Niedobór dehydrogenazy acyl-coa o łańcuchu średnim
Etiologia i przyczyny

Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim (MCADD) jest najczęstszym zaburzeniem oksydacji kwasów tłuszczowych, dziedziczonym autosomalnie recesywnie, z częstością około 1:8000 urodzeń w populacjach kaukaskich. Mutacje w genie ACADM (chromosom 1p31), zwłaszcza c.985A>G (80% przypadków klinicznych), prowadzą do utraty funkcji enzymu MCAD, co uniemożliwia β-oksydację średniołańcuchowych kwasów tłuszczowych (C6-C12). W efekcie dochodzi do hipoglikemii hipoketotycznej, gromadzenia się toksycznych kwasów tłuszczowych oraz uszkodzeń wątroby i mózgu, szczególnie podczas głodzenia, infekcji lub stresu metabolicznego. Aktywność resztkowa enzymu w klasycznym MCADD jest zwykle <1%, a u łagodniejszych postaci może wynosić 10-20%. Fenotyp kliniczny jest zmienny i zależy od dodatkowych czynników środowiskowych oraz genetycznych, a suplementacja ryboflawiną może stabilizować enzym poprzez zwiększenie dostępności FAD.

  1. Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim – Etiologia
    1. Podłoże genetyczne
    2. Dziedziczenie
    3. Różnice etniczne w występowaniu mutacji
    4. Patofizjologia
    5. Mechanizmy molekularne
    6. Konsekwencje metaboliczne
    7. Czynniki ryzyka wyzwalające objawy
    8. Kolejne rozdziały

Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim – Etiologia

Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim (MCAD deficiency, MCADD) to najczęstsze zaburzenie oksydacji kwasów tłuszczowych, które uniemożliwia prawidłowy rozkład średniołańcuchowych kwasów tłuszczowych i ich konwersję do energii, szczególnie w okresach bez pożywienia (głodzenia).123 Zaburzenie to jest dziedziczone autosomalnie recesywnie i występuje z częstością około 1:8000 urodzeń.4

Podłoże genetyczne

Przyczyną niedoboru MCAD są mutacje w genie ACADM zlokalizowanym na chromosomie 1p31, który koduje enzym dehydrogenazę acylo-CoA o średnim łańcuchu.56 Gen ACADM obejmuje 44 kb DNA i zawiera 12 intronów. Dotychczas zidentyfikowano około 400 różnych wariantów genu ACADM, z czego 68 zostało sklasyfikowanych jako patogenne, 82 jako prawdopodobnie patogenne, a około 165 jako „o niepewnym znaczeniu”.7 Około 69% mutacji wywołujących chorobę stanowią mutacje typu missense.8

Najczęstszą mutacją jest c.985A>G, która prowadzi do zamiany lizyny na kwas glutaminowy w pozycji 304 dojrzałego białka (pozycja 329 prekursora białka).910 Ta mutacja powoduje nieprawidłowe składanie białka, co skutkuje całkowitą utratą jego funkcji. Jest to najczęstsza mutacja wśród pacjentów z objawowym MCADD, występująca u około 80% osób jako mutacja homozygotyczna.1112 Może również występować w heterozygotyczności z innymi wariantami, co skutkuje łagodniejszą postacią choroby.13

Drugą częstą mutacją w niektórych populacjach jest 583G>A.14 Badania wykazały, że osoby homozygotyczne dla mutacji 985A>G lub 583G>A mają najwyższe poziomy oktanoilokarnityny, nawet gdy są bezobjawowe, i mają najcięższe objawy kliniczne.15

Dziedziczenie

Niedobór MCAD jest dziedziczony w sposób autosomalny recesywny.1617 Oznacza to, że oboje rodzice są nosicielami – każde z nich ma jedną zmutowaną kopię genu i jedną prawidłową, ale nie wykazują objawów choroby.1819 Dziecko z niedoborem MCAD dziedziczy dwie kopie zmutowanego genu – po jednej od każdego z rodziców.20

Częstość występowania nosicielstwa mutacji c.985A>G w genie ACADM wynosi od 1:40 do 1:100 wśród osób pochodzenia północnoeuropejskiego, co sugeruje efekt założyciela.21 Jeśli oboje rodzice są nosicielami zmutowanego genu, istnieje 25% prawdopodobieństwo, że ich dziecko będzie homozygotą dla niedoboru MCAD.2223

W badaniach populacyjnych osób ze zdiagnozowanym niedoborem MCAD zaobserwowano, że średnio 32% tych osób ma co najmniej jednego rodzeństwa ze zdiagnozowanym niedoborem MCAD lub zmarłego z błędnie zdiagnozowanym zespołem nagłej śmierci niemowląt (SIDS).24

Różnice etniczne w występowaniu mutacji

Mutacja c.985A>G jest najczęstsza wśród pacjentów pochodzenia europejskiego, jednak nie zidentyfikowano jej w przypadkach MCADD diagnozowanych w populacjach azjatyckich.2526 W populacji azjatyckiej niedobór MCAD jest niezwykle rzadkim zaburzeniem metabolicznym, a spektrum mutacji ACADM pozostaje w dużej mierze nieznane.27

U pacjentów pochodzenia azjatyckiego zidentyfikowano inne mutacje, w tym delecję 4 par zasad c.449_452delCTGA, która może stanowić częstą azjatycką mutację ACADM.28 U koreańskiego noworodka z niedoborem MCAD zidentyfikowano nową mutację typu missense 843A>T (R281S) i delecję 4 par zasad c.449_452delCTGA.29

Patofizjologia

Niedobór MCAD to zaburzenie oksydacji kwasów tłuszczowych zachodzące w mitochondriach.30 Enzym MCAD jest jedną z czterech dehydrogenaz acylo-CoA znajdujących się w mitochondriach, które przeprowadzają początkowy etap dehydrogenacji w procesie β-oksydacji kwasów tłuszczowych.31

Osoby z niedoborem MCAD mają zmniejszoną aktywność enzymu MCAD w mitochondriach i nie mogą przekształcać średniołańcuchowych kwasów tłuszczowych (o długości 6-12 atomów węgla) w acetylo-CoA do syntezy ATP, ketogenezy i wykorzystania w cyklu Krebsa.3233

Patofizjologia niedoboru MCAD wynika z niezdolności do przeprowadzenia pierwszego etapu β-oksydacji. Molekularne implikacje większości mutacji w tym zaburzeniu to utrata funkcji enzymatycznej z powodu nieprawidłowego fałdowania białka – podstawienia aminokwasów w wyniku mutacji genetycznych upośledzają uzyskanie prawidłowej trójwymiarowej struktury.34

W każdej sytuacji klinicznej, w której wymagana jest oksydacja kwasów tłuszczowych, takiej jak głodzenie lub stres metaboliczny spowodowany chorobą, następuje ciągłe zużycie glukozy i znacznie zmniejszona lub nieobecna odpowiednia produkcja ciał ketonowych.35 Badania z 2016 roku sugerują, że stres metaboliczny powodujący przeciążenie szlaku β-oksydacyjnego substratem może przyczyniać się do kompetycyjnego hamowania, zwiększając tym samym dekompensację metaboliczną.36

Mechanizmy molekularne

Na poziomie molekularnym niedobór MCAD jest uznawany za zaburzenie konformacyjne, jednak objawy kliniczne choroby obejmują szerokie spektrum ciężkości, nawet u pacjentów z tym samym genotypem.37 Fenotyp patogenny choroby wydaje się zależeć od dodatkowych czynników zewnętrznych i wewnętrznych, które nie są jasno zrozumiane.38

Badania sugerują, że suplementacja ryboflawiną ma pewną rolę w stabilizacji MCAD, prawdopodobnie dzięki zwiększonej dostępności pochodnej ryboflawiny – dinukleotydu flawinoadeninowego (FAD). Badania biochemiczne wykazują, że większość wariantów MCAD ma upośledzoną zdolność do zatrzymywania FAD podczas syntezy. Niektóre warianty mogą być jednak „strukturalnie ratowane” przez suplementację kofaktora ryboflawiny, co wyjaśnia heterogeniczność fenotypu MCADD u pacjentów z tym samym genotypem.39

Aktywność resztkowa enzymu obserwowana w klasycznym MCADD, spowodowanym homozygotycznością c.985A>G, wynosi zwykle poniżej 1%.40 Natomiast u pacjentów z łagodnym MCADD aktywność resztkowa może wynosić 10-20%.41

Konsekwencje metaboliczne

Gdy w organizmie nie ma wystarczającej ilości enzymu MCAD, średniołańcuchowe kwasy tłuszczowe nie mogą być rozkładane i przekształcane w energię. Prowadzi to do:4243

  • Niskiej energii i niskiego poziomu cukru we krwi (hipoglikemii)
  • Gromadzenia się kwasów tłuszczowych w tkankach organizmu
  • Uszkodzenia wątroby i mózgu

4243

Ostatecznym wynikiem klinicznym jest ciężka hipoglikemia i hipoketonuria z nagromadzeniem monokarboksylowych kwasów tłuszczowych i dikarboksylowych kwasów organicznych, które są strukturalnymi analogami kwasów tłuszczowych, które nie mogą przejść przez etap MCAD.44

Hipoglikemia i hiperamonemia łącznie odpowiadają za letarg i śpiączkę, które prowadzą do obrzęku mózgu, jeśli nie są leczone.45 Ponadto glukoneogeneza jest skutecznie wyłączona w niedoborze MCAD, ponieważ zależy od aktywności karboksylazy pirogronianowej do wytwarzania szczawiooctanu, reakcji, która jest regulowana w dół przez zmniejszony mitochondrialny acetylo-CoA.46

Niezdolność do dostarczania energii tkankom, gdy zapasy glikogenu są wyczerpane w wyniku niedoboru MCAD, powoduje szeroki zakres objawów. Hipoglikemia hipoketotyczna z wymiotami, przechodząca w drgawki i śpiączkę, to typowe objawy tej choroby. Uważa się, że niedobór MCAD odpowiada za niewielką część przypadków zespołu nagłej śmierci niemowląt (SIDS).4748

Czynniki ryzyka wyzwalające objawy

Choroba może ujawnić się we wczesnym dzieciństwie, zazwyczaj w ciągu pierwszych 24 miesięcy życia, lub pozostać bezobjawowa aż do dorosłości.4950 Objawy kliniczne zazwyczaj pojawiają się po 2-3 miesiącach życia i zwykle następują po głodzeniu (nawet tak krótkim jak 12 godzin).51

Chociaż czynniki genetyczne są najważniejsze, czynniki środowiskowe mogą wpływać na początek i nasilenie objawów. Infekcje, głodzenie (częste w niektórych praktykach religijnych) lub okresy choroby mogą wyczerpać zapasy energii i wywołać objawy niedoboru MCAD.52 Głodzenie, choroba i intensywna aktywność fizyczna mogą wyzwalać objawy u osób z niedoborem MCAD.53

Każda sytuacja kliniczna, w której wymagana jest oksydacja kwasów tłuszczowych, taka jak głodzenie lub stres metaboliczny spowodowany chorobą, powoduje ciągłe zużycie glukozy i znacznie zmniejszoną lub nieobecną odpowiednią produkcję ciał ketonowych.54 Jeśli osoba z niedoborem MCAD nie je przez jakiś czas, istnieje ryzyko, że ważne funkcje jej organizmu przestaną działać.55

Gdy organizm potrzebuje szybko rozłożyć tłuszcz (na przykład, gdy jesteś chory i nie jadłeś przez jakiś czas), energia nie może być wytwarzana wystarczająco szybko, aby zaspokoić potrzeby organizmu, a substancje powstałe przy częściowym rozkładzie tłuszczu mogą gromadzić się do szkodliwych poziomów w organizmie.56

Aspekt Charakterystyka
Gen odpowiedzialny ACADM (chromosom 1p31)
Najczęstsza mutacja c.985A>G (80% przypadków klinicznych)
Typ dziedziczenia Autosomalny recesywny
Częstość występowania 1:8000 – 1:27000 (populacje kaukaskie)
Najwyższa częstość Osoby pochodzenia północnoeuropejskiego
Światowa częstość występowania 1:14600
Defekt biochemiczny Zaburzenie oksydacji średniołańcuchowych kwasów tłuszczowych (C6-C12)
Główne czynniki wyzwalające objawy Głodzenie, infekcje, stres metaboliczny
Wieku wystąpienia objawów Zazwyczaj 1-24 miesiące, możliwe też w wieku dorosłym
Główne konsekwencje metaboliczne Hipoglikemia hipoketotyczna, gromadzenie się kwasów tłuszczowych

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  1. 10.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Medium-chain acyl-CoA dehydrogenase deficiency: MedlinePlus GeneticsLock
    https://medlineplus.gov/genetics/condition/medium-chain-acyl-coa-dehydrogenase-deficiency/
    Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). […] Mutations in the ACADM gene cause MCAD deficiency. This gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called medium-chain fatty acids. […] Mutations in the ACADM gene lead to a shortage (deficiency) of the MCAD enzyme within cells. Without sufficient amounts of this enzyme, medium-chain fatty acids are not metabolized properly. […] As a result, these fats are not converted to energy, which can lead to the characteristic signs and symptoms of this disorder such as lethargy and hypoglycemia. Medium-chain fatty acids or partially metabolized fatty acids may also build up in tissues and damage the liver and brain. This abnormal buildup causes the other signs and symptoms of MCAD deficiency.
  • #2 MCAD Deficiency
    https://my.clevelandclinic.org/health/diseases/21973-mcad-deficiency
    MCAD deficiency is a genetic condition that prevents your body from turning fats into energy. […] A genetic mutation of the ACADM gene causes MCAD deficiency. The ACADM gene tells your body to make medium-chain acyl-CoA dehydrogenase, which is an enzyme responsible for breaking down medium-chain fatty acids. […] Genetic mutations happen randomly and can’t be prevented. The genetic mutation of ACADM causes your body to produce fewer enzymes that break down medium-chain fatty acids. […] People acquire MCAD deficiency through an autosomal recessive pattern, which means that your parents (carriers) both passed a mutated gene onto you.
  • #3 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner. […] The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inherited fatty acid beta-oxidation disorder; it leaves affected individuals unable to break down medium-chain fats for energy. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a known cause of sudden infant death syndrome (SIDS).
  • #4 Sudden unexpected infant death (SUDI) in a newborn due to medium chain acyl CoA dehydrogenase (MCAD) deficiency with an unusual severe genotype | Italian Journal of Pediatrics | Full Text
    https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-38-59
    Medium chain acyl CoA dehydrogenase deficiency (MCAD) is the most common inborn error of fatty acid oxidation. This condition may lead to cellular energy shortage and cause severe clinical events such as hypoketotic hypoglycemia, Reye syndrome and sudden death. […] Medium chain acyl CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is an autosomal recessive disorder and represents the most common fatty acid oxidation disorder with an incidence around 1:8,000. The disease may present dramatically with severe hypoketotic hypoglycemia, Reye syndrome or sudden death, typically with a peak of frequency around 36 month, whilst neonatal SUDI is quite rare. […] The enzymatic defect results in a blockade of medium chain fatty acids breakdown and of ketone production. The enzymatic deficiency compromises the availability of ketones during prolonged fasting or acute illness. This energy shortage primarily affects function of skeletal and cardiac muscle as well as the brain, and can lead to death.
  • #5 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #6 Medium-chain acyl-CoA dehydrogenase deficiency: MedlinePlus GeneticsLock
    https://medlineplus.gov/genetics/condition/medium-chain-acyl-coa-dehydrogenase-deficiency/
    Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). […] Mutations in the ACADM gene cause MCAD deficiency. This gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called medium-chain fatty acids. […] Mutations in the ACADM gene lead to a shortage (deficiency) of the MCAD enzyme within cells. Without sufficient amounts of this enzyme, medium-chain fatty acids are not metabolized properly. […] As a result, these fats are not converted to energy, which can lead to the characteristic signs and symptoms of this disorder such as lethargy and hypoglycemia. Medium-chain fatty acids or partially metabolized fatty acids may also build up in tissues and damage the liver and brain. This abnormal buildup causes the other signs and symptoms of MCAD deficiency.
  • #7 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #8 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #9 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #10 Orphanet: Medium chain acyl-CoA dehydrogenase deficiency
    https://www.orpha.net/en/disease/detail/42
    MCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985AG, (K329E), p.(Lys329Glu), accounted for about 80% of clinical disease prior to newborn screening programs but many more individuals are now being identified with other ACADM mutations. […] 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.
  • #11 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #12 MCAD Deficiency Diagnosis and Treatment
    https://informnetwork.org/mcad-deficiency/
    Medium chain acyl-CoA dehydrogenase deficiency is an inherited disorder involving fat metabolism. The deficiency prevents the body from making enough energy when a person is stressed, ill, or fasting. […] MCAD deficiency occurs when an individual inherits one change (mutation) in the MCAD gene called ACADM from each parent. MCAD deficiency is unusual in that most affected people carry at least one copy of a specific common mutation that causes a change in the protein chain. In fact, 90% of those who inherit two ACADM mutations share one copy of this common mutation, and in approximately 70% of cases, those with MCAD deficiency have inherited this same common mutation from both parents.
  • #13 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The ACADM gene spans 44kb of DNA and has 12 introns. Current data reports 400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as „uncertain.” Around 69% of these disease-causing variations are missense mutations. […] The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.
  • #14 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD) Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/946755-clinical
    Because medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive trait, other affected members of a family pedigree are unlikely to be historically available to assist in diagnosis. […] The gene has been mapped to locus 1p31; more than 80 allelic variations have been reported. The most common mutation is 985AG, which refers to a substitution of a guanine nucleotide for an adenine nucleotide at the 985th residue. A second mutation, 583GA, is reportedly common in certain populations. One study reported that individuals homozygous for 985AG or 583GA mutations had the highest levels of octanoylcarnitine, even when asymptomatic, and had the most severe clinical manifestations. […] Acute hepatic failure in a previously healthy gravid female who is homozygous for the 985AG mutation has been reported, thus confirming the potential for later onset, as well as the severity of complications with this specific mutation.
  • #15 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD) Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/946755-clinical
    Because medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive trait, other affected members of a family pedigree are unlikely to be historically available to assist in diagnosis. […] The gene has been mapped to locus 1p31; more than 80 allelic variations have been reported. The most common mutation is 985AG, which refers to a substitution of a guanine nucleotide for an adenine nucleotide at the 985th residue. A second mutation, 583GA, is reportedly common in certain populations. One study reported that individuals homozygous for 985AG or 583GA mutations had the highest levels of octanoylcarnitine, even when asymptomatic, and had the most severe clinical manifestations. […] Acute hepatic failure in a previously healthy gravid female who is homozygous for the 985AG mutation has been reported, thus confirming the potential for later onset, as well as the severity of complications with this specific mutation.
  • #16 MCAD deficiency – Symptoms and causes – Mayo Clinic
    https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/symptoms-causes/syc-20353745
    Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an inherited disorder that prevents your body from breaking down certain fats and turning them into energy. […] MCAD deficiency is caused by a change in the ACADM gene. The condition is inherited from both parents in an autosomal recessive pattern. This means that both parents are carriers each has one changed gene and one unchanged gene but they don’t have symptoms of the condition. The child with MCAD deficiency inherits two copies of the changed gene one from each parent. […] When you don’t have enough of the MCAD enzyme in your body, certain fats called medium-chain fatty acids can’t be broken down and turned into energy. This leads to low energy and low blood sugar. Also, fatty acids can build up in body tissues and cause damage.
  • #17 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner. […] The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inherited fatty acid beta-oxidation disorder; it leaves affected individuals unable to break down medium-chain fats for energy. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a known cause of sudden infant death syndrome (SIDS).
  • #18 Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency | Children’s Hospital of Philadelphia
    https://www.chop.edu/conditions-diseases/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency
    MCAD deficiency is a genetic disorder caused by changes in the ACADM gene. The ACADM gene provides instructions to produce an enzyme that breaks down fatty acids and converts them into energy. If the body cant make enough of this enzyme, the fatty acids cant be broken down and cannot support the bodys function. […] MCAD deficiency is inherited autosomal recessively. That means your child would have to inherit a defective gene from both parents to have this condition. […] For children with MCAD deficiency, neither copy of the ACADM gene can provide the proper instructions to produce the enzyme.
  • #19 Newborn screening information for medium-chain acyl-CoA dehydrogenase deficiency | Baby’s First Test | Newborn Screening | Baby Health
    https://www.babysfirsttest.org/newborn-screening/conditions/medium-chain-acyl-coa-dehydrogenase-deficiency
    Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) is a condition in which the body is unable to break down certain fats. […] If your baby has medium-chain acyl-CoA dehydrogenase deficiency (MCAD), your babys body either does not make enough or makes non-working medium-chain acyl-CoA dehydrogenase enzymes. When this happens, your baby cannot use medium-length fatty acids for energy. This is harmful because your babys body needs fat for energy when his or her body runs out of sugars (such as between meals). The heart also needs fatty acids for energy. […] MCAD is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for MCAD, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with MCAD is rare, when both parents are carriers, they can have more than one child with the condition.
  • #20 MCAD deficiency | Altru Health System
    https://www.altru.org/health-library/conditions/mcad-deficiency
    MCAD deficiency is caused by a change in the ACADM gene. The condition is inherited from both parents in an autosomal recessive pattern. This means that both parents are carriers each has one changed gene and one unchanged gene but they don’t have symptoms of the condition. The child with MCAD deficiency inherits two copies of the changed gene one from each parent. […] When you don’t have enough of the MCAD enzyme in your body, certain fats called medium-chain fatty acids can’t be broken down and turned into energy. This leads to low energy and low blood sugar. Also, fatty acids can build up in body tissues and cause damage.
  • #21 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations and one in 17,759 in the United States. […] The carrier frequency for the c.985AG pathogenic variant in ACADM is between 1:40 and 1:100 in those of northern European ancestry, suggestive of a founder effect. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. […] Loss of function.
  • #22 MCAD deficiency | Encyclopedia.com
    https://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/mcad-deficiency-0
    Because MCAD deficiency is a recessive disease, both parents must be carriers of this trait in order for their children to be affected. […] If both parents carry a copy of the mutated gene, there is a 25% likelihood that their child will be homozygous for MCAD deficiency. […] In population studies of known MCAD deficient individuals, it has been observed that an average of 32% of these individuals have at least one sibling either known to be affected with MCAD deficiency or to have died with a misdiagnosis of SIDS.
  • #23 What Is MCAD Deficiency? – Klarity Health Library
    https://my.klarity.health/what-is-mcad-deficiency/
    It is a genetic disorder that is inherited, and it is a lifelong condition, however, treatments exist which will be discussed in the coming sections. […] MCAD deficiency, also known as MCADD, stands for Medium-Chain Acyl-Coenzyme A Dehydrogenase deficiency. It is a genetically inherited disorder that follows an autosomal recessive mode of inheritance, that is, for a person to suffer from the condition two alleles of the faulty gene need to be present. A person with only one allele of this condition is termed a carrier. MCAD is an enzyme that is essential in fat metabolism to break down medium-chain fatty acids in a form that is usable by the body for energy. As there is a deficiency in this enzyme, medium-chain fatty acids build up, which causes toxicity in the form of a metabolic crisis.
  • #24 MCAD deficiency | Encyclopedia.com
    https://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/mcad-deficiency-0
    Because MCAD deficiency is a recessive disease, both parents must be carriers of this trait in order for their children to be affected. […] If both parents carry a copy of the mutated gene, there is a 25% likelihood that their child will be homozygous for MCAD deficiency. […] In population studies of known MCAD deficient individuals, it has been observed that an average of 32% of these individuals have at least one sibling either known to be affected with MCAD deficiency or to have died with a misdiagnosis of SIDS.
  • #25 Medium-chain acyl-coenzyme A dehydrogenase deficiency – Wikipedia
    https://en.wikipedia.org/wiki/Medium-chain_acyl-coenzyme_A_dehydrogenase_deficiency
    Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency or MCADD) is a disorder of fatty acid oxidation that impairs the body’s ability to break down medium-chain fatty acids into acetyl-CoA. […] MCADD is inherited in an autosomal recessive manner, meaning an affected individual must inherit a mutated allele from both of their parents. […] There is a common mutation among Northern European Caucasians, replacement of an adenine at position 985 with guanine, which results in a substitution of lysine with glutamic acid at position 304 of the protein. […] The common mutation has not been identified in MCADD cases identified in Asian populations.
  • #26 Genotypic differences of MCAD deficiency in the Asian population: Novel genotype and clinical symptoms preceding newborn screening notification | Genetics in Medicine
    https://www.nature.com/articles/gim200568
    Purpose: In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985AG (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown. […] We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843AT (R281S), and a 4-bp deletion, c.449_452delCTGA. […] The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.
  • #27 Genotypic differences of MCAD deficiency in the Asian population: Novel genotype and clinical symptoms preceding newborn screening notification | Genetics in Medicine
    https://www.nature.com/articles/gim200568
    Although considered the most common fatty acid oxidation disorder, MCAD deficiency is a rare metabolic condition in Asians, and only limited information is available from the few published case reports. […] Interestingly, the 4-bp deletion, c.449_452delCTGA, identified in the presented Korean newborn was also detected in two of the three neonates from Hiroshima, and therefore, this deletion may represent a common Asian ACADM mutation; however, genotyping of additional Asian MCAD deficient patients is required.
  • #28 Genotypic differences of MCAD deficiency in the Asian population: Novel genotype and clinical symptoms preceding newborn screening notification | Genetics in Medicine
    https://www.nature.com/articles/gim200568
    Purpose: In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985AG (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown. […] We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843AT (R281S), and a 4-bp deletion, c.449_452delCTGA. […] The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.
  • #29 Genotypic differences of MCAD deficiency in the Asian population: Novel genotype and clinical symptoms preceding newborn screening notification | Genetics in Medicine
    https://www.nature.com/articles/gim200568
    Purpose: In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985AG (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown. […] We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843AT (R281S), and a 4-bp deletion, c.449_452delCTGA. […] The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.
  • #30 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations and one in 17,759 in the United States. […] The carrier frequency for the c.985AG pathogenic variant in ACADM is between 1:40 and 1:100 in those of northern European ancestry, suggestive of a founder effect. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. […] Loss of function.
  • #31 Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD) | Revvity
    https://www.revvity.com/disorders/medium-chain-acyl-coa-dehydrogenase-deficiency-mcad
    Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a disorder of fatty acid β-oxidation, occurring in at least 1 in 25,000 live births. The enzyme deficiency is medium-chain acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the β-oxidation of fatty acids. MCAD deficiency results in an impaired ability to oxidize dietary and endogenous fatty acids of medium-chain length (6-12 carbons). […] Detection of mutations in the MCAD gene on chromosome 1 in affected individuals confirms the biochemical results and accurately detects asymptomatic carriers among other family members. A common 985A>G mutation is responsible for up to 85% of cases. […] This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms.
  • #32 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations and one in 17,759 in the United States. […] The carrier frequency for the c.985AG pathogenic variant in ACADM is between 1:40 and 1:100 in those of northern European ancestry, suggestive of a founder effect. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. […] Loss of function.
  • #33 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. Biochemical studies demonstrate that most MCAD variants have an impaired capacity to retain flavin adenine dinucleotide during their synthesis. Some variants, however, can be „structurally rescued” by riboflavin cofactor supplementation, which explains the heterogeneity of the MCADD phenotype in patients with the same genotype.
  • #34 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. […] A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.
  • #35 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. […] A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.
  • #36 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. […] A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.
  • #37 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. Biochemical studies demonstrate that most MCAD variants have an impaired capacity to retain flavin adenine dinucleotide during their synthesis. Some variants, however, can be „structurally rescued” by riboflavin cofactor supplementation, which explains the heterogeneity of the MCADD phenotype in patients with the same genotype.
  • #38 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. Biochemical studies demonstrate that most MCAD variants have an impaired capacity to retain flavin adenine dinucleotide during their synthesis. Some variants, however, can be „structurally rescued” by riboflavin cofactor supplementation, which explains the heterogeneity of the MCADD phenotype in patients with the same genotype.
  • #39 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. Biochemical studies demonstrate that most MCAD variants have an impaired capacity to retain flavin adenine dinucleotide during their synthesis. Some variants, however, can be „structurally rescued” by riboflavin cofactor supplementation, which explains the heterogeneity of the MCADD phenotype in patients with the same genotype.
  • #40 A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report | Orphanet Journal of Rare Diseases | Full Text
    https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-26
    Biochemically, our patient resembled the four mild MCADD patients described by Zschocke et al. who had a residual MCAD activity (10-20%) of the same order of magnitude as in our patient. […] The residual enzyme activity observed in classical MCADD, caused by homozygosity for c.985AG, is usually below 1%. […] As a general rule, amino acid changes introduced in a mature protein affect its conformation and this may impact its final stability and function/activity. […] The Q24E variant has not been previously described. […] The major acylcarnitine produced from deuterated palmitate was octanoylcarnitine, other medium-chain (hexanoyl- and decanoyl-) carnitine esters being also generated in excess. […] The last but not least issue concerns the carnitine status of our patient at the time of metabolic decompensation.
  • #41 A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report | Orphanet Journal of Rare Diseases | Full Text
    https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-26
    Biochemically, our patient resembled the four mild MCADD patients described by Zschocke et al. who had a residual MCAD activity (10-20%) of the same order of magnitude as in our patient. […] The residual enzyme activity observed in classical MCADD, caused by homozygosity for c.985AG, is usually below 1%. […] As a general rule, amino acid changes introduced in a mature protein affect its conformation and this may impact its final stability and function/activity. […] The Q24E variant has not been previously described. […] The major acylcarnitine produced from deuterated palmitate was octanoylcarnitine, other medium-chain (hexanoyl- and decanoyl-) carnitine esters being also generated in excess. […] The last but not least issue concerns the carnitine status of our patient at the time of metabolic decompensation.
  • #42 MCAD deficiency | Altru Health System
    https://www.altru.org/health-library/conditions/mcad-deficiency
    MCAD deficiency is caused by a change in the ACADM gene. The condition is inherited from both parents in an autosomal recessive pattern. This means that both parents are carriers each has one changed gene and one unchanged gene but they don’t have symptoms of the condition. The child with MCAD deficiency inherits two copies of the changed gene one from each parent. […] When you don’t have enough of the MCAD enzyme in your body, certain fats called medium-chain fatty acids can’t be broken down and turned into energy. This leads to low energy and low blood sugar. Also, fatty acids can build up in body tissues and cause damage.
  • #43 Medium-chain acyl-CoA dehydrogenase (MCAD) Deficiency: Causes, Symptoms And Treatment
    https://www.netmeds.com/health-library/post/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency-causes-symptoms-and-treatment?srsltid=AfmBOorRzk7c5kl8kq-HRt-xToBANKvMcMM0m6zsiUl9B9DFylCu-O8g
    Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a type of genetic disorder that chiefly inhibits the body from breaking down certain fats and converting them into energy, particularly during periods without food (fasting). […] MCAD deficiency is genetic in nature and inherited from both the parents. If both parents are carriers of the mutated copy of the ACADM gene, i.e., each has one abnormal gene and no characteristic symptoms of the condition (autosomal recessive), the child still inherits two copies of the abnormal gene and gets affected with the condition. […] When there is insufficient MCAD enzyme in the body, the medium chain fatty acids can’t be broken down and converted into energy. This results in hypoglycemia and low energy levels. […] Additionally, fatty acids can build up in the body tissues and cause damage to the liver and brain.
  • #44 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. […] A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.
  • #45 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated. […] Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA.
  • #46 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated. […] Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA.
  • #47 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    The inability to provide energy to tissues when glycogen stores are depleted secondary to MCADD results in a wide array of symptoms. Hypoketotic hypoglycemia with vomiting, progressing to seizures, and coma are typical presentations of this disease. MCADD is also thought to be responsible for a small portion of sudden infant death syndrome (SIDS) cases. This disease may become evident in early childhood, typically within the first 24 months of life, or remain asymptomatic until adulthood.
  • #48 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1424/
    Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner. […] The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inherited fatty acid beta-oxidation disorder; it leaves affected individuals unable to break down medium-chain fats for energy. […] Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a known cause of sudden infant death syndrome (SIDS).
  • #49 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK560837/
    The inability to provide energy to tissues when glycogen stores are depleted secondary to MCADD results in a wide array of symptoms. Hypoketotic hypoglycemia with vomiting, progressing to seizures, and coma are typical presentations of this disease. MCADD is also thought to be responsible for a small portion of sudden infant death syndrome (SIDS) cases. This disease may become evident in early childhood, typically within the first 24 months of life, or remain asymptomatic until adulthood.
  • #50 How Serious Is MCAD Deficiency?
    http://www.msn.com/en-us/health/other/how-serious-is-mcad-deficiency/ar-AA1Aoxj2?ocid=BingNewsVerp&apiversion=v2&noservercache=1&domshim=1&renderwebcomponents=1&wcseo=1&batchservertelemetry=1&noservertelemetry=1
    Medium chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency) is a rare and potentially serious inherited condition that affects the body’s ability to convert a certain fat into energy. […] MCAD deficiency occurs due to the lack of the enzyme called medium-chain acyl-CoA dehydrogenase (ACADM). The deficiency is caused by a mutation of the ACADM gene which can be passed from parents to a child during conception. […] The gene mutation is passed in an autosomal recessive pattern. What this means is that both parents must be carriers of the ACADM gene mutation for the child to inherit and develop the disorder. […] There are several mutations of the ACADM gene that could lead to MCAD deficiency, which may explain why some children have worse symptoms than others.
  • #51 Beta-Oxidation Cycle Disorders – Pediatrics – MSD Manual Professional Edition
    https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/beta-oxidation-cycle-disorders
    This deficiency is the most common defect in the beta-oxidation cycle. […] Clinical manifestations typically begin after 2 to 3 months of age and usually follow fasting (as little as 12 hours). […] Diagnosis of MCADD is by detecting medium-chain fatty acid conjugates of carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured fibroblasts; however, DNA testing can confirm most cases. […] Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate. […] Prevention is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting.
  • #52 Understanding MCAD Deficiency: Symptoms, Causes, and What You Need to Know
    https://tap.health/mcad-deficiency-symptoms/
    MCAD deficiency is caused by a genetic mutation that affects the body’s ability to break down medium-chain fatty acids, a vital energy source. This genetic defect is inherited in an autosomal recessive pattern, meaning both parents must carry the mutated gene for a child to inherit the condition. […] Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a genetic disorder impacting the body’s ability to break down certain fats for energy. While the exact cause is a genetic mutation inherited from parents, understanding the risk factors is crucial, especially in regions like India and other tropical countries. […] MCAD deficiency is an autosomal recessive disorder. This means that both parents must carry the faulty gene for a child to inherit the condition. If both parents are carriers, there’s a 25% chance with each pregnancy that their child will inherit the condition. Family history is therefore a significant risk factor. […] While genetics are paramount, environmental factors could influence symptom onset and severity. Infections, fasting (common in some religious practices), or periods of illness can deplete energy stores and trigger the manifestation of MCAD deficiency symptoms.
  • #53 MCAD Deficiency: Symptoms, Causes, Treatment | Qwark
    https://qwarkhealth.com/conditions/mcad-deficiency?srsltid=AfmBOopnoa4c5QuWBiyQ-OuJCf3uDkiYwpmGNP1QBUp3X7N48akQGNhH
    MCAD deficiency is caused by a mutation in the ACADM gene, which provides instructions for making the MCAD enzyme. This enzyme is responsible for breaking down medium-chain fatty acids as an energy source. If the enzyme is not functioning correctly or is absent altogether, the body cannot use these fatty acids for energy, which can result in low blood sugar levels and an overproduction of certain acids in the body. […] The genetic factors that contribute to MCAD deficiency are mutations in the ACADM gene. These mutations can be inherited from one or both parents, and they can be either homozygous or heterozygous. Homozygous mutations mean that an individual has two copies of the ACADM gene with the mutation, while heterozygous mutations mean that an individual has one normal copy of the gene and one copy with the mutation. […] MCAD deficiency is not typically caused by external factors but is instead a genetic disorder. However, certain factors can trigger symptoms in individuals with MCAD deficiency, such as fasting, illness, and heavy physical activity.
  • #54 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/946755-overview
    The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. […] A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.
  • #55 Required Disorders
    https://nensp.umassmed.edu/screening-programs/massachusetts/required-disorders/
    Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) is included in the required screening mandated by Massachusetts Department of Public Health. […] Babies and patients with fatty acid oxidation disorders, such as MCAD deficiency, cannot use the fats that they have stored in their body for emergency energy. When a person with such a disorder does not eat for a while, there is a risk that important functions of their body will stop working.
  • #56 MCADD
    https://www.nhs.uk/conditions/mcadd/
    MCADD is caused by a fault in the gene that provides the instructions to make an enzyme called medium-chain acyl-CoA dehydrogenase (MCAD). […] This genetic fault causes the enzyme to either not work properly or be missing entirely, which means the body cannot fully break down fat to release energy. […] If the body needs to break down fat quickly (for example, if you’re unwell and have not eaten for a while), energy cannot be produced quickly enough to meet the body’s needs and substances created when fat is partially broken down can build up to harmful levels in the body. […] This can lead to serious problems if not treated quickly.

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