Niedobór dehydrogenazy acylo-coa średniołańcuchowej

Niedobór dehydrogenazy acylo-coa średniołańcuchowej
Epidemiologia

Niedobór dehydrogenazy acylo-CoA średniołańcuchowej (MCADD) jest najczęstszym zaburzeniem oksydacji kwasów tłuszczowych, o częstości występowania globalnej około 1:14 600 żywych urodzeń, z wyraźnym zróżnicowaniem geograficznym i etnicznym. Najwyższa częstość obserwowana jest w Europie Północnej (np. 1:4 900 w północnych Niemczech, 1:8 500 w Holandii), natomiast w populacjach azjatyckich MCADD jest znacznie rzadszy (np. 1:51 000 w Japonii, 1:263 500 na Tajwanie). Wprowadzenie badań przesiewowych noworodków z wykorzystaniem tandemowej spektrometrii mas (MS/MS) znacząco zwiększyło wykrywalność MCADD, częstość wykrywania wzrosła nawet czterokrotnie w porównaniu do diagnoz klinicznych (np. w Danii 1:8 954 vs. 1:39 691). Częstość nosicielstwa mutacji patogennych w genie ACADM w populacjach północnoeuropejskich wynosi od 1:40 do 1:100, co uzasadnia zalecenia dotyczące badań genetycznych u partnerów reprodukcyjnych pacjentów z MCADD.

Epidemiologia niedoboru dehydrogenazy acylo-coa średniołańcuchowej (MCADD)

Rozpowszechnienie światowe MCADD
Rozpowszechnienie MCADD według regionów geograficznych
Wpływ badań przesiewowych na epidemiologię MCADD
Nosicielstwo genetyczne MCADD
Zróżnicowanie etniczne w epidemiologii MCADD
Genetyczne podłoże epidemiologii MCADD

Nadzór i monitorowanie MCADD

Programy badań przesiewowych
Systemy nadzoru
Skuteczność badań przesiewowych i interwencji
Wyzwania w monitorowaniu MCADD
Badania obserwacyjne i monitorowanie wyników leczenia
Monitorowanie przy wykorzystaniu biomarkerów
Kolejne rozdziały

Epidemiologia niedoboru dehydrogenazy acylo-coa średniołańcuchowej (MCADD)

Niedobór dehydrogenazy acylo-CoA średniołańcuchowej (MCADD) jest najczęstszym zaburzeniem oksydacji kwasów tłuszczowych oraz jednym z najczęściej diagnozowanych wrodzonych błędów metabolizmu. Dokładne dane epidemiologiczne dotyczące częstości występowania MCADD różnią się w zależności od regionu geograficznego i populacji.¹²

Rozpowszechnienie światowe MCADD

Ogólnoświatowa częstość występowania MCADD szacowana jest na około 1:14 600 żywych urodzeń, z zauważalnymi różnicami między grupami etnicznymi.¹² Metaanaliza obejmująca badania przesiewowe przeprowadzone u ponad 8,2 miliona noworodków, głównie pochodzenia europejskiego, potwierdziła tę częstość występowania.³ W badaniach wykorzystujących tandemową spektrometrię mas (MS/MS) w przesiewowych badaniach noworodków, częstość MCADD wahała się od 1:13 500 do 1:15 900.⁴

Rozpowszechnienie MCADD według regionów geograficznych

Częstość występowania MCADD wykazuje znaczące zróżnicowanie geograficzne:

Ameryka Północna: W Stanach Zjednoczonych częstość występowania MCADD szacuje się na 1:15 000 do 1:20 000 urodzeń, przy czym poszczególne stany raportują różne częstości – od 1:10 000 do 1:30 000.¹² W Kanadzie badania przeprowadzone przy użyciu programu Canadian Paediatric Surveillance Program wykazały częstość około 1:23 400.³
Europa: Najwyższą częstość występowania MCADD obserwuje się w Europie Północnej. W Holandii częstość ta wynosi około 1:8 500.¹ W północnych Niemczech zgłaszana jest częstość 1:4 900, natomiast w Austrii około 1:24 900.² W Anglii badania prospektywne wykazały częstość 1:30 900 przypadków klinicznie zdiagnozowanych, natomiast w badaniach przesiewowych wykryto znacznie więcej przypadków.³
Azja: W populacjach azjatyckich MCADD występuje znacznie rzadziej. W Japonii częstość szacuje się na 1:51 000, a na Tajwanie 1:263 500.¹² W Korei w badaniu przesiewowym obejmującym 79 179 noworodków nie wykryto żadnego przypadku MCADD.³
Bliski Wschód: W Arabii Saudyjskiej częstość MCADD wynosi około 1:18 000.¹²
Australia: W Nowej Południowej Walii w Australii częstość występowania MCADD określono na 1:19 000.¹

Wpływ badań przesiewowych na epidemiologię MCADD

Wprowadzenie badań przesiewowych noworodków z wykorzystaniem tandemowej spektrometrii mas (MS/MS) miało istotny wpływ na wykrywalność MCADD.¹ Badania wykazały, że w krajach, gdzie wdrożono powszechne badania przesiewowe, liczba wykrytych przypadków MCADD jest ponad dwukrotnie wyższa niż liczba diagnozowanych na podstawie objawów klinicznych.¹

Przykładowo, w Danii badania przesiewowe noworodków obejmujące 519 350 noworodków wykazały częstość MCADD wynoszącą 1:8 954, co jest czterokrotnie wyższą wartością niż 1:39 691 przypadków zdiagnozowanych klinicznie w okresie 10 lat przed wprowadzeniem badań przesiewowych.¹

W Stanach Zjednoczonych, do czerwca 2005 roku, badania przesiewowe w kierunku MCADD zostały wdrożone w 32 stanach, a w kolejnych 5 planowano ich wprowadzenie.¹ Podobnie, w wielu krajach europejskich, takich jak Wielka Brytania, Niemcy, Holandia, Portugalia i Hiszpania, MCADD został włączony do programów badań przesiewowych noworodków.¹

Nosicielstwo genetyczne MCADD

Częstość nosicielstwa mutacji patogennych związanych z MCADD różni się znacząco w zależności od populacji. W populacjach północnoeuropejskich częstość nosicielstwa wynosi od 1:40 do 1:100.¹ Ta wysoka częstość nosicielstwa uzasadnia zalecenie wykonywania badań genetycznych u partnerów reprodukcyjnych pacjentów z MCADD.²

Zróżnicowanie etniczne w epidemiologii MCADD

MCADD występuje znacznie częściej w populacjach pochodzenia północnoeuropejskiego.¹² Szacowana częstość w populacjach kaukaskich wynosi od 1:4 900 do 1:27 000.³ W populacjach pochodzenia nieeuropejskiego MCADD występuje rzadziej.¹

Interesujące dane epidemiologiczne pochodzą z Półwyspu Iberyjskiego, gdzie Portugalia ma jedną z najwyższych częstości występowania MCADD (1:8 380). Jest to spowodowane faktem, że ponad 90% portugalskich pacjentów z MCADD pochodzi z populacji romskiej, charakteryzującej się wysokim stopniem spokrewnienia.¹

Genetyczne podłoże epidemiologii MCADD

Niedobór MCADD jest dziedziczony jako cecha autosomalna recesywna.¹² Wysoką częstość MCADD wśród osób pochodzenia północnoeuropejskiego przypisuje się efektowi założyciela.³

Przed wprowadzeniem badań przesiewowych noworodków, około 80% pacjentów z MCADD było homozygotami pod względem mutacji c.985A>G w genie ACADM.¹ Wraz z wprowadzeniem powszechnych badań przesiewowych zidentyfikowano drugą częstą mutację c.199T>C (częstość alleli około 6%).¹

Metaanaliza obejmująca 43 badania, raportujące częstość mutacji c.985A>G u ponad 10 milionów osób, wykazała znaczące różnice w częstości tej mutacji w różnych regionach. Proporcja osób homozygotycznych pod względem tej mutacji była najwyższa w Europie Zachodniej (4,1 na 100 000), następnie w Nowym Świecie, obejmującym Stany Zjednoczone, Kanadę i Australię (3,2), Europie Południowej (1,2) i Europie Wschodniej (0,9). Nie zidentyfikowano przypadków z tą mutacją w Azji ani na Bliskim Wschodzie.¹

W populacjach wschodnioazjatyckich najczęstszą mutacją związaną z MCADD jest c.449_452delCTGA, z częstością alleli wynoszącą 46,2% (12/26 alleli).¹

Nadzór i monitorowanie MCADD

Programy badań przesiewowych

Nadzór nad MCADD opiera się głównie na programach badań przesiewowych noworodków, które są obecnie powszechnie stosowane w wielu krajach.¹ Badania przesiewowe wykorzystujące tandemową spektrometrię mas (MS/MS) pozwalają na wczesne wykrycie MCADD, przed wystąpieniem objawów klinicznych.¹

Powszechny przesiew noworodków w kierunku MCADD został wprowadzony w Stanach Zjednoczonych, Kanadzie, Wielkiej Brytanii, Niemczech, Holandii, Portugalii, Hiszpanii i wielu innych krajach.¹² Wartość predykcyjna dodatnia testu przesiewowego dla MCADD wynosi około 46%.¹²

Systemy nadzoru

Poza badaniami przesiewowymi, w niektórych krajach istnieją specjalne systemy nadzoru nad MCADD. Przykładem jest Canadian Paediatric Surveillance Program (CPSP), który przeprowadził trzyletnie badanie monitorujące częstość występowania MCADD w Kanadzie.¹²

W Wielkiej Brytanii przeprowadzono prospektywne badanie nadzoru nad MCADD, które wykazało częstość 4,5 przypadków na 100 000 urodzeń w Anglii.¹ Badanie to pomogło uzasadnić wprowadzenie powszechnych badań przesiewowych noworodków w Anglii i Szkocji.²

Skuteczność badań przesiewowych i interwencji

Badania wykazały, że w przypadku braku badań przesiewowych noworodków w kierunku MCADD, przedwczesna śmierć lub poważna niepełnosprawność występuje u 20-25% dzieci z tym zaburzeniem.¹² Częstość zgonów wśród nieleczonych pacjentów z MCADD jest różnie raportowana – od wartości tak wysokich jak 50% do tak niskich jak 2%.¹

Badania przesiewowe noworodków w kierunku MCADD wyraźnie zapobiegają śmierci i niepełnosprawności u wielu dzieci z tym zaburzeniem.¹ Bez wczesnego wykrycia bezobjawowego, co najmniej połowa dzieci z MCADD doświadczy kryzysu metabolicznego, a do 1 na 10 osób, które przeżyją, rozwinie poważną niepełnosprawność rozwojową.¹

Wyzwania w monitorowaniu MCADD

Pomimo zwiększonej świadomości klinicznej, śmiertelność i zachorowalność z powodu MCADD pozostają wysokie.¹ Nadal istnieje potrzeba systematycznego gromadzenia i analizy danych dotyczących wyników w kohortach poddanych badaniom przesiewowym.¹

Jednym z wyzwań w monitorowaniu MCADD jest fakt, że nie jest to rozpoznanie ujęte w Międzynarodowej Klasyfikacji Chorób (ICD-10), co utrudnia śledzenie kosztów hospitalizacji i obciążeń związanych z zachorowalnością i śmiertelnością.¹

Ponadto, penetracja genotypów MCAD jest nieznana – istnieje znaczna liczba bezobjawowych osób z MCADD i pewna niepewność co do tego, którzy pacjenci będą manifestować objawy, a którzy pozostaną bezobjawowi.²³

Badania obserwacyjne i monitorowanie wyników leczenia

Przeprowadzono różne badania obserwacyjne w celu oceny wpływu MCADD na system opieki zdrowotnej i wyniki leczenia pacjentów. Badania te wykazały, że dzieci z MCADD korzystają z usług zdrowotnych znacznie częściej niż populacja ogólna, szczególnie w pierwszych latach życia.¹

W badaniu przeprowadzonym w Ontario w Kanadzie stwierdzono, że dzieci z MCADD (n=40) doświadczały istotnie wyższych wskaźników wszystkich rodzajów usług zdrowotnych, niezależnie od wieku w momencie wizyty. Wskaźniki korzystania z usług w tej populacji stopniowo zmniejszały się po 24 miesiącach życia.²

Istnieje również potrzeba standaryzacji wyników raportowanych w badaniach dotyczących MCADD. Analiza literatury wykazała znaczną heterogeniczność raportowanych wyników i instrumentów pomiaru wyników, co podkreśla potrzebę opracowania podstawowych zestawów wyników dla tych chorób.¹²

Monitorowanie przy wykorzystaniu biomarkerów

Monitorowanie pacjentów z MCADD opiera się głównie na pomiarze biomarkerów, takich jak oktanoilokarnityna (C8) i stosunek C8/C10.¹ Badania wykazały, że są to najlepsze markery do badań przesiewowych w kierunku MCADD.²

Jednakże, stężenie oktanoilokarnityny mierzone w badaniach przesiewowych noworodków nie koreluje z genotypem ani z aktywnością resztkową enzymu.¹ Badania wykazały, że obecnie najskuteczniejszym i najbardziej wiarygodnym narzędziem oceny ryzyka różnych genotypów ACADM jest pomiar utleniania oktanoilo-CoA w limfocytach.¹

Prowadzone są badania nad identyfikacją nowych biomarkerów i ścieżek metabolicznych specyficznych dla MCADD, wykorzystując zaawansowane techniki metabolomiczne.¹ Podejście to może pozwolić na dokładniejszą diagnostykę i monitorowanie pacjentów z MCADD.²

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Materiały źródłowe

#1 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
The most common fatty acid oxidation disorder, medium chain acyl-CoA dehydrogenase deficiency (MCADD), has become the focal point for the adoption of tandem mass spectrometry to detect it and related inborn errors of metabolism. […] Currently available information from screening studies on the frequency of detection of MCADD in newborns, as well as the frequency of homozygotes for the common mutation in the ACADM gene, is summarized. In the United States, the average incidence of the disorder is from 1 in 15,000 to 1 in 20,000 births, with individual states reporting frequencies from 1 in 10,000 to 1 in 30,000 births. […] It seems that in the absence of newborn screening for MCADD, premature death or serious disability occurs in 20% to 25% of children with the disorder. […] The recent incorporation of medium chain acyl-CoA dehydrogenase deficiency (MCADD) in newborn screening programs has facilitated the expansion of epidemiologic knowledge of this treatable disorder.
#1 Orphanet: Medium chain acyl-CoA dehydrogenase deficiency
https://www.orpha.net/en/disease/detail/42
The estimated birth prevalence of MCADD is thought to range from 1/4,900 to 1/27,000 in Caucasian populations and is highest in individuals of Northern European descent. The worldwide birth prevalence is 1/14,600. […] MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain.
#1 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update – PubMed
https://pubmed.ncbi.nlm.nih.gov/16617240/
The most common fatty acid oxidation disorder, medium chain acyl-CoA dehydrogenase deficiency (MCADD), has become the focal point for the adoption of tandem mass spectrometry to detect it and related inborn errors of metabolism. […] Currently available information from screening studies on the frequency of detection of MCADD in newborns, as well as the frequency of homozygotes for the common mutation in the ACADM gene, is summarized. In the United States, the average incidence of the disorder is from 1 in 15,000 to 1 in 20,000 births, with individual states reporting frequencies from 1 in 10,000 to 1 in 30,000 births. […] In addition, a systematic review was undertaken of the published literature on the frequency of mortality and developmental disabilities among children with MCADD, both in screened and unscreened cohorts. It seems that in the absence of newborn screening for MCADD, premature death or serious disability occurs in 20% to 25% of children with the disorder. Systematic collection and analysis of follow-up data are still needed to ascertain the frequencies of outcomes in screened cohorts.
#1 Medium-chain acyl-CoA dehydrogenase deficiency – Genomics Education Programme
http://www.genomicseducation.hee.nhs.uk/documents/medium-chain-acyl-coa-dehydrogenase-deficiency/
MCADD has a worldwide birth prevalence of 1 in 15,000, however this is higher in northern European populations (for example, 1 in 8,500 in the Netherlands). […] The carrier frequency of this pathogenic variant in Northern European populations is between 1 in 40 and 1 in 100. This high frequency means that genetic testing should be offered to reproductive partners of patients with MCADD.
#1 Merged Actionability Release – Clinical Genome Resources
https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC1016
Prevalence of the Genetic Condition Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inborn error of metabolism and occurs in an estimated 5.3 (99% CI: 4.1-6.7) per 100,000 births. […] In the US, prevalence ranges from 1/13,000 to 1/19,000 live births. […] Estimates for incidence across the world are 1/51,000 in Japan, 1/18,000 in Saudi Arabia, 1/263,500 in Taiwan, 1/19,000 in New South Wales of Australia, 1/4900 in northern Germany, 1/24,900 in Austria, 1/23,000 in central Italy, and 1/23,400 in Canada. […] Newborn screening followed by confirmatory variant analysis of 519,350 newborns in Denmark estimates the incidence of MCAD deficiency as 1/8954. This estimate is four times higher than the incidence of 1/39,691 of clinically presenting cases during the 10-year period prior to initiation of newborn screening.
#1 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid Î²-oxidation, especially in newborns. […] The birth prevalence of MCADD has been estimated in North America and Northern Europe to be approximately 1:5000 to 1:20,000. […] In Saudi Arabia, MCADD has a prevalence of 1/18,000. […] Importantly, the prevalence of MCADD only accounts for patients with obvious symptoms who had clinical visits and underwent clinical examinations without including the suspected MCADD patients without signs and at high risk. […] Thus, the true incidence of MCADD should not be underestimated and requires accurate investigation. […] Early diagnosis of MCADD helps alleviate the disease complications and improves affected newbornsâ health outcomes by providing proper treatments and interventions.
#1 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
The prevalence of clinically diagnosed MCADD among cohorts of children in geographically defined populations was 1 in 30,900 in England; 1 in 42,200 in German states not using MS/MS newborn screening; and 1 in 47,300 in New South Wales, Australia, from 1990 to 1994. […] In each of those countries, the number of children with MCADD detected by screening was more than twice the number diagnosed on the basis of symptoms. […] The overall mortality rate among all children with MCADD is necessarily lower than that among those who experience metabolic crises, because a fraction of individuals with the disorder do not manifest signs and symptoms in childhood. […] The frequency of deaths among older siblings of children with MCADD seems elevated relative to that among probands. […] Newborn screening for MCADD clearly prevents death and disability in many children with the disorder.
#1 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
As of June 2005, screening for MCADD had been implemented in 32 states, and implementation planned in 5 additional states. […] Despite the increase in screening, understanding of the natural history of unscreened MCADD remains limited. […] The major preventable outcomes of concern are death and intellectual disability. […] The frequency of death in untreated MCADD is said to be as high as 50% or as low as 2%. […] Accurate assessment of the incidence of MCADD requires analysis of test results from a birth cohort representative of a geographic population. […] The estimated frequency of MCADD at birth ranges from 1 in 10,000 to 1 in 27,000 among populations of mostly European descent and is less common in populations of non-European origin. […] In the United States, MCADD seems even less likely to be diagnosed in the absence of newborn screening.
#1
https://scite.ai/reports/ethnicity-of-children-with-homozygous-gykwdK
It has been suggested that homozygous c.985AG medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. […] This bias in the ethnical distribution of MCADD patients represents a significant difference in MCADD epidemiology in Iberia, namely Portugal, in comparison with other European countries where patients are almost exclusively of non-Gypsy origin (Khalid et al 2008). […] Data reveals that Iberia has one of the highest FAOD prevalence in Europe (1:7,914) and that Portugal has the highest birth prevalence of FAOD reported so far (1:6,351), strongly influenced by the high prevalence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD; 1:8,380), one of the highest ever reported. […] This is justified by the fact that more than 90% of Portuguese MCADD patients are of Gypsy origin, a community characterized by a high degree of consanguinity. […] Considering that FAOD are one of the justifications for MS/MS NBS, the now estimated birth prevalences stress the need to screen all Iberian newborns for this group of inherited metabolic disorders.
#1 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/946755-overview
Inherited as an autosomal recessive trait, MCAD deficiency was found in at least one series, which used a population-screening technique, to occur in approximately 1 in every 8500 live births. […] This figure seems somewhat high, but the true incidence rate is almost certainly among the highest of the inborn errors of metabolism, rivaling that of phenylketonuria. In part because of the supposed frequency of the disorder, nationwide debate has resulted in many states adding MCAD to their existing newborn metabolic screening programs. […] The application of tandem mass spectrometry to newborn metabolic screening in many other countries throughout the world has supplied a better understanding of the worldwide incidence of MCAD deficiency. […] The average incidence rate among more than 8 million babies was 1 per 14,600 live births, with a range of 1 per 13,500 to 1 per 15,900. […] Early diagnosis is imperative because serious morbidity and mortality is associated with initial onset in more than 25% of undiagnosed individuals.
#1 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is the most common inherited disorder of fatty acid metabolism presenting with hypoglycaemia, hepatopathy and Reye-like symptoms during catabolism. […] MCAD (EC 1.3.99.3) catalyzes the oxidation of fatty acids with chain lengths between C4 and C12. […] The clinical phenotype is generally induced by catabolism. Increased energy demand beyond the availability of glucose, prolonged fasting, illness or childhood immunization may induce metabolic derangement with clinical symptoms such as hypoketotic hypoglycemia, hepatic dysfunction and neurological impairment. […] Newborns with elevated octanoyl-carnitine levels in the newborn screen go generally for genetic tests and additionally enzymatic activity measurements. […] Before newborn screening when MCAD was identified on the basis of clinical findings, c.985AG was identified as the most prevalent mutation in the ACADM gene where approximately 80% of patients exhibited homozygosity for this change.
#1 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110
With the advent of newborn screening, where many newborns are identified in the absence of a clinical presentation, a second prevalent mutation was identified c.199TC (allele frequency approximately 6%). […] As in other metabolic enzyme deficiencies with implementation of newborn screening many asymptomatic patients are reported. […] Therefore it would be of great relevance to identify parameters which could serve as reliable predictors of disease severity. […] The distinction between patients at risk of symptomatic disease and individuals who may never develop symptomatic disease in the long term is very important. […] Here we analyzed the genetic basis for the increase in octanoyl-carnitine in 65 individuals analyzed by newborn screening. […] Our results, however, indicate that certain ACADM mutations do not categorically cause symptomatic MCAD deficiency.
#1
https://omim.org/entry/201450
In a prospective tandem mass spectrometry screening of 930,078 blood spots from neonates in the U.S. population, Andresen et al. (2001) determined the frequency of MCAD deficiency to be 1 in 15,001. Mutation analysis showed that the MS/MS-based method is excellent for detection of MCAD deficiency. The frequency of the 985A-G (607008.0001) mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. […] In a meta-regression analysis of 43 studies reporting the frequency of the c.985A-G mutation in over 10 million individuals, Leal et al. (2014) found significant variation in the frequency of the mutation across regions. The proportion of individuals homozygous for the mutation was highest in western Europe (4.1 per 100,000), followed by the New World, including the United States, Canada, and Australia (3.2), southern Europe (1.2), and eastern Europe (0.9). No cases with the mutation were identified in Asia or the Middle East. The findings were consistent with a founder effect originating in northern Europe.
#1 KoreaMed Synapse
https://synapse.koreamed.org/articles/1011774
The c.449_452delCTGA mutation, which was identified in the 2 patients in the present report, was first reported in 2 of 3 Japanese patients with MCADD in 2005 and also detected in 1 Korean patient. […] Thus, the allele frequency of the c.449_452delCTGA mutation, including the 2 present cases, is 46.2% (12/26 alleles), making this mutation the most common mutation associated with MCADD in East Asians. […] In summary, we have described 2 Korean pediatric patients with MCADD that was diagnosed by molecular studies; 1 of the cases showed a novel mutation, c.461TG, in the ACADM gene. We conclude that c.449_452delCTGA is a common mutation in Korean MCADD patients.
#1 MCAD deficiency – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/symptoms-causes/syc-20353745
MCAD deficiency is present from birth and is a lifelong condition. In the United States, all states test for MCAD deficiency at birth as part of newborn screening. Many other countries also provide routine newborn screening for MCAD deficiency. […] In the United States and many other countries, newborn screening programs test for MCAD deficiency.
#1 Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening
https://pmc.ncbi.nlm.nih.gov/articles/PMC3381659/
The benefits of identifying affected infants by newborn screening include prevention of death and intervention before development of symptoms, thus preventing neurodevelopmental injury by enabling long-term follow-up of affected individuals. […] The number of cases identified in the present study was less than expected based on the reported incidence of MCADD. […] The lower incidence in the present study could be due to incomplete reporting to the CPSP program, and incomplete or under-ascertainment of MCADD cases, especially in provinces in which MCADD was not included in newborn screening programs. […] Based on the present study, and the published data, we believe that universal newborn screening for MCADD should be performed in all Canadian provinces and territories to prevent serious complications and deaths from this treatable disease.
#1 (PDF) The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario
https://www.academia.edu/26952119/The_first_three_years_of_screening_for_medium_chain_acyl_CoA_dehydrogenase_deficiency_MCADD_by_newborn_screening_ontario
Based on the experience of Newborn Screening Ontario, the positive predictive value of a screen positive for MCADD was 46.3% (31/67) (excluding unresolved cases). […] During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were foundâan average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. All cases ascertained by newborn screening were asymptomatic. […] The data support population-based newborn screening for MCADD.
#1 Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening
https://pmc.ncbi.nlm.nih.gov/articles/PMC3381659/
The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. […] During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. […] The data support population-based newborn screening for MCADD. […] Determining the incidence of MCADD in Canada is a vital step in the decision-making process of public health policy makers who will decide whether to include this disorder in provincial and territorial newborn screening programs.
#1 Prospective surveillance study of medium chain acyl-CoA dehydrogenase deficiency in the UK | Archives of Disease in Childhood
https://adc.bmj.com/content/79/2/116.abstract
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a common disorder of fatty acid oxidation in north west Europe. […] It is believed to be considerably underdiagnosed. […] Of 62 affected individuals identified, 57 were from England, giving an incidence of 4.5 cases/100000 births. […] Despite increased clinical awareness, the mortality and morbidity from MCAD deficiency remain high. […] The frequency and severity of the disease support the case for the introduction of universal neonatal screening in England and Scotland.
#1 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
Without early asymptomatic detection, at least half of children with MCADD will experience a metabolic crisis, and up to 1 in 10 survivors will develop a serious developmental disability. […] Conservatively, between one in five and one in four children with MCADD will experience death or severe disability without newborn screening for the disorder.
#1 Medium chain acylâCoA dehydrogenase deficiency: Human genome epidemiology review | Genetics in Medicine
https://www.nature.com/articles/gim1999194
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inherited error of fatty acid metabolism. There is a high frequency of MCADD among people of Northern European descent, which is believed to be due to a founder effect. MCADD is inherited in an autosomal recessive manner. […] Hospitalization costs attributable to morbidity and mortality from MCADD are unknown; MCADD is not a diagnosis in the International Classification of Disease, 10th Revision (ICD-10) codebook. Furthermore, the penetrance of the MCAD genotypes is unknown; there appears to be a substantial number of asymptomatic MCADD individuals and some uncertainty regarding which individuals will manifest symptoms and which individuals will remain asymptomatic. […] State programs are beginning to offer screening in newborns for MCADD using MS/MS. In addition, a private company currently offers voluntary supplemental newborn screening for MCADD to birthing centers.
#1 ICES | Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: a cohort study in Ontario, Canada
https://www.ices.on.ca/publications/journal-articles/health-services-use-among-children-diagnosed-with-medium-chain-acyl-coa-dehydrogenase-deficiency-through-newborn-screening-a-cohort-study-in-ontario-canada/
Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. […] This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.
#1 Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1276-1
Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies. […] The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). […] Death was the most frequently reported outcome. […] For MCAD deficiency, we identified 83 outcomes from 52 articles. […] For PKU, we identified 97 outcomes from 343 articles. […] The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). […] Phenylalanine concentration was the most frequently reported outcome.
#1 (PDF) Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening
https://www.academia.edu/118646219/Incidence_of_medium_chain_acyl_CoA_dehydrogenase_deficiency_in_Canada_using_the_Canadian_Paediatric_Surveillance_Program_Role_of_newborn_screening
Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. […] This is the first report of the results from neonatal screening for MCADD in Spain. […] The incidence of severe metabolic crises in medium chain acyl-CoA dehydrogenase deficiency (MCADD) patients homozygous for the common c.985A G mutation, who had been identified by neonatal screening, was assessed prospectively and compared to retrospective cohort data in unscreened patients with identical genotypes. […] Neonatal screening appears to reduce the rate of severe metabolic crisis or death in the most prevalent subset of MCADD.
#1 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110
Residual activities in lymphocytes of compound heterozygous children carrying c.199TC or c.127GA on one allele were 31% and 60%. […] These activities are clearly in the range of proven heterozygotes that do not have a risk of symptomatic disease. […] Furthermore, our literature research disclosed that both mutations, c.199TC and c.127GA, never caused any clinical symptoms. […] All these data support that both mutations, c.199TC and c.127GA, do not have a significant effect on MCAD function and must be classified as variants with no clinical relevance. […] Our data further demonstrate that the octanoyl-carnitine concentration measured on newborn screening is not significant. […] The lack of correlation between the octanoyl-carnitine concentration on screening and genotype or residual activity in our cohort was obvious and is perfectly in line with previous reports.
#1 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110
The severity of novel genotypes can neither be estimated/predicted via ACADM gene analysis nor via octanoyl-carnitine concentration on newborn screening. […] In conclusion, our results clearly demonstrate that octanoyl-CoA oxidation in lymphocytes is currently the most efficient and reliable tool for risk assessment of different especially novel ACADM genotypes.
#1 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
However, the NBS programsâ efficiency in detecting IMDs, including MCADD, shows drawbacks concerning clinical diagnosis. […] Thus, a study suggested utilizing the genetic sequencing of DBS from false-positive-diagnosed MCADD patients as a validation method for the diagnosed patients. […] Therefore, the positive NBS results for MCADD are confirmed using molecular genetic testing, such as whole or exosome sequencing, which detects mutations in the ACADM gene. […] Based on these drawbacks associated with the NBS program and genetic approaches, there have been demands in the clinical field to identify other alternative and complementary diagnostic approaches for MCADD. […] This approach allows for identifying IMD-specific biomarkers and pathways. […] Thus, we aimed to investigate potential metabolic biomarkers and pathways for MCADD by using DBS samples from MCADD newborns and healthy newborns to be analyzed by a high-throughput untargeted metabolomics approach.
#2 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/946755-overview
Inherited as an autosomal recessive trait, MCAD deficiency was found in at least one series, which used a population-screening technique, to occur in approximately 1 in every 8500 live births. […] This figure seems somewhat high, but the true incidence rate is almost certainly among the highest of the inborn errors of metabolism, rivaling that of phenylketonuria. In part because of the supposed frequency of the disorder, nationwide debate has resulted in many states adding MCAD to their existing newborn metabolic screening programs. […] The application of tandem mass spectrometry to newborn metabolic screening in many other countries throughout the world has supplied a better understanding of the worldwide incidence of MCAD deficiency. […] The average incidence rate among more than 8 million babies was 1 per 14,600 live births, with a range of 1 per 13,500 to 1 per 15,900. […] Early diagnosis is imperative because serious morbidity and mortality is associated with initial onset in more than 25% of undiagnosed individuals.
#2 The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario | BMC Pediatrics | Full Text
https://bmcpediatr.biomedcentral.com/articles/10.1186/1471-2431-10-82
Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of mitochondrial fatty acid oxidation and is one of the most common inborn errors of metabolism. Identification of MCADD via newborn screening permits the introduction of interventions that can significantly reduce associated morbidity and mortality. This study reports on the first three years of newborn screening for MCADD in Ontario, Canada. […] From April 2006 through March 2009, approximately 439 000 infants were screened for MCADD in Ontario. […] The estimated birth prevalence of MCADD in Ontario is approximately 1 in 14 000. […] The birth prevalence of MCADD and positive predictive value of the screening test were similar to those identified by other newborn screening programs internationally. […] Newborn screening for MCADD has yielded an international birth prevalence of 1 in 14 600 based on the screening of nearly 8.2 million newborns of mainly European descent.
#2 Medium-chain acyl-CoA dehydrogenase deficiency: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/medium-chain-acyl-coa-dehydrogenase-deficiency/
In the United States, the estimated incidence of MCAD deficiency is 1 in 17,000 people. The condition is more common in people of northern European ancestry than in other ethnic groups. […] The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update.
#2 Merged Actionability Release – Clinical Genome Resources
https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC1016
Prevalence of the Genetic Condition Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inborn error of metabolism and occurs in an estimated 5.3 (99% CI: 4.1-6.7) per 100,000 births. […] In the US, prevalence ranges from 1/13,000 to 1/19,000 live births. […] Estimates for incidence across the world are 1/51,000 in Japan, 1/18,000 in Saudi Arabia, 1/263,500 in Taiwan, 1/19,000 in New South Wales of Australia, 1/4900 in northern Germany, 1/24,900 in Austria, 1/23,000 in central Italy, and 1/23,400 in Canada. […] Newborn screening followed by confirmatory variant analysis of 519,350 newborns in Denmark estimates the incidence of MCAD deficiency as 1/8954. This estimate is four times higher than the incidence of 1/39,691 of clinically presenting cases during the 10-year period prior to initiation of newborn screening.
#2 KoreaMed Synapse
https://synapse.koreamed.org/articles/1011774
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid -oxidation. […] MCADD is the most frequently diagnosed clinical defect of fatty acid metabolism in Caucasians. The frequency of the disease ranges from 1:10,000 to 1:30,000 in the United States, and it is detected during newborn screening using tandem mass spectrometry. […] However, this disorder is relatively rare in Asian populations. […] The incidence of MCADD is 1:51,000 in the Japanese population, and there were no cases of the disorder among the 79,179 newborns screened in Korea. […] To date, 1 Korean and 11 Japanese patients have been confirmed to be positive for MCADD by molecular analysis. […] The mutation frequency in the ACADM gene shows ethnic variation.
#2 Medium-chain acyl-CoA dehydrogenase deficiency – Genomics Education Programme
http://www.genomicseducation.hee.nhs.uk/documents/medium-chain-acyl-coa-dehydrogenase-deficiency/
MCADD has a worldwide birth prevalence of 1 in 15,000, however this is higher in northern European populations (for example, 1 in 8,500 in the Netherlands). […] The carrier frequency of this pathogenic variant in Northern European populations is between 1 in 40 and 1 in 100. This high frequency means that genetic testing should be offered to reproductive partners of patients with MCADD.
#2 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
As of June 2005, screening for MCADD had been implemented in 32 states, and implementation planned in 5 additional states. […] Despite the increase in screening, understanding of the natural history of unscreened MCADD remains limited. […] The major preventable outcomes of concern are death and intellectual disability. […] The frequency of death in untreated MCADD is said to be as high as 50% or as low as 2%. […] Accurate assessment of the incidence of MCADD requires analysis of test results from a birth cohort representative of a geographic population. […] The estimated frequency of MCADD at birth ranges from 1 in 10,000 to 1 in 27,000 among populations of mostly European descent and is less common in populations of non-European origin. […] In the United States, MCADD seems even less likely to be diagnosed in the absence of newborn screening.
#2 Medium chain acylâCoA dehydrogenase deficiency: Human genome epidemiology review | Genetics in Medicine
https://www.nature.com/articles/gim1999194
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inherited error of fatty acid metabolism. There is a high frequency of MCADD among people of Northern European descent, which is believed to be due to a founder effect. MCADD is inherited in an autosomal recessive manner. […] Hospitalization costs attributable to morbidity and mortality from MCADD are unknown; MCADD is not a diagnosis in the International Classification of Disease, 10th Revision (ICD-10) codebook. Furthermore, the penetrance of the MCAD genotypes is unknown; there appears to be a substantial number of asymptomatic MCADD individuals and some uncertainty regarding which individuals will manifest symptoms and which individuals will remain asymptomatic. […] State programs are beginning to offer screening in newborns for MCADD using MS/MS. In addition, a private company currently offers voluntary supplemental newborn screening for MCADD to birthing centers.
#2 MCAD deficiency – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/symptoms-causes/syc-20353745
MCAD deficiency is present from birth and is a lifelong condition. In the United States, all states test for MCAD deficiency at birth as part of newborn screening. Many other countries also provide routine newborn screening for MCAD deficiency. […] In the United States and many other countries, newborn screening programs test for MCAD deficiency.
#2 The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario | BMC Pediatrics | Full Text
https://bmcpediatr.biomedcentral.com/articles/10.1186/1471-2431-10-82
The positive predictive value of a screen positive for MCADD was 46%. […] Our analysis of 3 years of data from Newborn Screening Ontario, including approximately 439 000 infants screened since the introduction of universal screening for MCADD, has allowed us to establish the first evidence based birth prevalence rate for MCADD in the province of Ontario. The birth prevalence of 1 in 14 157 live births is in the range of that reported by other newborn screening programs.
#2 Medium-chain acyl-coenzyme A dehydrogenase deficiency – CPSP
https://cpsp.cps.ca/surveillance/study-etude/medium-chain-acyl-coenzyme-a-dehydrogenase-deficiency
Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening […] Incidence of medium chain acyl-coenzyme A dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program (September 2005 September 2008)
#2 Prospective surveillance study of medium chain acyl-CoA dehydrogenase deficiency in the UK | Archives of Disease in Childhood
https://adc.bmj.com/content/79/2/116.abstract
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a common disorder of fatty acid oxidation in north west Europe. […] It is believed to be considerably underdiagnosed. […] Of 62 affected individuals identified, 57 were from England, giving an incidence of 4.5 cases/100000 births. […] Despite increased clinical awareness, the mortality and morbidity from MCAD deficiency remain high. […] The frequency and severity of the disease support the case for the introduction of universal neonatal screening in England and Scotland.
#2 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
Without early asymptomatic detection, at least half of children with MCADD will experience a metabolic crisis, and up to 1 in 10 survivors will develop a serious developmental disability. […] Conservatively, between one in five and one in four children with MCADD will experience death or severe disability without newborn screening for the disorder.
#2 ICES | Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: a cohort study in Ontario, Canada
https://www.ices.on.ca/publications/journal-articles/health-services-use-among-children-diagnosed-with-medium-chain-acyl-coa-dehydrogenase-deficiency-through-newborn-screening-a-cohort-study-in-ontario-canada/
Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. […] This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.
#2 Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1276-1
Our findings suggest that evaluative studies of interventions for MCAD deficiency and PKU would benefit from COSs given the multitude of outcomes in the literature. […] Substantial heterogeneity exists in the outcomes reported in the MCAD deficiency and PKU literature and a diversity of outcome measurement instruments was used to measure many of these outcomes.
#2 (PDF) Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening
https://www.academia.edu/118646219/Incidence_of_medium_chain_acyl_CoA_dehydrogenase_deficiency_in_Canada_using_the_Canadian_Paediatric_Surveillance_Program_Role_of_newborn_screening
Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. […] This is the first report of the results from neonatal screening for MCADD in Spain. […] The incidence of severe metabolic crises in medium chain acyl-CoA dehydrogenase deficiency (MCADD) patients homozygous for the common c.985A G mutation, who had been identified by neonatal screening, was assessed prospectively and compared to retrospective cohort data in unscreened patients with identical genotypes. […] Neonatal screening appears to reduce the rate of severe metabolic crisis or death in the most prevalent subset of MCADD.
#2 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
However, the NBS programsâ efficiency in detecting IMDs, including MCADD, shows drawbacks concerning clinical diagnosis. […] Thus, a study suggested utilizing the genetic sequencing of DBS from false-positive-diagnosed MCADD patients as a validation method for the diagnosed patients. […] Therefore, the positive NBS results for MCADD are confirmed using molecular genetic testing, such as whole or exosome sequencing, which detects mutations in the ACADM gene. […] Based on these drawbacks associated with the NBS program and genetic approaches, there have been demands in the clinical field to identify other alternative and complementary diagnostic approaches for MCADD. […] This approach allows for identifying IMD-specific biomarkers and pathways. […] Thus, we aimed to investigate potential metabolic biomarkers and pathways for MCADD by using DBS samples from MCADD newborns and healthy newborns to be analyzed by a high-throughput untargeted metabolomics approach.
#3 The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario | BMC Pediatrics | Full Text
https://bmcpediatr.biomedcentral.com/articles/10.1186/1471-2431-10-82
Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of mitochondrial fatty acid oxidation and is one of the most common inborn errors of metabolism. Identification of MCADD via newborn screening permits the introduction of interventions that can significantly reduce associated morbidity and mortality. This study reports on the first three years of newborn screening for MCADD in Ontario, Canada. […] From April 2006 through March 2009, approximately 439 000 infants were screened for MCADD in Ontario. […] The estimated birth prevalence of MCADD in Ontario is approximately 1 in 14 000. […] The birth prevalence of MCADD and positive predictive value of the screening test were similar to those identified by other newborn screening programs internationally. […] Newborn screening for MCADD has yielded an international birth prevalence of 1 in 14 600 based on the screening of nearly 8.2 million newborns of mainly European descent.
#3 Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening
https://ir.lib.uwo.ca/paedpub/2070/
BACKGROUND: The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. […] During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found – an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. […] The data support population-based newborn screening for MCADD.
#3 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
The prevalence of clinically diagnosed MCADD among cohorts of children in geographically defined populations was 1 in 30,900 in England; 1 in 42,200 in German states not using MS/MS newborn screening; and 1 in 47,300 in New South Wales, Australia, from 1990 to 1994. […] In each of those countries, the number of children with MCADD detected by screening was more than twice the number diagnosed on the basis of symptoms. […] The overall mortality rate among all children with MCADD is necessarily lower than that among those who experience metabolic crises, because a fraction of individuals with the disorder do not manifest signs and symptoms in childhood. […] The frequency of deaths among older siblings of children with MCADD seems elevated relative to that among probands. […] Newborn screening for MCADD clearly prevents death and disability in many children with the disorder.
#3 KoreaMed Synapse
https://synapse.koreamed.org/articles/1011774
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid -oxidation. […] MCADD is the most frequently diagnosed clinical defect of fatty acid metabolism in Caucasians. The frequency of the disease ranges from 1:10,000 to 1:30,000 in the United States, and it is detected during newborn screening using tandem mass spectrometry. […] However, this disorder is relatively rare in Asian populations. […] The incidence of MCADD is 1:51,000 in the Japanese population, and there were no cases of the disorder among the 79,179 newborns screened in Korea. […] To date, 1 Korean and 11 Japanese patients have been confirmed to be positive for MCADD by molecular analysis. […] The mutation frequency in the ACADM gene shows ethnic variation.
#3 Orphanet: Medium chain acyl-CoA dehydrogenase deficiency
https://www.orpha.net/en/disease/detail/42
The estimated birth prevalence of MCADD is thought to range from 1/4,900 to 1/27,000 in Caucasian populations and is highest in individuals of Northern European descent. The worldwide birth prevalence is 1/14,600. […] MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain.
#3 Medium chain acylâCoA dehydrogenase deficiency: Human genome epidemiology review | Genetics in Medicine
https://www.nature.com/articles/gim1999194
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inherited error of fatty acid metabolism. There is a high frequency of MCADD among people of Northern European descent, which is believed to be due to a founder effect. MCADD is inherited in an autosomal recessive manner. […] Hospitalization costs attributable to morbidity and mortality from MCADD are unknown; MCADD is not a diagnosis in the International Classification of Disease, 10th Revision (ICD-10) codebook. Furthermore, the penetrance of the MCAD genotypes is unknown; there appears to be a substantial number of asymptomatic MCADD individuals and some uncertainty regarding which individuals will manifest symptoms and which individuals will remain asymptomatic. […] State programs are beginning to offer screening in newborns for MCADD using MS/MS. In addition, a private company currently offers voluntary supplemental newborn screening for MCADD to birthing centers.
#3 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110
With the advent of newborn screening, where many newborns are identified in the absence of a clinical presentation, a second prevalent mutation was identified c.199TC (allele frequency approximately 6%). […] As in other metabolic enzyme deficiencies with implementation of newborn screening many asymptomatic patients are reported. […] Therefore it would be of great relevance to identify parameters which could serve as reliable predictors of disease severity. […] The distinction between patients at risk of symptomatic disease and individuals who may never develop symptomatic disease in the long term is very important. […] Here we analyzed the genetic basis for the increase in octanoyl-carnitine in 65 individuals analyzed by newborn screening. […] Our results, however, indicate that certain ACADM mutations do not categorically cause symptomatic MCAD deficiency.
#4 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/946755-overview
Inherited as an autosomal recessive trait, MCAD deficiency was found in at least one series, which used a population-screening technique, to occur in approximately 1 in every 8500 live births. […] This figure seems somewhat high, but the true incidence rate is almost certainly among the highest of the inborn errors of metabolism, rivaling that of phenylketonuria. In part because of the supposed frequency of the disorder, nationwide debate has resulted in many states adding MCAD to their existing newborn metabolic screening programs. […] The application of tandem mass spectrometry to newborn metabolic screening in many other countries throughout the world has supplied a better understanding of the worldwide incidence of MCAD deficiency. […] The average incidence rate among more than 8 million babies was 1 per 14,600 live births, with a range of 1 per 13,500 to 1 per 15,900. […] Early diagnosis is imperative because serious morbidity and mortality is associated with initial onset in more than 25% of undiagnosed individuals.