Генотип-фенотип корелации при миотонични дистрофии тип 1 и тип 2
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Дата
2018-02-09
Автори
Шопова/Shopova, Ана Вескова/Ana Veskova
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SUMARRY: Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG trinucleotide repeat in the gene DMPK. Although the
CTG repeat correlates with the disease phenotype, because of the mitotical instability of the DMPK CTG repeat length,
and the somatic mosaicism, the results are still controversial. The aim of this study was the phenotypic characterization and elucidation of genotype-phenotype
correlations in myotonic dystrophy and defining the size of expansion in order to predict the clinical manifestation of the
disease and determine the risk of anticipation- more severe
and early expression in subsequent generations. In total 90
patients with the clinical diagnosis myotonic dystrophy
molecular genetic testing confirmed the diagnosis in 84 of 23
families and mutations in the genes responsible for DM1 and
DM2 were identified. The following methods have been
used: laboratory tests, manual muscle testing,
electromyography, functional respiratory testing,
electrocardiography, echocardiography, Holter ECG, neuroophthalmology
consultation in order to evaluate the affected
systems in DM patients. We assessed disease expression by
clinical evaluation and the molecular genetic test in 56 DM1-
patients identified by accurate clinical diagnosis and family
segregation. The DM1 patients were separated in two groups
according to the expansion size (< 400 and >400 CTG
repeats). It was found significant correlation between gender
and the age of onset of the disease in the group of patients
with onset below 30 years of age, dominated by women. A
correlation between the earlier age of onset in patients with
the greater size of expansion was reported when analyzing
the genetic results. There was no correlation between the type of the first symptoms of the disease and the age of onset of the disease. There was no correlation found between the degree of
involvement of the muscular system and the size of
expansion. Results do not show dependencies between the
phenomenon anticipation and the number of CTG repeats,
and the connection between the existence of this
phenomenon and maternal inheritance. A similar correlation
was not found between the maternal or paternal line of
inheritance and the size of the expansion. In support of the
multisystem nature of DM1 the following conclusions were
made: a large percentage of patients with DM1 are with data
for cardiac disorders, mainly rhythm conduction
abnormalities, but without definite correlation with the size
of the expansion; reduced respiratory parameters in patients
with DM1 do not correlate with cardiac disorders and
number of CTG repeats; reported data for axon type peripheral
neuropathy in DM1 is not correlated to the number of CTG
repeats; no relationships were found between the size of
expansion and thus, elevated levels of creatine
phosphokinase, gamma-glutamyltransferase and reduced
levels of immunoglobulin type G.
A comparative analysis was made between the two
types of myotonic dystrophy in the clinical manifestations,
take into account the differences in the effect of individual
systems. Although routine clinical tests can identify
myotonic dystrophy, forms of DM1 and DM2 in adulthood
can not be reliably distinguished from each other using only
clinical criteria.
Our results confirm the multisystem disturbances in DM.
This study demonstrates a correlation between the earlier age of onset in DM1 patients with the greater size of expansion, which can be considered as a useful tool for DM1 phenotype assessment and presymptomatic testing.
Описание
Дисертация за присъждане на образователна и научна степен „доктор по медицина“; Научна специалност: 030119 - Неврология; Научен ръководител: Проф. д-р И. Търнев, дмн. София, 2014 г.
Ключови думи
миотонични дистрофии тип І и тип ІІ; генотип-фенотип корелации; клинична картина; определяне на риска , Myotonic dystrophies type 1 and type 2; genotype-phenotype correlations; clinical manifestation; risk determination