ||Ataxin-2 ||CAG repeat in coding region ||15–31 ||36–63 |
|SCA3 (Machado-Joseph disease) ||SCA3, MJD1 ||14q32.1 ||Ataxin-3 ||CAG repeat in coding region ||12–40 ||55–84 |
|SCA6 ||SCA6 ||19p13 ||α1A subunit of voltage-gated Ca2+ channel ||CAG repeat in coding region ||4–18 ||21–33 |
|SCA7 ||SCA7 ||3p12-13 ||Ataxin-7 ||CAG repeat in coding region ||4–35 ||37–306 |
|SCA8 ||SCA8 ||13q21 ||None ||CTG repeat in the 3′ terminal exon (antisense) ||16–37 ||110–250 |
|SCA10 ||SCA10 ||22q13ter ||Ataxin-10 ||Pentanucleotide (ATTCT) repeat in the intron ||10–20 ||500–4500 |
|SCA12 ||SCA12 ||5q31-33 ||Protein phosphatase 2A ||CAG repeat in 5′ UTR ||7–28 ||66–78 |
|SCA17 ||TBP ||6qter ||TATA-binding protein ||CAG repeat in coding region ||29–42 ||47–55 |
|DRPLA ||DRPLA ||12q ||Atrophin-1 ||CAG repeat in coding region ||6–35 ||49–88 |
|FXTAS ||FMR1 ||Xq27.3 ||FMRP ||CGG repeat in 5′ UTR ||6–60 ||60–200 |
Besides tolerating different CAG repeat lengths, the gene products of mutated genes in polyglutamine diseases vary widely in function. The affected gene product in SCA1, ataxin-1, seems to be important for learning and memory; it is predominantly a nuclear protein that shuttles to the cytoplasm and can bind RNA in vitro, which suggests that it might play a role in RNA transport and processing. The affected gene product in SCA6, CACNA1A, is the α1A subunit of the voltage-gated Ca2+ channel; interestingly enough, loss-of-function mutations in the gene (not caused by CAG repeats) have been reported in patients with episodic ataxia and familial hemiplegic migraine. In SCA17 the affected gene product is the TATA box-binding protein, an essential transcription factor. The affected product in dentatorubropallidoluysian atrophy, atrophin-1, is thought to be a corepressor based on functional studies of its probable ortholog in Drosophila. Despite these differences, some pathogenetic mechanisms may be common to the polyglutamine diseases, as discussed later in this chapter.
A few spinocerebellar ataxias are caused by unstable trinucleotide repeats other than CAG (Table 44–2). Spinocerebellar ataxia type 8 is caused by an expansion of a CTG repeat in the 3′ untranslated region of a transcribed RNA with no open reading frames. The mutation responsible for SCA12 is a CAG repeat, but it occurs in a noncoding region upstream of a brain-specific regulatory subunit of the protein phosphatase 2A. Spinocerebellar ataxia type 10 is unique in that it is caused by massive expansion of a pentanucleotide (ATTCT) repeat in the intron of a novel gene. The pathogenic mechanisms accounting for the dominant phenotypes in spinocerebellar ataxia types 8, 10, and 12 are not yet known.