Page 177 - Motor Disorders Third Edition

the SCA28 form of inherited ataxia, wherein mutation in the
ATPase family gene 3-like 2 (AFG3L2) gene, which is selec-
tively expressed in cerebellar Purkinje neurons and involved
in the maintenance of the mitochondrial proteome (20). In
other instances, the relevant tissue-specific pattern of gene
expression may be related more to the profile of its interact- trophy (CMD) (27). Studies indicate SEPN1 is involved in
ing partners, as may be the case in myotonic dystrophy types
1 (DM1) and 2 (DM2), wherein transcribed CTG repeats in
the 3-prime-untranslated region of the dystrophia myotonica
protein kinase (DMPK) gene are expressed in tissues affected
by DM1, while intronic CCTG expansion in the MBNL gene
occur in DM2, which elaborates a protein that functions as a
target-specific regulator of pre-mRNA splicing (21). In these
instances, mutant proteins become neurotoxic to specific cell
subtypes due to highly selective protein-protein interactions
driven by the unique properties of the pathogenic protein.
One disease producing genetic mechanism involves
errors of RNA processing leads to alternative splicing and
transcript editing. In the normal situation, these processes
are a means of generating various products from a single
gene, illustrating why the number of genes in humans is
far less than had been anticipated, given the wide diversity
of protein products. RNA processing involves multiple dif-
ferent players, and several genes. This is illustrated by the
contribution of the transcriptional repressor TARDBP gene,
which encodes the TAR DNA-binding protein (TDP43), and
the fused in sarcoma (FUS) gene that encodes the regulatory
transcription nucleoprotein; the cognate protein products
are involved in RNA-processing pathways implicated in
inherited ALS (22, 23). Other examples include defects in
a particular gene that encodes proteins called snRNP, criti-
cal factors in the assembly of the survival of motor neurons
gene 1 (SMN1), mutations of which cause spinal muscular
atrophy (SMA (24). Splicing errors may also explain vari-
ability in clinical manifestations when the same gene is
involved, such as occurs in disruption of the open reading
frame of the dystrophin gene, resulting in the classic DMD
phenotype; whereas preservation of the reading frame leads
instead to the milder Becker phenotype (25).
Discovery of the gene defects can lead to the elucidation
of novel mechanisms of disease. For example, mutations
in the ABHD12 gene encoding abhydrolase domain con-
taining 12, the cause of AR polyneuropathy, hearing loss,
ataxia, retinitis pigmentosa, and cataract (abbreviated as
PHARC) (26) due to an enzymatic defect of 2-arachidonoyl
glycerol (2-AG) hydrolysis, involved in the metabolism of
an endogenous transmitter acting on cannabinoid recep-
tors. Dysregulation of the endocannabinoid system has not
been previously implicated in ataxia or any other neurode-
generative disorders. This discovery and others may ulti-
mately enable development of rational therapies based on
understanding of disease processes.
The elucidation of disease mechanisms is, in turn,
NEUROGENETIC EVALUATION OF MOTOR DISORDERS / 159
shedding new light on poorly understood physiology,
illustrated by the recent characterization of defects in selo-
noprotein N (SEPN1), a cause of congenital muscular dys-
the regulation of ryanodine receptors and cellular redox
homeostasis, as well as the regulation of satellite cell func-
tion. Pathogenic mutations have been identified in the gene
encoding selenocysteine insertion sequence-binding pro-
tein 2 (SECISBP2 or SBP2), which mediates the generation
of selenoproteins. Affected individuals with SBP2 muta-
tions have axial muscular dystrophy with features similar
to the myopathy caused by mutations in SEPN1, and shared
molecular pathways may explain the commonalities in clin-
ical presentations (28).
As shown above, investigation of putative disease
mechanisms may reveal convergent disease pathways that
explain overlapping clinical manifestations. Several studies
suggest the function of RNA-processing proteins is affected
by their sequestration by trinucleotide repeat expanded
mRNA (29). As there is extensive coupling between RNA
processing events, it is likely that multiple physiologic
pathways are disrupted. Adult-onset of symptoms could
reflect the protracted time it takes to breach a pathologic
threshold in post-mitotic cells within muscle and brain,
with somatic expansion of the repeats over an individual’s
lifespan. Another basis for diseases with shared features can
be disruption of a particular signaling pathway as may be
seen in NeuroCardioFacioCutaneous (NCFC), Noonan,
CFC, and Costello syndrome, wherein distinct causal gene
defects lead to abnormalities of RAS-MAP kinase signaling
and similar manifestations (30).
A common feature of several neurological diseases is the
presence of abnormal protein aggregates, which can be in
the form of extracellular and intracellular protein depos-
its that develop respectively, from amyloid b-protein as in
senile plaques in Alzheimer disease (AD), or a-synuclein
in Parkinson disease (PD) (31). Although the relationship
between deposits and neuronal loss is not fully understood,
there is agreement that these observations are surrogate
markers of specific neurodegenerative disorders.
In several disorders, including those associated with
motor neuron disease (MND), spastic paraplegia, and
peripheral neuropathy, gene defects that encode proteins
that have a role in both anterograde and retrograde axonal
transport have been identified (32). Similarly, genetic disor-
ders associated with leukodystrophy are causally related to
genes that encode proteins with roles in the generation and
maintenance of myelin (33).
Neuronal loss and dysfunction related to genetic defects
are likely mediated by one or more pathologic mechanisms,
including excitotoxicity and oxidative stress. Misfolded
proteins within the endoplasmic reticulum (ER) may over-
whelm ER-associated degradation (ERAD), resulting in