Microscopicexaminationrevealsseverelossofneuronsfromaffectedregionsofthestriatumalongwithgliosis.Themedium-sized,spinyneuronsthatreleasetheneurotransmittersγ-aminobutyricacid(GABA),enkephalin,dynorphin,andsubstancePareespeciallysensitive,disappearingearlyinthedisease.Thereisastrongcorrelationbetweenthedegreeofdegenerationinthestriatumandtheseverityofmotorsymptoms;thereisalsoanassociationbetweencorticalneuronallossanddementia.Inremainingstriatalneuronsandinthecortex,thereareintranuclearinclusionsthatcontainaggregatesofubiquitinatedhuntingtinprotein(see
Fig.23.28 ,inset).
Spinocerebellar ataxias (SCAs) are a heterogeneous group of several dozen diseases with clinical findings that include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy. They are distinguished from one another based on different
Fig. 23.28 Huntingtondisease.Normalhemisphere(left) comparedwithahemispherewithHuntingtondisease(right) showingatrophyofthestriatumandventriculardilation.Inset, Anintranuclearinclusioninacorticalneuronisstronglyimmunoreactiveforubiquitin.(Gross photo courtesy of Dr.Vonsattel, Columbia University, New York, New York.) http://ebooksmedicine.net causative mutations, patterns of inheritance, age at onset, and signs and symptoms. This group of diseases affects, to a variable extent, the cerebellar cortex, spinal cord, other brain regions, and peripheral nerves. Degeneration of neurons, often without other distinctive histopathologic changes, occurs in the affected areas and is associated with mild gliosis. The additional clinical symptoms that accompany the ataxia can help distinguish between well-characterized subtypes. Although many distinct genetic types of SCA have been identified, there remain many cases that do not fall into one of the already characterized forms.
As with HD, several forms of SCA are caused by CAG repeat expansions encoding polyglutamine tracts in various genes. In these forms of SCA, as is true for HD, neuronal intranuclear inclusions are present containing the abnormal protein, and there is an inverse correlation between the degree of repeat expansion and age of onset. Other SCAs are caused by repeat expansions in untranslated regions or by other types of mutations.
Friedreich ataxia is an autosomal recessive disorder that generally manifests in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria. Most patients develop pes cavus and kyphoscoliosis, and there is a high incidence of cardiac disease and diabetes. The disease usually is caused by a GAA trinucleotide repeat expansion in the gene encoding frataxin, a protein that regulates cellular iron levels, particularly in the mitochondria. The repeat expansion results in decreased protein levels through transcriptional silencing; decreased frataxin leads to mitochondrial dysfunction as well as increased oxidative damage.
Amyotrophic lateral sclerosis (ALS) results from the death of lower motor neurons in the spinal cord and brain stem as well as upper motor neurons (Betz cells) in the motor cortex. The loss of lower motor neurons results in denervation of muscles, muscular atrophy (the “amyotrophy” of the condition), weakness, and fasciculations, while the loss of upper motor neurons results in paresis, hyperreflexia, and spasticity, along with a Babinski sign. An additional consequence of upper motor neuron loss is degeneration of the corticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”). Sensation usually is unaffected, but cognitive impairment is not infrequent.