Коллагенопатия VI типа. Болезнь Ульриха. Клинический случай

Institute of Mother and Child, Moldova, Chisinau, Centre of Reproductive Health and Medical Genetics, Moldova, Chisinau, University Medical Center Hamburg-Eppendorf, Germany, HamburColagenul tipul VI este un colagen microfibriliar localizat în matrixul extracelular predominant de țesuturi conjuctive. Este compus din 3 lanțuri α codate de trei gene independente. Mutațiile în aceste gene provoacă maladii musculare de un anumit grup care pot fi referiți ca miopatii lincate de colagenul VI. Aceste miopatii cuprind un spectru de maladii ce cuprind cazuri de la cele mai severe cazuri precum distrofia musculară congenitală Ullrich (DMCU) urmat de fenotipuri de tranziție severă spre miopatia mai ușoară Bethlem (MB). În adiție, fenotipul contractural, referit drept mioscleroza, este cunoscut și asociat cu mutația în gena COL6A2. DMCU a fost inițial descris într-o serie de articole din anii 1930 de către Otto Ullrich, care s-a referit la condiție drept, distrofia musculară atonică-sclerotică cu progresul contracturilor. MB a fost descrisă în 1976 de către Bethlem și van Wijngaarden drept o condiție autosomal dominantă găsitaă în 28 de indivizi din cadrul a 3 familii Olandeze, acești indivizi având specific contracții de flexie a degetelor. În acest articol noi descriem un caz a unui pacient Moldovean cu fenotip clinic de DMCU și rolul colagenului VI în patogeneza acestuia.Коллаген шестого типа представляет собой микрофибриллярный коллаген, локализованный в матриксе большинства соединительных тканей. Он состоит из трёх альфа цепей, кодирующихся тремя отдельными генами. Мутации в этих генах приводят к заболеваниям, известным как миопатии, связанные с коллагеном шестого типа. Эти миопатии включают в себя широкий спектр заболеваний, начиная от самых тяжёлых по типу врождённой мышечной дистрофии Ульриха (ВМДУ) через серию фенотипов переходной тяжести к более лёгкой миопатии Бетлема (МБ). Также известен преимущественно контрактурный фенотип, называемый миосклерозом и связанный с мутациями в гене COL6A2. ВМДУ была впервые описана Отто Ульрихом в серии статей, опубликованной в 1930-х годах, где он называл её «атоническо-склеротической мышечной дистрофией» с прогрессирующими контрактурами. МБ была описана в 1976 году Бетлемом и ван Винжгаарденом как аутосомно-доминантно наследуемое заболевание. Описание было составлено на основе анализа 28 больных из трёх голландских семей, имевших сгибательные контрактуры пальцев. В этой статье мы описываем клинический случай молдавского пациента с клиническим фенотипом ВМДУ и роль коллагена шестого типа в патогенезе болезни

Dereglarea metabolismului sfingolipidelor: maladia Krabbe

Instituţia Medico-Sanitară Publică Institutul Mamei și Copilului, Centrul Medical Universitar Hamburg-Eppendorf, Hamburg, GermaniaIntroducere. Maladia Krabbe reprezintă o patologie neurodegenerativă determinată genetic de defi ciența enzimei lizozomale galactocerebrozidaza (β-GALC), al cărei rol este esențial în dezvoltarea și maturarea mielinei. Defi citul acesteia este responsabil de acumularea galactozilceramidei, care produce o substanță toxică, numită psychosina, ce afectează substanța albă a sistemului nervos central și periferic. Incidența acestei patologii este estimată în jur de 1 la 100.000 de nașteri, 90% atribuindu-se formei infantile [1], cu mecanismul de transmitere autosomal recesiv. Se cunosc peste 75 de mutații în gena GALC care pot provoca maladia Krabbe, însă corelarea genotip–fenotip până în prezent ramâne o provocare [3]. Singura excepție o prezintă ”deleția 30-kb” în gena GALC în stare homozigotă, care rezultă cu activitate nulă a enzimei β-GALC și este predictivă pentru debutul infantilă–precoce al maladiei [6]. Ținând cont de vârsta de debut, se cunosc 4 forme clinice ale bolii Krabbe: infantilă, infantilă-tardivă, juvenilă și forma adultă. Tratamentul acestei patologii se rezumă la transplantul de celule stem (HSCT), eficacitatea căruia este demonstrată doar în perioada presimptomatică

Профиль аминокислот в диагностике врождённых заболевания обмена веществ

Institute of Mother and Child, Chisinau, Moldova, Scientific Center of Medicine of State University of Medicine and Pharmacy, Chisinau, Moldova, “Petru Poni” Institute of Macromolecular Chemistry, Romanian Academy, Iasi, Romania, “C. D. Nenitescu” Centre of Organic Chemistry, Romanian Academy, Bucharest, RomaniaIntroducere: Erorile înnăscute de metabolism (EIM) reprezintă un grup eterogen fenotipic și genetic de tulburări cauzate de defect într-o cale metabolică cu consecințe defectuoase în funcționarea metabolismului și/sau acumularea de metaboliți intermediari toxici la nivelul organismului. În prezent, sunt descrise în jur de 1015 IEM, în timp ce individual sunt rare, incidență estimată cumulativ este de 1:500-800. Materiale și metode: Cuantificarea aminoacizilor a fost efectuată în plasma a 2 pacienți suspecți pentru o eroare metabolică. Plasma a fost deproteinizată și analizată în vederea cuantificării aminoacizilor prin cromatografie lichidă de înaltă performanță (HPLC) folosind sistemul “Shimadzu LC-20” și “Agilent 1260”. Rezultate și discuții: În rezultatul analizei cromatogramelor obținute au fost identificate concentrații anormal crescute ale unor aminoacizi sugestiv pentru o EIM. În primul caz, aminoacidul fenilalanina avea valori foarte crescute (1064 μmol/L), iar tirozina și aminoacizii concurenți pentru sistemul de transport LNAA (valină, leucină, izoleucină) erau în cantități joase, pacientul facându-se suspect pentru maladia fenilcetonurie (PKU), fiind imediat supus dietoterapiei. Concentrația ridicată de alanină (572 μmol/L) și raportul alanină/lizină crescut de 6,8 a completat profilul investigațiilor metabolice ale pacientului următor cu sugestii importante pentru o eroare metabolică cu implicare mitocondrială. Cuantificarea aminoacizilor la pacienții testați au contribuitt la stabilirea diagnosticului și inițierea terapiei corespunzătoare cu monitorizarea periodica a valorilor aminoacizilor. Concluzie: Identificarea biomarkerilor din spectrul aminoacizilor prin Cromatografie lichidă de înaltă performanță oferă posibilitatea obținerii unui spectru larg de metaboliți utili în stabilirea diagnosticului sau monitorizarea atât a pacientului acut bolnav cât celui supus unei terapii specifice pentru a evalua eficiența tratamentului.Введение: Врождённые заболевания обмена веществ представляют собой гетерогенную группу нарушений, вызванных дефектом метаболического пути с нарушениями метаболизма и/или накоплением токсичных метаболитов в организме. В настоящее время описано около 1015 заболеваний, но кумулятивная частота составляет 1:500-800. Материалы и методы. Количественный анализ аминокислот проводился в плазме 2 пациентов с подозрением на нарушения метаболизма. Плазму депротеинизировали и анализировали для определения аминокислот с помощью высокоэффективной жидкостной хроматографии с использованием систем «Shimadzu LC-20» и «Agilent 1260». Результаты и обсуждение: В результате анализа полученных хроматограмм были выявлены аномально высокие концентрации некоторых аминокислот, наводящие на мысль о наличии врождённые заболеваний обмена веществ. В первом случае было выявлена высокая концентрация фенилаланина (1064 мкмоль/л), а тирозин и конкурирующие аминокислоты для транспортной системы LNAA (валин, лейцин, изолейцин) были в малых количествах, что заставило заподозрть болезнь фенилкетонурию у пациента. Полученные данные определили начало диетотерапии. Высокая концентрация аланина (572 мкмоль/л) и увеличенное соотношение аланин/лизин до 6,8 дополнили профиль метаболических исследований следующего пациента с подозрением на метаболические нарушения с вовлечением митохондрий. Количественное определение аминокислот у испытуемых пациентов способствовало постановке диагноза и началу соответствующей терапии с периодическим мониторингом значений аминокислот. Заключение: Идентификация биомаркеров в спектре аминокислот с помощью высокоэффективной жидкостной хроматографии даёт возможность получить широкий спектр метаболитов, полезных для установления диагноза или мониторинга как при тяжёлых формах болезни пациентов, так и у пациентов, проходящих специальную терапию, для оценки эффективности лечения

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations

Phenylketonuria screening and management in southeastern Europe - survey results from 11 countries

Background: We aimed to assess the current state of PKU screening and management in the region of southeastern Europe. Methods: A survey was performed involving all identified professionals responsible for the PKU management in the 11 countries from South-Eastern region of Europe (Albania, Bulgaria, Bosnia and Herzegovina, Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, Slovenia). The questionnaire was designed to assess the characteristics regarding PKU management in three main areas: nation-wide characteristics, PKU screening, and characteristics of the PKU management in the responding centre. It consisted of 56 questions. The distribution and collection of the questionnaires (via e-mail) was taking place from December 2013 to March 2014. Results: Responses from participants from 11 countries were included; the countries cumulative population is approx. 52.5 mio. PKU screening was not yet introduced in 4 of 11 countries. Reported PKU incidences ranged from 1/7325 to 1/39338 (and were not known for 5 countries). National PKU guidelines existed in 5 of 11 countries and 7 of 11 countries had PKU registry (registries included 40 to 194 patients). The number of PKU centers in each country varied from1 to 6. Routine genetic diagnostics was reported in 4 of 11 countries. Most commonly used laboratory method to assess phenylalanine levels was fluorometric. Tetrahydrobiopterine was used in only 2 of 11 countries. Most frequently, pediatricians were caring for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments were performed in 6 of 11 countries. Patient's PKU society existed in 7 of 11 countries. Conclusions: The region of southeastern Europe was facing certain important challenges of PKU screening and management. Neonatal PKU screening should be introduced throughout the region. Furthermore, PKU management was falling behind internationally established standards-of-care in many aspects

Phenylketonuria screening and management in southeastern Europe - survey results from 11 countries

Background: We aimed to assess the current state of PKU screening and management in the region of southeastern Europe. Methods: A survey was performed involving all identified professionals responsible for the PKU management in the 11 countries from South-Eastern region of Europe (Albania, Bulgaria, Bosnia and Herzegovina, Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, Slovenia). The questionnaire was designed to assess the characteristics regarding PKU management in three main areas: nation-wide characteristics, PKU screening, and characteristics of the PKU management in the responding centre. It consisted of 56 questions. The distribution and collection of the questionnaires (via e-mail) was taking place from December 2013 to March 2014. Results: Responses from participants from 11 countries were included; the countries cumulative population is approx. 52.5 mio. PKU screening was not yet introduced in 4 of 11 countries. Reported PKU incidences ranged from 1/7325 to 1/39338 (and were not known for 5 countries). National PKU guidelines existed in 5 of 11 countries and 7 of 11 countries had PKU registry (registries included 40 to 194 patients). The number of PKU centers in each country varied from1 to 6. Routine genetic diagnostics was reported in 4 of 11 countries. Most commonly used laboratory method to assess phenylalanine levels was fluorometric. Tetrahydrobiopterine was used in only 2 of 11 countries. Most frequently, pediatricians were caring for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments were performed in 6 of 11 countries. Patient's PKU society existed in 7 of 11 countries. Conclusions: The region of southeastern Europe was facing certain important challenges of PKU screening and management. Neonatal PKU screening should be introduced throughout the region. Furthermore, PKU management was falling behind internationally established standards-of-care in many aspects

Untreated PKU patients without intellectual disability: what do they teach us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders (“conditions”) then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40–50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together

Genetic counseling in cardiac anomalies

Introduction: CATCH 22 syndrome is a well known developmental congenital syndrome. The most frequent genetic syndrome is velocardiofacial syndrome due to a microdeletion on chromosome 22ql 1.2. It is associated with abnormalities in heart, brain, thymus and parathyroid glands with an increased risk of immunodeficiency. The aim of this study was to estimate the prevalence of fetal cardiac anomalies in the first trimester of pregnancy in pregnant women with high degree of genetic risk. Methods: We analyzed data regarding ultrasound examination, the nuchal translucency, visualization of the four-chamber view, the outflow tracts, double test measured in first trimester of pregnancy, in 128 pregnant women who have been investigated for medico-genetic counseling in 2009-2010. Results: In 44 (34,4%) pregnant women (average age 26,1 ± 5,3 years) was estimated medium degree of genetic risk, in 30 (23,4%) - high risk and in 54 (42,2%) - low risk. Prenatal diagnosis has contributed to the identification of severe fetal pathologies in 16 (12,5%) pregnant women. The most common cardiac defects included 6 atrial and 2 ventricular septum defects (37,5% and 12,5% respectively), anomalies of the aortic arch or its major branches 5 (31,3%), D-transposition of the great arteries in 3 (18,5%) cases. Amniocentesis with the study of fetal karyotype allowed the identification of numerical and structural chromosomal abnormalities in 18 patients (14,0%), in 2 of them were detected structural chromosomal abnormalities with 22q chromosome. Conclusions: Investigation on methods of primary prevention prenatal diagnosis (fetal ultrasound, karyotyping) is essential to reduce the frequency of chromosomal abnormalities and congenital malformations