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Spinocerebellar Ataxias

Friedreich Ataxia



What is spinocerebellar degenration?

This group of diseases affects, to a variable extent, the cerebellar cortex, spinal cord,
peripheral nerves, and other regions of the neuraxis.

The clinical spectrum includes cerebellar
and sensory ataxia
, spasticity, and sensorimotor peripheral neuropathy.

This is a clinically and
genetically heterogeneous group of illnesses, with differences in patterns of inheritance, age at
onset, and signs and symptoms
. Degeneration of neurons, sometimes without other distinctive
histopathologic changes, occurs in the affected areas and is associated with gliosis. Genetic
analysis continues to redefine and subclassify these illnesse


What are Spinocerebellar Ataxias

This is a group of genetically distinct diseases characterized by signs and symptoms referable
to the cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves, as well as
other brain regions in different subtypes.

Pathologically they are characterized by neuronal loss
from the affected areas and secondary degeneration of white-matter tracts.


The list of spinocerebellar ataxias (SCAs) has expanded to reach 29 distinct entities at this time.
Three distinct types of mutations have been recognized: polyglutamine diseases linked to
expansion of a_________,similar to HD;

expansion of__________, similar to
myotonic dystrophy; and other types of mutations.


  •  CAG repeat, 
  •  non–coding region repeats


Expanded polyglutamine repeats
affecting different proteins underlie six forms of SCA (SCA1, 2, 3 [also known as _____________, 6, 7, and 17). 

Joseph disease]


Intranuclear inclusions can be found in these forms of SCA, but
just as in HD it remains unclear whether this contributes to or protects against neuronal injury.
Putative disease mechanisms include sequestration and depletion of chaperone proteins by the
formation of abnormal aggregates driven by the polyglutamine tracts as well as transcriptional

In general, these forms of SCA show anticipation. The basis for the targeting of the cerebellar system for specific injury remains unknown


In the diseases caused by non–coding region repeat expansions (SCA8, 10, and 12), the
underlying mechanisms are even more obscure.

Point mutations have been found in βIII
spectrin (SCA5), a voltage-gated potassium channel (Kv3.3 in SCA13), protein kinase Cγ
(SCA14), and fibroblast growth factor 14 (SCA27). These have been linked to a wide range of
potential disease mechanisms without any obvious shared pathways of neuronal injury.


What is Friedreich ataxia? 

It is a distinctive spinocerebellar degeneration, is an autosomal recessive
progressive illness, generally beginning in the first decade of life with gait ataxia, followed by
hand clumsiness and dysarthria.

Deep tendon reflexes are depressed or absent, but an
extensor plantar reflex is typically present.

Joint position and vibratory sense are impaired, and
there is sometimes loss of pain and temperature sensation and light touch.

Most affected
individuals develop pes cavus and kyphoscoliosis.

There is a high incidence of cardiac
arrhythmias and congestive heart failure.

Concomitant diabetes is found in about 10% of

Most patients become wheelchair-bound within about 5 years of onset; the cause of
death is intercurrent pulmonary infections and cardiac disease.


What is the caused of Friedreich ataxia? 


USMLE question!!!

It is caused by expansion of a GAA trinucleotide-repeat in the first intron of a
gene on chromosome 9q13
that encodes a protein called frataxin. [65]


Affected individuals have
extremely low levels of the protein, which normally localizes to the inner mitochondrial
membrane, where it may have a role in regulation of iron levels.

Because iron is an essential
component o
f many of the complexes of the oxidative phosphorylation chain, mutations in
frataxin have been suggested to result in generalized mitochondrial dysfunction.



Friedreich ataxia shares biologic features with other____________(anatomic distribution of pathology
and trinucleotide-repeat expansion) as well as the mitochondrial encephalopathies.



What is the morphology of Friedrieich ataxia?

The spinal cord shows loss of axons and gliosis in the posterior columns, the
distal portions of corticospinal tracts, and the spinocerebellar tracts.



What degeneration occurs in Friedreich ataxia?

There is degeneration
of neurons in the spinal cord (Clarke column), the brainstem (cranial nerve nuclei VIII, X, and
, the cerebellum (dentate nucleus and the Purkinje cells of the superior vermis), and the
Betz cells of the motor cortex.

Large dorsal root ganglion neurons are also decreased in
number; their large myelinated axons, traveling both in the dorsal roots and in dorsal
columns, undergo secondary degeneration.

The heart is enlarged and may have pericardial

Multifocal destruction of myocardial fibers with inflammation and fibrosis is detectable in about half the affected individuals who come to autopsy.


What is Ataxia-telangiectasia? 

It is an autosomal recessive disorder characterized by an
ataxic-dyskinetic syndrome beginning in early childhood, with the subsequent development of
telangiectasias in the conjunctiva and skin; and immunodeficiency.



The ataxia-telangiectasia
mutated (ATM) gene on chromosome ____________encodes a kinase with a critical role in
orchestrating the cellular response to double-stranded DNA breaks ( Chapter 7 ).

Cells from
individuals with the disease show increased sensitivity to x-ray-induced chromosome
abnormalities; these cells continue to replicate damaged DNA rather than stopping to allow repair or undergoing apoptosis. The carrier frequency of ataxia-telangiectasia has been
estimated at 1%; in these individuals the mutated ATM allele may underlie an increased risk of
cancer, specifically breast cancer.

The link between DNA repair mechanisms and
neurodegenerative disease is harder to understand than the connection to neoplasia.

It has
been suggested that mutations in ATM result in failure to remove cells with DNA damage from
the developing nervous system, predisposing it to degeneration.



What is the morpholoygy of Friedreich ataxia?

The abnormalities are predominantly in the cerebellum, with loss of Purkinje
and granule cells; there is also degeneration of the dorsal columns, spinocerebellar tracts,
and anterior horn cells, and a peripheral neuropathy. Telangiectatic lesions have been
reported in the CNS as well as in the conjunctiva and skin of the face, neck, and arms. Cells
in many organs (e.g., Schwann cells in dorsal root ganglia and peripheral nerves,
endothelial cells, pituicytes) show a bizarre enlargement of the nucleus to two to five times
normal size and are referred to as amphicytes.

The lymph nodes, thymus, and gonads are


What is the clinical feature of Friedreich ataxia?

The disease is relentlessly progressive, with death early in the second decade.

individuals first come to medical attention because of recurrent sinopulmonary infections and
unsteadiness in walking.

Later on, speech is noted to become dysarthric, and eye movement
abnormalities develop.

Many affected individuals develop lymphoid neoplasms, often T-cell
gliomas and carcinomas have been reported in some.