Page 178 - Motor Disorders Third Edition

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activation of ER-stress responses, and triggering a vicious
cycle that ultimately leads to cell death or dysfunction (34). interest in unraveling this phenomenon as it may provide
Special considerations apply to mitochondrial disorders
related to the distinctive role of these organelles in cellu-
lar metabolism and the presence of separate mitochondrial
DNA (mtDNA), as each cell may contain several mitochon-
dria, each with a different burden of mutation (35). Cells in
the brain and muscle with an increased demand for aerobic
metabolism can be compromised by mtDNA mutation-
impairing ATP generation. Those with exclusively mutant
mtDNA termed homoplasmy, may demonstrate a more
severe phenotype, in contrast to those with a mixed popu-
lation of mutant and normal mtDNA termed heteroplasmy.
For instance, a high load of the mtDNA T8993G mutation
leads to fatal childhood maternally inherited Leigh syn-
drome (MILS), whereas a lower mutant threshold causes
the syndrome of neuropathy, ataxia and retinitis pigmen-
tosa (NARP) (36). Recent investigations have shown that
the mtDNA background may also play an important role in
modulating the biochemical defects and clinical outcome in
NARP/MILS (37).
CLINICAL IMPLICATIONS
Several lessons have been learned from characterization of
gene defects associated with different neurogenetic disor-
ders. These have led to recognition of various phenomena,
which are important to understand so test results can be
placed in their proper context.
Genetic heterogeneity, which refers to the manifesta-
tion of a single phenotype despite different mutated genes,
describes a diverse group of genetic neurological disor-
ders. The equivalent phenotypes of limb girdle muscular
dystrophy type 1 (LGMD1) and type 3 (LGMD2A) derive,
respectively, from mutation in the myotillin (MYOT) gene,
which leads to a defective structural protein important in
stabilizing and anchoring thin filaments to the Z-disc dur-
ing myofibrillogenesis, while calpain-3 (CAPN3) encodes a
different muscle-specific calcium-activated neutral prote-
ase that plays a role in disassembling sarcomeric proteins
(38). When testing for a limited number of genes, a nega-
tive result may not exclude the clinical diagnosis under con-
sideration. As new gene defects are described on a regular
basis, it is generally worthwhile to re-examine a patient
without an etiologic diagnosis, if several years have passed
since testing was last performed.
Variable expressivity refers to the different patterns of
clinical manifestations that occur with the same mutation,
suggesting the influence of other factors and modifiers
that interact with the gene defect to cause the disease. This
observation implies patients with the same clinical diag-
nosis and gene defect can have a different disease course.
The presence of disease modifiers and how they exert their
influence is an area of limited knowledge. There is immense
insights into biochemical or cellular pathways that may be
modifiable pharmacologically to delay disease onset or slow
its progression.
Penetrance refers to the likelihood of manifesting a dom-
inantly inherited disease phenotype such that when low, not
every carrier of the gene defect will necessarily develop the
disease, as in mutations of the torsin (TOR) gene and the
leucine-rich repeat kinase 2 (LRRK2) gene associated with
increased risk respectively, of developing torsion dystonia
and PD (39, 40). All relatives of an affected individual may
be a carrier of the same gene defect and should undergo
appropriate genetic counseling, as they can still pass on a
genetic trait to their descendant even when asymptomatic.
Thus, no assumptions about carrier status should be made
based on the presence or absence of symptoms in a relative
of an affected person.
Anticipation, which refers to the increasing severity of an
AD-inherited disorder in subsequent generations, occurs in
inherited ataxia caused by dynamic mutations comprised
of multiple iterations of tri-, tetra-, or penta-nucleotide
repeats, in contrast to nucleotide substitutions that involves,
instead, single base defects or point mutations (41).
Imprinting is an epigenetic process that leads to parent-
specific expression of certain genes, as may occur in two
distinct neurodevelopmental disorders, Prader Willi (PWS)
and Angelman syndrome (AS). De novo paternal deletions
of the imprinted NDN, and SNRPN genes, and possibly
other genes within the chromosome region 15q11-q13,
lead to PWS, manifested by diminished fetal activity, obe-
sity, muscular hypotonia, mental retardation, short stature,
hypogonadotropic hypogonadism, small hands and feet. De
novo maternal deletions involving the same chromosome
region and involving the gene encoding the ubiquitin-pro-
tein ligase E3A gene (UBE3A) lead to AS, associated with
mental retardation, and movement, balance and behavioral
disturbances, with severe limitations in speech (42). Imbal-
anced chromosome translocations leading to inherited
small interstitial deletions or mutations in the UBE3A gene
can be transmitted from an asymptomatic parent, without
detection by prenatal testing.
Germline or gonadal mosacism refers to the occurrence of
affected siblings in whom the mutation has not been estab-
lished in a parent (43). Such may be the case in unsuspected
families with an affected DMD boy in whom the gene defect
may reside in the gamete of seemingly unaffected carrier par-
ent as the mutation is not found in parental DNA obtained
from blood or other tested tissues specimens. This infrequent
event, an important confounder, raised in the counseling of
families, can help in educating them about concerns related
to future reproductive risks and available options.