Фенотипни характеристики и генотип-фенотип корелации при наследствените спастични парапарези
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Дата
2015-01-23
Автори
Андреева/Andreeva, Албена Каменова/Albena Kamenova
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Резюме
ІІ. ПОСТАНОВКА НА ИЗСЛЕДВАНЕТО -
ІІ.1 Цели, хипотези и задачи -
Цел на настоящото проучване е фенотипното характеризиране и изясняването на генотип-фенотип корелациите при наследствените спастични параплегии, дължащи се на различни генетични дефекти, с оглед ефективно насочване за молекулярно-генетично изследване и създаване на възможности за генетична профилактика на засегнатите фамилии.
Литературният обзор, данните от предварителните клинични изследвания и нарастващият брой генетично верифицирани пациенти и фамилии с НСП в България позволяват да се формират следните хипотези:
Мултиетническият състав на българската популация предполага голяма клинична и генетична хетерогенност на наследствените спастични парапарези. Очакваме, подобно на други европейски държави, да преобладават АД форми. Едновременно с това, наличието на затворени, ендогамни общности и групи в България предполага, че ще се откриват често и АР форми сред тях.
Друга наша хипотеза е, че наследствени спастични парапарези със сходен фенотип могат да се дължат на мутации в различни гени и да се обуславят от различни патогенетични механизми, и обратно - различни мутации в един и същи ген могат да
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причиняват различни клинични профили на заболяването. Клиничният фенотип вероятно зависи от вида и локализацията на мутацията и нейния ефект върху белтъчната структура и функция.
Проучването има следните по-конкретни задачи:
1/ Детайлно фенотипизиране на фамилии с различни форми на наследствена спастична парапареза с използването на клинични и невроизобразяващи методи
2/ Генеалогично проучване на засегнатите фамилии с оглед изясняване типа на унаследяване
3/ Събиране на кръвни проби и насочване за молекулярно-генетично изследване
4/ Проучване на интра- и интерфамилните вариации в клиничното протичане на наследствените спастични парапарези, причинени от една и съща мутация.
5/ Сравняване фенотипните прояви при наследствени спастични парапарези, причинени от известни генетични дефекти с описаните в литературата.
6/ Сравняване на фенотипната характеристика на наследствени спастични парапарези, причинени от мутации в различни гени.
7/ Сравняване на фенотипната характеристика на наследствени спастични парапарези, причинени от различни мутации в един и същи ген.
8/ Изработване на клинични насоки за диференцирано молекулярно-генетично изследване на фамилни и спорадични случаи с наследствени спастични парапарези в България. ***** SUMMERY
Hereditary spastic paraplegias (HSPs) are group of neurodegenerative disorders with great clinical and genetic heterogeneity characterized by insidiously progressive spasticity of lower limbs. Their main pathological feature is degeneration of pyramidal tracts. HSPs are devided into pure and complicated forms depending on weather spasticity occurs in isolation or is associated with additional signs and symptoms such as neuropathy, cerebellar ataxia, optic atrophy, cognitive impairment, seizures and retinal pigmentary degeneration. The mode of inheritance can be autosomal dominant (AD), autosomal-recessive (AR) or X-inked. Untill now more than 48 different forms have been reported: 16 AD, 27 AR and 5 X-chromosome-linked.
The aim of our study was to describe the phenotype characteristics and to perform genotype-phenotype analyses of the different forms of HSPs in Bulgarian population.
Materials and methods: After obtaining informed written consent we studied 397 patients from 140 families referred to our hospital with the diagnosis hereditary spastic paraplegia. The examined patients were from Bulgarian, Turkish and Gypsy origin. The neurological evaluation was based on specific scales as Ashworth spasticity scale (1964), Spastic paraplegia rating scale (Schule et al, 2006) and Scale for assessment and rating of ataxia (Schmitz-Hübsch T et al. 2006).
Pyramidal involvement was measured by using 5 grade scale, where grade 0 is normal reflexes, grade 1 is brisk tendon reflexes, grade 2 is polykinetic reflexes, grade 3 is clonus and/or extensor plantar responses, grade 4 is spasticity at lower limbs, grade 5 spastic paraparesis at lower limbs.
The severity of the disease was measured by using a 5 grade scale, where grade 1 is normal or very slight stiffness in the legs, 2 is moderate gait stiffness, 3 is unable to run but able to walk alone, 4 is walk with help, 5 is wheelchair-bound (Fonknechten et al., 2000).
To evaluate the presence of cortical and cerebellar atrophy and unspecific white matter leasions brain MRI was performed.
Nerve conduction studies and electromyography were performed with a Dantec–Keypoint portable electromyograph (Natus, Copenhagen, Denmark).
The involvement of optic nerve was assessed by using optic coherent tomography (OCT).
Results: Genetic studies confirmed the diagnosis in 68 patients from 32 kindreds. Mutations in genes encoding proteins spastin, atlastin, spataxin and paraplegin have been found. Spastin gene mutations were identified in 36 patients from 22 families. Thirteen of the described mutations are new. Genetic analyses confirmed atlastin gene mutations in 11 patients from two families. The two mutations desribed in these families are also new. Spataxin gene mutations were observed in two sisters from one family. A single pL78X mutation in paraplegin gene was found at homozygous state in 19 patients and in 53 family members at heterozygous state. These patients belong to 7 Gypsy families. This mutation was previously described by Arnoldi in 2008 and can be considered as a founder in this subisolate.
The most frequent form of HSP reported worldwide is SPG4. It accounts for approximately 50% of AD-HSP. In our study we discovered spastin gene mutations in 53% of all HSP patients. These mutations were found in all three main ethnic groups of Bulgarian population. The mode of inheritance was AD in 19 families (86%) and 3 of the cases were sporadic (14%). The age of onset was between 2 and 65 years. The mean age of onset is 30.2 years. The mean age when independent walking was impossible is 43.4 years. Pure phenotype was observed in 20 families and complicaten in two kindreds. Early onset (before 35 years) had 9 families and late onset had 13 families. Missense mutations were the most common type of the discovered gene defects in our study.
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The second most frequent AD form reported worldwide is SPG3A. It represents about 40% of the young-onset AD-HSP when spastin gene mutations are excluded. In our study we described 2 families with atlastin gene mutations from Bulgarian and Gypsy origin. The Bulgarian family has complicated phenotype and the Gypsy kindred have pure phenotype. In our study this form accounts approximately 16% of all cases.
Surprisingly the second most common form of HSPs in Bulgaria is SPG7. We found a single mutation in paraplegin gene in 7 Gypsy families. The examined Bulgarian and Turkish families were not carriers of the mutation. This mutation was previously described by Arnoldi in 2008 and can be considered as a founder in this subisolate. It accounts about 28% of all cases in Bulgaria. We found mutation pL78X at homozygous state in 19 patients. The main complicating feature was cerebellar ataxia. One of the patients had optic nerve involvement and one patient had myogenic EMG pattern. There was heterogeneity in phenotipic features in this group of patients as there were patients with mild pyramidal involvement and patients with marked spasticity and cerebellar ataxia. Heterozygous carriers of the mutation are 53 family members. Clinical heterogeneity can be found in this group also as some of the patients had mild signs of pyramidal involvement. In one of the families heterozygous mutation was found in three family members – 2 brothers and the daughter of one of them. One of the brothers and his child had marked signs of spastic paraparesis of lower limbs. In this family may be additional disease modifying factors play certain role.
The most common AR form in Europe is those connected with spataxin mutations. In our study we found SPG11 mutation in one family. It accounts 3% of all cases in our study.
Описание
Дисертация за присъждане на образователна и научна степен „Доктор”; Научна cпециалност:Неврология - 03.01.19.; Научен ръководител: Проф. Д-р Ивайло Търнев, д.м.н; Научно жури в състав:
1. Проф. Д-р А. Капрелян, дм (рецензия); 2. Доц. Д-р В. Гергелчева, дм (рецензия); 3. Проф. Д-р И. Търнев, дмн (становище); 4. Проф. Д-р Л. Мавлов, дмн (становище)
5. Доц. Д-р Н. Никоевски, дмн (становище) ; София - 2013
Ключови думи
Нервна система - болести - дисертации; Генетични болести, вродени - дисертации; Парапарези, спастични - дисертации. , Nervous System Diseases - dissertations; Genetic Diseases, Inborn - dissertations; Paraparesis, Spastic - dissertations