Page 179 - Motor Disorders Third Edition

Founder effects, a phenomenon of shared identity by NEUROGENETIC EVALUATION OF MOTOR DISORDERS / 161
common descent, which explains the increased frequency
of certain conditions within a particular group of disorders disorganized neurofilaments are noted in patients with
such as hereditary inclusion body myopathy (IBM) among AD CMT2E caused by mutation at the 8p21.2 locus of the
Ashkenazi Jews due to glucosamine (UDP-N-acetyl)- NEFL gene (48). Focally folded myelin sheaths are seen in
2-epimerase (GNE) mutations, with a carrier frequency cutaneous nerve biopsy of patients with AR CMT4B due to
of 1 in 20 susceptible individuals (44). The AR progressive mutation at the 11q21 locus of the MTMR2 gene (49), while
fatal infantile neurodegenerative disorder Tay Sachs disease distinctive Schwann cell proliferation with multiple small
(TSD), is caused by mutation in the alpha subunit of the onion bulbs occur in AR CMT4C due to homozygous or
hexosaminidase (HEXA) gene among Ashkenazi Jews, the compound mutation at the 5q32 locus of the SH3TC2 gene
causality of which has been associated with a limited num- (50). Two allelic forms of CMT, AD type 2A2 and HMSN6,
ber of mutations. Screening programs can be introduced due to heterozygous mutation at the 1p36.22 locus of the
that offer a high detection rate within the community. MFN2 gene, respectively, show loss of large myelinated
Indeed, among the ultra-Orthodox Jews, screening prior to fibers but no myelin abnormalities (51) or a mixed axonal
marriage introductions has led to the reduction in the inci- pattern of axonal and demyelinating neuropathy with small
dence of TSD without the need for pregnancy terminations, onion bulbs (52).
as matches or marriages between carriers are discouraged.
ASSIGNMENT OF A GENE DEFECT
CLUES TO GENETIC DIAGNOSIS
The demonstration of a gene sequence alteration does not
Initial clues to the diagnosis of a genetic disorder may be automatically assign the cause of a disease to a specific
derived from careful clinical and laboratory analysis of the genetic defect. Instead, the process of assigning a gene defect
affected patient by a trained geneticist. Currently, readily proceeds through a series of well-defined steps. First, the sug-
available random genetic testing that employ disease-based gestion of causality requires functional correlation, such as
panels are cost ineffective and run the risk of engendering elaboration of the mutant protein or demonstration of a loss
spurious results such as incidental sequence alternations of function as in absent or diminished enzyme activity. Sec-
or changes whose significance is uncertain. Evolving tech- ond, assignment of a given genetic defect requires proof of a
niques employed in genetic diagnosis are anticipated to given pattern of segregation and inheritance, such that the
bring the costs of testing down significantly. mutation is detectable in affected relatives but absent in unaf-
fected family members. Third, identification of the mutation
Clues to the cause of myopathic disorders with an in other patient cohorts, but not in the general population of
LGMD phenotype commences with a family pedigree to otherwise healthy people, suggests even stronger causality. A
elucidate the pattern of inheritance, supplemented by elec- fourth step involves detailed molecular analyses in silico of
trodiagnostic studies and direct histological examination the gene sequence change employing certain computerized
of muscle tissue (as indicated). The presence of dystrophic programs directing attention to the corresponding amino
muscle pathology should prompt the performance of spe- acid sequence, and the potential consequences of a change
cific immunostaining and western blot analysis for evidence in protein structure. A next step involves identification and
of a corresponding sarcoglycanopathy, calveolinopathy, clarification of the gene defect, especially with regard to ori-
calpainopathy, dysferlinopathy, or a-dystroglycanopathy gin by carrier parents, transmission within a family, or the
(45). The demonstration of complete or partial protein defi- presence of a de novo gene mutation.
ciency can then be pursued by molecular analysis of the
suspected gene mutation. The identification of the causal basis of many genetic
diseases, which in several instances may be polygenic, has
Clues to the cause of an inherited peripheral neuropathy enabled classification of those as well as others with often
may similarly be obtained by rigorous evaluation employing shared phenotypes. For example, a conceptual framework
electrodiagnostic studies and histopathological examina- based upon the role or function of the defective gene prod-
tion of an affected cutaneous nerve, prompting appropri- uct has impacted on the approach toward understanding
ately selective molecular testing of the relevant suspected of diverse forms of CMD. The CMD phenotype results
gene involved (46). The cutaneous nerve tissue findings of from pathogenic mutation in more than one gene encod-
giant axonal swellings filled with densely packed bundles ing a defective structural protein or enzyme (53). Struc-
of neurofilaments and segregation of other axoplasmic tural proteins implicated in CMD include those localized
organelles should suggest giant axonal neuropathy (GAN) to the sarcolemma, as well as others to the nuclear and
due to AR mutations at the 16q23.2 locus of the GAN gene basement membranes.
encoding gigaxonin (47). Similar giant axons containing
The elucidation of genetic mechanisms has also derived
from experimental murine models of a given disease