Triple-Repeat Inherited Neurodegenerations

Age range: 2 to 85 years (mean age: 40)

Incidence: 2 to 4.7 per 1 million individuals/year

Prevalence: 5 to 8 per 100,000 individuals

No gender predominance

Autosomal dominant disorder caused by expanded CAG repeats in the HD gene on chromosome 4p resulting in abnormal encoding of Huntington protein

Interaction of mutated Huntington protein with other proteins results in neuron death

Huntington disease occurs with trinucleotide repeats >38 (normal 15 to 32)

Earlier age of onset and increased rate of disease progression associated with longer repeat sizes

Insidious onset of movement abnormalities (chorea), psychiatric manifestations (irritability, depression, anxiety), and cognitive abnormalities (memory loss, diminished decision-making ability, decreased concentration)

Successive generations have expanded trinucleotide repeat number with earlier and more severe phenotype (anticipation)

Fatal disease, duration of illness ranges from 2 to 45 years (mean age: 17)

Symptomatic treatment for involuntary movements and psychiatric symptoms

Imaging nonspecific; MRI may demonstrate striatal and cortical atrophy

Appearance based on stage of disease

Mild to marked cerebral atrophy with striking volume loss of the caudate nucleus and putamen, resulting in ex vacuo hydrocephalus

Degeneration of medium spiny neurons of neostriatum (caudate, putamen) with reactive gliosis in a dorsal to ventral pattern

Neuronal loss in cortical layers III, V, VI, hippocampus, amygdala, and entorhinal cortex

Vonsattel grading: determines pathologic severity in postmortem brains of patients with Huntington disease based on both neostriatum macroscopic atrophy and microscopic changes

• Grade 0: no gross changes; 30% to 40% loss of striatal neurons without astrocytosis

• Grade 1: no gross changes; 50% loss of striatal neurons with moderate astrocytosis in medial caudate and dorsal putamen

• Grade 2: macroscopic atrophy of head of caudate nucleus and putamen with mild globus pallidus atrophy; evident neuronal loss in head/body/tail of caudate nucleus and dorsal putamen and associated astrocytosis

• Grade 3: macroscopic severe atrophy of head of caudate nucleus and putamen with mild globus pallidus atrophy; evident neuronal loss in head/body/tail of caudate nucleus and dorsal putamen and associated astrocytosis; mild astrocytosis in globus pallidus

• Grade 4: macroscopic very severe atrophy of head of caudate nucleus and putamen with severe globus pallidus atrophy; evident neuronal loss (>90%) in head/body/tail of caudate nucleus and dorsal putamen and associated severe astrocytosis; astrocytosis in nucleus accumbens

Immunohistochemical studies for ubiquitin may demonstrate dystrophic neurites and neuronal nuclear inclusions within the cerebral cortex and hippocampus (inclusions less commonly found in the striatum, amygdala, dentate nucleus, and red nucleus)

Intranuclear inclusions and dystrophic neurites may also be identified by immunohistochemistry for Huntingtin protein and expanded polyglutamine repeats

Other Huntington disease–like syndromes

Frontotemporal lobe degeneration

Pick disease

Multiple system atrophy

Corticobasal degeneration

Spinocerebellar ataxia (SCA) 17

FA is the most common hereditary ataxia, accounting for about 50% of cases

Usually affects children and young adults, most frequently during puberty

• Range 2 to 27 years (average age 15); 85% of patients present before age 20

Estimated incidence 2 per 100,000 individuals/year; prevalence 1 per 29,000 individuals

Predominant in whites, rare in black and Asian populations

Carrier frequency 2 to 3 in 180 individuals

No gender predominance