Niedobór dehydrogenazy acylo-coa średniołańcuchowej

Niedobór dehydrogenazy acylo-coa średniołańcuchowej
Patofizjologia i mechanizm

Niedobór dehydrogenazy acylo-CoA średniołańcuchowej (MCADD) to autosomalne recesywne zaburzenie metaboliczne wynikające z mutacji w genie ACADM (chromosom 1p31), prowadzące do defektu mitochondrialnej β-oksydacji średniołańcuchowych kwasów tłuszczowych (C6-C12, z maksymalną aktywnością dla C8-CoA). Najczęstszą mutacją jest 985A→G (K304E), obecna homozygotycznie u ~80% pacjentów z objawową postacią choroby. Mutacje te powodują nieprawidłowe zwijanie białka MCAD, skutkując utratą funkcji enzymu i zaburzeniem produkcji acetylo-CoA, co uniemożliwia ketogenezę i prowadzi do hipoglikemii hipoketonemicznej podczas stresu metabolicznego lub głodzenia. Klinicznie obserwuje się ciężką hipoglikemię, kwasicę metaboliczną, encefalopatię oraz dysfunkcję mięśni szkieletowych. Diagnostyka opiera się na wykryciu charakterystycznych metabolitów w płynach ustrojowych, takich jak średniołańcuchowe kwasy tłuszczowe, estry acyloglicyny i acylkarnityny oraz kwasy dikarboksylowe. W badaniach noworodków z MCADD stwierdzono zwiększone markery stresu oksydacyjnego, w tym podwyższony poziom glutationu i utlenionych lipidów, co sugeruje rolę dysfunkcji mitochondrialnej i nadprodukcji ROS w patogenezie choroby.

Patogeneza niedoboru dehydrogenazy acylo-CoA średniołańcuchowej

Genetyczne podstawy MCADD
Strukturalne i funkcjonalne konsekwencje mutacji

Molekularny mechanizm dysfunkcji MCAD

Zaburzenia metaboliczne w MCADD
Wpływ na glukoneogenezę i metabolizm energetyczny

Mechanizmy patofizjologiczne w MCADD

Sekwestracja CoA i akumulacja metabolitów
Stres oksydacyjny i uszkodzenie mitochondriów
Dysfunkcja kompleksów oddechowych

Fenotypowa heterogenność MCADD

Wpływ temperatury na fenotyp molekularny
Potencjalne mechanizmy kompensacyjne

Konsekwencje kliniczne MCADD

Hipoglikemia i dekompensacja metaboliczna
Zmiany patologiczne w organach
Kolejne rozdziały

Patogeneza niedoboru dehydrogenazy acylo-CoA średniołańcuchowej

Niedobór dehydrogenazy acylo-CoA średniołańcuchowej (MCADD) jest dziedziczonym autosomalnie recesywnie zaburzeniem metabolicznym charakteryzującym się upośledzeniem mitochondrialnego utleniania kwasów tłuszczowych. MCADD jest najczęstszym zaburzeniem β-oksydacji kwasów tłuszczowych, z częstością występowania nawet 1 na 10 000 urodzeń.¹² Choroba ta wynika z mutacji w genie ACADM zlokalizowanym na chromosomie 1p31, kodującym enzym odpowiedzialny za katabolizm średniołańcuchowych kwasów tłuszczowych.³⁴

Genetyczne podstawy MCADD

Gen ACADM obejmuje 44 kb DNA i zawiera 12 intronów. Obecne dane wskazują na istnienie około 400 różnych wariantów genu ACADM, z czego 68 sklasyfikowano jako patogenne, 82 jako prawdopodobnie patogenne, a około 165 jako „niepewne”. Około 69% zmian patogennych to mutacje typu missense.⁵ Najczęściej występującą mutacją jest zamiana 985A→G, prowadząca do zastąpienia lizyny na pozycji 304 kwasem glutaminowym (K304E), co powoduje niewłaściwe zwijanie się białka i całkowitą utratę jego funkcji.⁶⁷ Ta mutacja występuje jako homozygotyczna u około 80% pacjentów z objawową postacią choroby, może również występować w heterozygotyczności z innymi wariantami, prowadząc do łagodniejszej formy choroby.⁸

W japońskiej populacji pacjentów najczęstszą mutacją jest delecja 4 par zasad (c.449_452delCTGA) zidentyfikowana w 25 allelach ACADM. Inne częste mutacje w tej kohorcie to R17H, G362E, R53C i R281S, które łącznie stanowią 60% wszystkich zidentyfikowanych mutacji.⁹

Strukturalne i funkcjonalne konsekwencje mutacji

Dehydrogenaza acylo-CoA średniołańcuchowa (MCAD) jest flawoenzymem mitochondrialnym uczestniczącym w β-oksydacji kwasów tłuszczowych. MCAD katalizuje pierwszy etap tego procesu, polegający na α,β-dehydrogenacji acylo-CoA o średniej długości łańcucha. Preferuje substraty C6- do C12-CoA, przy czym maksymalną aktywność katalityczną wykazuje dla C8-CoA.¹⁰

Gen ACADM koduje MCAD. Przetłumaczony łańcuch polipeptydowy jest importowany do mitochondriów, gdzie następuje formowanie dojrzałego funkcjonalnego białka poprzez odcięcie N-terminalnego peptydu sygnałowego. Następnie białko zwija się w dojrzałe monomery składające się z 396 reszt aminokwasowych. Prawidłowe białko MCAD jest tetramerem złożonym z 4 identycznych podjednostek.¹¹

Patogenne mutacje zakłócają ten proces, powodując powstawanie skróconych białek, zmianę miejsc splicingowych lub nieprawidłowe zwijanie się białek MCAD, co czyni enzym nieskutecznym lub całkowicie dysfunkcyjnym.¹²¹³ Eksperymenty wykazały, że MCADD wywołany przez mutacje missense jest chorobą związaną z nieprawidłowym zwijaniem się białka z fenotypem molekularnym utraty funkcji.¹⁴

Szczególnie podatna na strukturalne zaburzenia i destabilizację jest centralna domena β białka MCAD. Mutacje mapujące do domeny β predysponują do silnej destabilizacji.¹⁵¹⁶ Analiza strukturalnych konsekwencji podstawień łańcuchów bocznych w białku MCAD przyczynia się do lepszego zrozumienia mechanizmów leżących u podstaw nieprawidłowego zwijania się białka wywołanego mutacją i utraty funkcji enzymu.¹⁷

Molekularny mechanizm dysfunkcji MCAD

Dysfunkcja MCAD zakłóca etap dehydrogenacji w β-oksydacji wewnątrz mitochondriów. Prowadzi to do zmniejszonej produkcji acetylo-CoA, który jest niezbędny do ketogenezy. Brak acetylo-CoA uniemożliwia wytwarzanie ciał ketonowych podczas ketogenezy, co jest kluczowe dla produkcji energii podczas długotrwałego głodzenia lub stresu katabolicznego.¹⁸¹⁹

Zaburzenia metaboliczne w MCADD

W warunkach, gdy wymagane jest utlenianie kwasów tłuszczowych, takich jak głodzenie lub stres metaboliczny spowodowany chorobą, obserwuje się ciągłe zużycie glukozy przy znacznie zmniejszonej lub nieobecnej odpowiedniej produkcji ciał ketonowych. Badania z 2016 roku sugerują, że stres metaboliczny powodujący zalanie szlaku β-oksydacji substratem może przyczyniać się do kompetycyjnego hamowania, zwiększając tym samym dekompensację metaboliczną.²⁰

Organizm próbuje kompensować deficyt poprzez maksymalizację glukoneogenezy, jednak gdy zapasy glikogenu zostają wyczerpane, następuje szybka progresja do hipoglikemii hipoketonemicznej. Ostatecznym klinicznym rezultatem jest ciężka hipoglikemia i hipoketonuria z akumulacją monokarboksylowych kwasów tłuszczowych i dikarboksylowych kwasów organicznych, które są analogami strukturalnymi kwasów tłuszczowych, które nie mogą przejść przez etap MCAD.²¹²²

Kwas oktanowy (kwas tłuszczowy C8), który gromadzi się podczas nadchodzącej dekompensacji metabolicznej u pacjenta, jest znaną toksyną mitochondrialną; może to wyjaśniać zakłócenie metabolizmu amoniaku, które często towarzyszy klinicznej prezentacji niedoboru MCAD.²³

Wpływ na glukoneogenezę i metabolizm energetyczny

Glukoneogeneza jest skutecznie uniemożliwiona w niedoborze MCAD, ponieważ zależy od aktywności karboksylazy pirogronianowej w produkcji szczawiooctanu, reakcji, która jest regulowana w dół przez zmniejszony mitochondrialny acetylo-CoA. W konsekwencji glukoneogeneza nie może kompensować ciągłego zużycia istniejącej glukozy i niezdolności do przejścia na utlenianie alternatywnych paliw, w szczególności kwasów tłuszczowych.²⁴

Niedobór MCAD prowadzi do nieefektywnej mitochondrialnej fosforylacji oksydacyjnej. Upośledzone mitochondrialne zużycie tlenu zmniejsza funkcję mięśni szkieletowych, co objawia się osłabieniem. Ponadto akumulacja średniołańcuchowych kwasów tłuszczowych i ich pochodnych prowadzi do dysfunkcji neurologicznej, która jest obserwowana jako encefalopatia u tych pacjentów.²⁵²⁶

Mechanizmy patofizjologiczne w MCADD

W MCADD osoby z defektem enzymatycznym mają zmniejszoną funkcję enzymu MCAD w mitochondriach i nie mogą przekształcać średniołańcuchowych kwasów tłuszczowych (o długości 6-10 atomów węgla) w acetylo-CoA do syntezy ATP, ketogenezy i wykorzystania w cyklu Krebsa.²⁷

Sekwestracja CoA i akumulacja metabolitów

MCADD znacznie zmniejsza przepływ szlaku i wolny CoASH, ten ostatni z powodu sekwestracji CoA jako estrów średniołańcuchowych acylo-CoA. Wyczerpanie CoASH i spadek przepływu mogą zaburzyć ketogenezę i powodować hipoglikemię.²⁸ Niedobór MCAD upośledza dostarczanie energii do tkanek obwodowych poprzez zmniejszenie substratów fosforylacji oksydacyjnej i ketogenezy, zwiększając w ten sposób zależność od glukozy i jej wykorzystanie. Prowadzi to do hipoglikemii hipoketotycznej, kwasicy metabolicznej, choroby wątroby i letargu, które postępują do śpiączki i śmierci, gdy zapasy glikogenu zostają wyczerpane.²⁹

Metabolity wykrywalne w płynach ustrojowych (krew, mocz, żółć) obejmują średniołańcuchowe kwasy tłuszczowe, odpowiednie estry acyloglicyny i acylkarnityny oraz kwasy dikarboksylowe. Akumulacja tych metabolitów może powodować uszkodzenia oksydacyjne.³⁰

Stres oksydacyjny i uszkodzenie mitochondriów

Badania wykazały, że noworodki z MCADD mogą mieć objawy stresu oksydacyjnego jako oznaki choroby.³¹ Najbardziej dotknięte szlaki metaboliczne u noworodków z MCADD to szlaki fenyloalaniny, tyrozyny i tryptofanu. Metabolity związane ze stresem oksydacyjnym komórkowym i mechanizmami obronnymi, takie jak utlenione lipidy i glutation, były znacząco zmienione.³²

Badania wykazały zwiększone stężenie utlenionych lipidów, w tym utlenionych fosfatydyloseryn i CDP-diacylogliceroli jako zmienionych rodzajów lipidów występujących w MCADD. Dysfunkcyjne mitochondria, obserwowane w stanie MCADD, mogą być skorelowane z nadmierną produkcją reaktywnych form tlenu (ROS), które mogą być następnie postrzegane jako główna przyczyna stresu oksydacyjnego.³³

Po raz pierwszy odnotowano, że DBS (dried blood spots – suchej kropli krwi) od noworodków z MCADD miały podwyższony poziom glutationu i zmienione pewne rodzaje utlenionych lipidów, zwłaszcza tych niewykazanych wcześniej, co sugeruje zwiększone zdarzenia stresu oksydacyjnego. Po dalszych badaniach walidacyjnych glutation mógłby również być stosowany jako potencjalny biomarker metaboliczny dla MCADD.³⁴

Dysfunkcja kompleksów oddechowych

Postuluje się również dysfunkcję mitochondrialnego kompleksu I-III w wątrobie i mięśniach szkieletowych jako mechanizm patogenezy choroby w mysich modelach niedoboru MCAD.³⁵ Ze względu na niedobór MCAD, utrata ta może powodować zakłócenie superkompleksu fosforylacji oksydacyjnej, co prowadzi do defektu wtórnej fosforylacji oksydacyjnej i dysfunkcji oddychania mitochondrialnego.³⁶

Fenotypowa heterogenność MCADD

MCADD jest uważany za „zaburzenie konformacyjne”, jednak kliniczne objawy choroby obejmują szerokie spektrum ciężkości, nawet u pacjentów z tym samym genotypem. Patogenny fenotyp choroby wydaje się zależeć od dodatkowych zewnętrznych i wewnętrznych czynników, które nie są jasno zrozumiane.³⁷³⁸

Wpływ temperatury na fenotyp molekularny

Kliniczna obserwacja, że dekompensacja metaboliczna jest znacznie nasilona podczas gorączki, doprowadziła do założenia, że temperatura pacjenta ma wpływ na fenotyp molekularny. Badania wykazały, że mutacje w genie ACADM obniżają próg temperatury, przy którym następuje utrata funkcji MCAD. W konsekwencji podwyższona temperatura, jak to się dzieje podczas zakażeń współistniejących, znacznie zwiększa ryzyko dalszego zaburzenia konformacyjnego i utraty funkcji enzymu MCAD, co wyjaśnia zagrażające życiu przebiegi kliniczne obserwowane podczas epizodów gorączki u pacjentów cierpiących na MCADD.³⁹

Potencjalne mechanizmy kompensacyjne

Wyniki badań sugerują, że MCADD jest zaburzeniem poligenowym, z mutowanym allelem wykazującym niepełną penetrację. Inny gen może hamować fenotyp MCADD u niektórych osobników z homozygotycznym genotypem mutanta.⁴⁰

Model sugeruje pewne potencjalne mechanizmy ratunkowe, które zwiększają przepływ i CoASH, zwłaszcza zwiększenie poziomu dehydrogenazy acylo-CoA krótkołańcuchowej (SCAD). Jest to możliwość ratunku dla MCADD, która nie była wcześniej eksplorowana.⁴¹

Izoenzymi SCAD i VLCAD katalizują tę samą reakcję co MCAD, ale z preferencją odpowiednio dla krótszych lub dłuższych długości łańcucha acylowego. W MCADD obserwuje się kombinację dwóch efektów: znaczną redukcję przepływu szlaku i poważne wyczerpanie CoASH.⁴²

Regulacja w górę SCAD, MTP i ACOT, a także regulacja w dół CPT2, mają pozytywny wpływ na przepływ i stężenie CoASH w MCADD w warunkach przeciążenia.⁴³ Badania kliniczne testujące aktywność MCAD w limfocytach pacjentów z MCADD wykazały zwiększoną aktywność enzymu po suplementacji ryboflawiną, co sugeruje, że suplementacja ryboflawiną odgrywa pewną rolę w stabilizacji MCAD, prawdopodobnie poprzez zwiększoną dostępność pochodnej ryboflawiny, flawinoadeninodynukleotydu.⁴⁴

Konsekwencje kliniczne MCADD

Niedobór MCAD może prowadzić do ostrej dekompensacji i prezentować się z powikłaniami takimi jak krwotok płucny niezależnie od funkcji serca.⁴⁵ U pacjentów z wcześniej niezdiagnozowanym MCADD, serie przypadków wskazują na śmiertelność sięgającą 50% u dorosłych z ostrą prezentacją, w porównaniu do około 25% w populacji niemowląt.⁴⁶

Hipoglikemia i dekompensacja metaboliczna

Cechą charakterystyczną niestabilności metabolicznej w MCADD jest hipoglikemia z względną hipoketozą wtórną do zaburzonego utleniania kwasów tłuszczowych, a tym samym nieadekwatnej ketogenezy. Należy zauważyć, że ketoza może nie być nieobecna, raczej nieodpowiednia dla stopnia hipoglikemii. Napady hipoglikemiczne mogą prowadzić szybko do dekompensacji metabolicznej z ryzykiem śmierci.⁴⁷

Zmniejszona zdolność do metabolizowania średniołańcuchowych kwasów tłuszczowych staje się problematyczna, gdy osoby stoją w obliczu dodatkowych wymagań metabolicznych lub zmniejszonego przyjmowania pokarmów. Najczęściej stres wywołany głodzeniem lub infekcją, podczas których zapotrzebowanie na utlenianie kwasów tłuszczowych jest szczególnie wysokie, prowadzi do objawowej prezentacji.⁴⁸

Zmiany patologiczne w organach

Mikropęcherzykowe i makropęcherzykowe stłuszczenie wątroby obserwowane u myszy MCAD−/− jest zgodne z pierwotnym znaleziskiem patologicznym obserwowanym u pacjentów MCAD w stresie związanym z głodzeniem.⁴⁹

Sporadyczne zmiany sercowe u myszy MCAD−/− były interesującym i nieoczekiwanym odkryciem. Rozproszona kardiomiopatia z wieloogniskową degeneracją miocytów i martwicą obserwowana u myszy MCAD−/− nie została zgłoszona u pacjentów MCAD, jednak arytmie serca i dysfunkcja zostały odnotowane u pacjentów z niedoborem MCAD.⁵⁰

Patogeneza rabdomiolizy u osób z FAOD (zaburzeniami utleniania kwasów tłuszczowych) jest słabo zrozumiana. Wiadomo jednak, że rabdomioliza może być wywołana przez okresy głodzenia lub wysiłku, skutkujące niewystarczającym dostarczaniem adenozynotrifosforanu do komórek mięśniowych, co zakłóca integralność komórkową, ostatecznie prowadząc do rozpadu komórek.⁵¹ W FAOD wyczerpane zapasy glikogenu w połączeniu z niezdolnością do przetwarzania kwasów tłuszczowych powodują niedobór adenozynotrifosforanu w komórkach mięśniowych, prowadząc do rabdomiolizy.⁵²

Potencjalny stres sercowy, często wieloczynnikowy, który może wystąpić u pacjentów zarówno z MCADD, jak i zaburzeniami odżywiania, budzi znaczne obawy. Ponadto stan głodzenia, niezależnie od zaburzeń odżywiania, wpływa psychologicznie, prowadząc do objawów depresji i lęku. Wynikająca z tego utrata koncentracji w tych stanach psychologicznych mogłaby teoretycznie nasilić zachowania ryzykowne i niezdolność do przestrzegania lub ustanowienia planów zarządzania.⁵³

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) — New England Consortium of Metabolic Programs
https://www.newenglandconsortium.org/mcadd
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is the most frequent of the fatty acid oxidation disorders (FAOD) and one of the most frequently identified inborn errors of metabolism. The incidence of MCADD may be as high as 1/10,000 with mortality rates of 13-43% at initial crises. It is caused by an intramitochondrial defect in the – oxidation of fatty acids and is a major cause of hypoketotic hypoglycemia. MCADD is also a cause for lethargy, liver dysfunction with hepatomegaly, metabolic acidosis, hyperammonemia and sudden death. […] The pathophysiological process begins with reduced glucose intake as a result of a fasting state or increased energy needs from a catabolic state (infection, stress, fever, etc…) not sufficiently provided for by caloric intake. The resulting hypoglycemia leads to mobilization of free fatty acids (FFAs) from adipose tissue which enters the mitochondria via the carnitine cycle. In the mitochondria, as shown in the diagram above, the fatty acids in the acyl-CoA form are normally oxidized to acetyl-CoA which is used to produce the ketones that can supply the energy needs to compensate for the lack of adequate glucose. The block at MCAD prevents oxidation of medium chain CoA to short chain CoA, thereby markedly reducing the production of ketones. This block also results in the accumulation of fatty acid intermediates that inhibit gluconeogenesis (thus preventing endogenous glucose production), have a toxic effect on the liver and produce metabolic acidosis.
#2 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. […] MCADD is a mitochondrial fatty acid oxidation disorder that results from inactivity or deficiency of the medium chain acyl-CoA dehydrogenase (MCAD) protein. The MCAD protein is an enzyme that catalyzes the beta-oxidation of fatty acids. This process is critical to the formation of ketone bodies in the liver, which provide an alternative energy source during periods of prolonged fasting or increased energy demands. […] The calculated mortality risk in MCADD depends on the length of follow-up, because deaths associated with the disorder can occur through at least 3 years of age.
#3 SciELO Brazil – Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence
https://www.scielo.br/j/jiems/a/5CCSBv6vW4LtKwSWCS35sRv/
Medium chain acyl-coA dehydrogenase deficiency (MCADD) is the most common disorder of fatty acid oxidation with a varied prevalence depending on ethnicity. MCADD is an autosomal recessively inherited condition due to genetic mutations in the ACADM gene on chromosome 1p31, which codes for the enzyme responsible for medium chain fatty acid catabolism. The most common associated genotype is a homozygous missense mutation of 985AG in ACADM, which results in lysine being substituted for glutamic acid in the protein in position 304 (p.Lys304Glu); this is found in approximately 80% of patients. This results in protein misfolding, loss of function, insufficient medium chain acyl-CoA dehydrogenase enzyme production and ultimately accumulation of medium chain acylcarnitines. […] Patients with MCADD are at risk of several life-threatening issues should they develop metabolic decompensation. In previously undiagnosed patients, case series have quoted mortality rates as high as 50% in adults with acute presentations, compared to approximately 25% in the infantile population.
#4 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
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.
#5 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
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
https://omim.org/entry/607008
Matsubara et al. (1986) stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (606885), medium-chain (EC 1.3.99.3), and long-chain (609576) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (243500); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene. […] Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (Matsubara et al., 1986). […] In 9 patients with MCAD deficiency, Matsubara et al. (1990) identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; 607008.0001) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles.
#7 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
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 | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
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
https://www.omim.org/entry/607008
Tajima et al. (2016) sequenced the ACADM gene in a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of MCAD deficiency. The most prevalent mutation was a 4-bp deletion (c.449_452delCTGA; 607008.0016) identified in 25 ACADM alleles of 22 subjects from 19 families. Other prevalent mutations in this cohort included R17H, G362E, R53C, and R281S. These 5 mutations accounted for 60% of the mutations identified in this patient cohort.
#10 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
Medium-chain acyl-CoA dehydrogenase (MCAD) is a mitochondrial flavoenzyme involved in mitochondrial fatty acid -oxidation. MCAD catalyzes the first step in this process, which involves and -dehydrogenation of acyl-CoAs of medium chain lengths. It favors C6- to C12-CoA substrates and has maximum catalytic activity for C8-CoA. The ACADM gene encodes MCAD. The translated polypeptide chain is imported into the mitochondria, where it undergoes mature functional protein formation via cleavage of the N-terminal signal peptide. Subsequent protein folding into mature monomers of 396 residues occurs. A normal MCAD protein is a tetramer of 4 identical subunits. Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.
#11 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
Medium-chain acyl-CoA dehydrogenase (MCAD) is a mitochondrial flavoenzyme involved in mitochondrial fatty acid -oxidation. MCAD catalyzes the first step in this process, which involves and -dehydrogenation of acyl-CoAs of medium chain lengths. It favors C6- to C12-CoA substrates and has maximum catalytic activity for C8-CoA. The ACADM gene encodes MCAD. The translated polypeptide chain is imported into the mitochondria, where it undergoes mature functional protein formation via cleavage of the N-terminal signal peptide. Subsequent protein folding into mature monomers of 396 residues occurs. A normal MCAD protein is a tetramer of 4 identical subunits. Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.
#12 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
Medium-chain acyl-CoA dehydrogenase (MCAD) is a mitochondrial flavoenzyme involved in mitochondrial fatty acid -oxidation. MCAD catalyzes the first step in this process, which involves and -dehydrogenation of acyl-CoAs of medium chain lengths. It favors C6- to C12-CoA substrates and has maximum catalytic activity for C8-CoA. The ACADM gene encodes MCAD. The translated polypeptide chain is imported into the mitochondria, where it undergoes mature functional protein formation via cleavage of the N-terminal signal peptide. Subsequent protein folding into mature monomers of 396 residues occurs. A normal MCAD protein is a tetramer of 4 identical subunits. Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.
#13 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 rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. […] MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional. […] MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress.
#14 The Domain-Specific and Temperature-Dependent Protein Misfolding Phenotype of Variant Medium-Chain acyl-CoA Dehydrogenase | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093852
The implementation of expanded newborn screening programs reduced mortality and morbidity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD) caused by mutations in the ACADM gene. […] Missense induced MCADD is a protein misfolding disease with a molecular loss-of-function phenotype. […] Based on protein conformation, thermal stability and kinetic stability, the molecular phenotype in MCADD depends on the structural region that is affected by missense-induced conformational changes with the central -domain being particularly prone to structural derangement and destabilization. […] Experimental evidence led to the current view that missense induced MCADD is a protein misfolding disease with a loss-of-function molecular phenotype. […] The analysis of the structural consequences of side-chain replacements in the MCAD protein may contribute to a better understanding of the mechanisms underlying mutation-induced protein misfolding and loss of enzyme function.
#15 The Domain-Specific and Temperature-Dependent Protein Misfolding Phenotype of Variant Medium-Chain acyl-CoA Dehydrogenase | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093852
The implementation of expanded newborn screening programs reduced mortality and morbidity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD) caused by mutations in the ACADM gene. […] Missense induced MCADD is a protein misfolding disease with a molecular loss-of-function phenotype. […] Based on protein conformation, thermal stability and kinetic stability, the molecular phenotype in MCADD depends on the structural region that is affected by missense-induced conformational changes with the central -domain being particularly prone to structural derangement and destabilization. […] Experimental evidence led to the current view that missense induced MCADD is a protein misfolding disease with a loss-of-function molecular phenotype. […] The analysis of the structural consequences of side-chain replacements in the MCAD protein may contribute to a better understanding of the mechanisms underlying mutation-induced protein misfolding and loss of enzyme function.
#16
https://www.omim.org/entry/607008
Maier et al. (2009) analyzed the impact of 10 ACADM mutations (see, e.g., 607008.0001 and 607008.0011) on conformation, stability and enzyme kinetics of the corresponding mutant proteins. Partial to total rescue of aggregation by overexpression of GroES (HSPE1; 600141) and GroEL (HSPD1; 118190) suggested protein misfolding as a pathogenic mechanism. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the beta-domain of the protein predisposed to severe destabilization. In silico structural analysis of the affected amino acid residues revealed involvement in functionally relevant networks. Maier et al. (2009) concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency. […] Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics.
#17 The Domain-Specific and Temperature-Dependent Protein Misfolding Phenotype of Variant Medium-Chain acyl-CoA Dehydrogenase | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093852
The implementation of expanded newborn screening programs reduced mortality and morbidity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD) caused by mutations in the ACADM gene. […] Missense induced MCADD is a protein misfolding disease with a molecular loss-of-function phenotype. […] Based on protein conformation, thermal stability and kinetic stability, the molecular phenotype in MCADD depends on the structural region that is affected by missense-induced conformational changes with the central -domain being particularly prone to structural derangement and destabilization. […] Experimental evidence led to the current view that missense induced MCADD is a protein misfolding disease with a loss-of-function molecular phenotype. […] The analysis of the structural consequences of side-chain replacements in the MCAD protein may contribute to a better understanding of the mechanisms underlying mutation-induced protein misfolding and loss of enzyme function.
#18 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients.
#19 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 rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. […] MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional. […] MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress.
#20 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.
#21 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients.
#22 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.
#23 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/946755-overview
Octanoic acid (a C8 fatty acid), which accumulates during an impending metabolic decompensation in an affected patient, is a well-known mitochondrial toxin; this may account for the disruption of ammonia metabolism that often accompanies the clinical presentation of MCAD deficiency. […] 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. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.
#24 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/946755-overview
Octanoic acid (a C8 fatty acid), which accumulates during an impending metabolic decompensation in an affected patient, is a well-known mitochondrial toxin; this may account for the disruption of ammonia metabolism that often accompanies the clinical presentation of MCAD deficiency. […] 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. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.
#25 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients.
#26 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 rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. […] MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional. […] MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress.
#27 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] 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. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency.
#28 Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients | BMC Biology | Full Text
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01652-9
Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. […] Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients if untreated are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. […] MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. […] CoASH depletion and flux decline could impair ketogenesis and cause hypoglycaemia.
#29 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] 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. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency.
#30 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] 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. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency.
#31 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. […] The most affected metabolic pathways in MCADD newborns were the phenylalanine, tyrosine, and tryptophan pathways. […] Cellular oxidative stress and defense-mechanism-related metabolites such as oxidized lipids and glutathione were significantly affected. […] Our study has further highlighted oxidized lipids, including oxidized phosphatidylserines and CDP-diacylglycerols, as the altered lipid species that are found in MCADD. […] Dysfunctional mitochondria, as seen in the MCADD condition, can be correlated with the excessive production of the reactive oxygen species (ROS) oxidants, which can be subsequently viewed as a leading cause of oxidative stress. […] Our study is the second that has used untargeted metabolomics for the DBS samples from MCADD newborns.
#32 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. […] The most affected metabolic pathways in MCADD newborns were the phenylalanine, tyrosine, and tryptophan pathways. […] Cellular oxidative stress and defense-mechanism-related metabolites such as oxidized lipids and glutathione were significantly affected. […] Our study has further highlighted oxidized lipids, including oxidized phosphatidylserines and CDP-diacylglycerols, as the altered lipid species that are found in MCADD. […] Dysfunctional mitochondria, as seen in the MCADD condition, can be correlated with the excessive production of the reactive oxygen species (ROS) oxidants, which can be subsequently viewed as a leading cause of oxidative stress. […] Our study is the second that has used untargeted metabolomics for the DBS samples from MCADD newborns.
#33 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. […] The most affected metabolic pathways in MCADD newborns were the phenylalanine, tyrosine, and tryptophan pathways. […] Cellular oxidative stress and defense-mechanism-related metabolites such as oxidized lipids and glutathione were significantly affected. […] Our study has further highlighted oxidized lipids, including oxidized phosphatidylserines and CDP-diacylglycerols, as the altered lipid species that are found in MCADD. […] Dysfunctional mitochondria, as seen in the MCADD condition, can be correlated with the excessive production of the reactive oxygen species (ROS) oxidants, which can be subsequently viewed as a leading cause of oxidative stress. […] Our study is the second that has used untargeted metabolomics for the DBS samples from MCADD newborns.
#34 Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
https://www.mdpi.com/1422-0067/24/11/9657
Our data are consistent with the previously published data that used targeted metabolomics analyses on DBS from MCADD patients, and which also showed elevated oxidized phospholipids, particularly oxidized phosphatidylcholines. […] In contrast, an animal study, which conducted in vitro experiments, focused on understanding the pathological mechanisms involved in the neurologic symptoms in MCADD patients. […] For the first time, we reported that the DBS from MCADD newborns had elevated glutathione and had altered certain types of oxidized lipids, notably those not reported before, which is suggestive of increased oxidative stress events. […] Thus, after further validation studies, glutathione could also be used as a potential metabolic biomarker for MCADD.
#35 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] 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. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency.
#36 A Review: Medium-Chain Acyl-CoA Dehydrogenase Deficiency
https://www.linkedin.com/pulse/review-medium-chain-acyl-coa-dehydrogenase-deficiency-annie-flatley?trk=pulse-article_more-articles_related-content-card
Medium-Chain Acyl-CoA deficiency (MCADD) is the most common genetic disorder that affects the mitochondrial fatty acid -oxidation pathway. The hallmark of this disorder is the patients inability to process medium-chain fatty acids through the -oxidation pathway by cause of the lack of medium-chain acyl-CoA dehydrogenase (MCAD). […] The cause for this missense mutation is the conversion of an adenine to a guanine in nucleotide 985 (c.985AG) on exon 11 in ACADM, consequentially leading to loss of function resulting in MCADD. […] Since there is a mutation in MCAD, there is an accumulation of substances (acylcarnitines, acyl-glycine, and dicarboxylic organic acids) and a decreased production of Acetyl-CoA. This causes a decrease in the Krebs Cycle, ATP synthesis and Ketogenesis. […] The biological consequence of this mutation in MCAD is the disruption of the process of fatty acid oxidation which fuels hepatic ketogenesis, which is a central source of energy once the local glycogen storage deposits have been depleted. MCAD also results in the accumulation of fatty acid intermediates like octanoic acid and decanoic acids, as a result, they can inhibit mitochondrial oxygen consumption thereby inducing oxidative stress aiding the pathogenesis of MCADD. […] Due to the deficiency of MCAD, this loss may result in the disruption of the OXPHOS super complex. […] Due to this conclusion, this prompts a defect in the secondary OXPHOS and the dysfunction of mitochondrial respiration.
#37 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24897
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.
#38 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560837/
MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] A clinical trial testing MCAD activity in the lymphocytes of patients with MCADD reported increased enzyme activity after riboflavin supplementation. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. […] 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.
#39 The Domain-Specific and Temperature-Dependent Protein Misfolding Phenotype of Variant Medium-Chain acyl-CoA Dehydrogenase | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093852
The introduction of expanded NBS programs including early detection of MCADD raised uncertainties about the clinical relevance of novel ACADM mutations identified in individuals showing biochemical abnormalities in the first days of life. […] Based on the data from the present study, all mutations mapping to D can be categorized as prone to misfolding, unfolding, and functional inactivation. […] The clinical observation of metabolic decompensation being considerably aggravated with fever has led to the assumption that the patients temperature has impact on the molecular phenotype. […] We showed here that mutations in the ACADM gene lower the temperature threshold at which MCAD loss-of-function occurs. […] Consequently, increased temperature as it happens during intercurrent infections, significantly enhances the risk of further conformational derangement and loss of function of the MCAD enzyme explaining the life-threatening clinical courses observed during fever episodes in patients suffering from MCADD.
#40 MCAAD Study – ACKCS Charitable Trust
https://ackcscharitabletrust.org/mcaad-study/
Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is one of the most commonly diagnosed inborn errors of metabolism in humans. […] The results of our testing suggest that MCADD is a polygenic disorder with the mutant allele displaying incomplete penetrance. Another gene suppresses the MCADD phenotype in some dogs with a homozygous mutant genotype. […] The blood level of fatty acids in phenotypically asymptomatic Cavaliers should be compared to the levels in phenotypically symptomatic Cavaliers to determine if the difference in phenotype is due to a mechanism(s) that permits the asymptomatic dog to compensate for elevated blood levels of medium chain fatty acids.
#41 Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients | BMC Biology | Full Text
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01652-9
We hypothesised that an ability to maintain sufficient mitochondrial CoASH and pathway flux might distinguish asymptomatic from symptomatic patients. […] The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. […] This is a rescue for MCADD that has not been explored before. […] Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. […] The combined results point to a qualitative difference between SCADD, MCADD and VLCADD. […] In MCADD, we see a combination of two effects: a substantial reduction in pathway flux and severe CoASH depletion. […] We hypothesised that clinically asymptomatic MCADD patients may implement compensatory mechanisms that increase pathway flux and CoASH concentration.
#42 Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients | BMC Biology | Full Text
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01652-9
We hypothesised that an ability to maintain sufficient mitochondrial CoASH and pathway flux might distinguish asymptomatic from symptomatic patients. […] The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. […] This is a rescue for MCADD that has not been explored before. […] Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. […] The combined results point to a qualitative difference between SCADD, MCADD and VLCADD. […] In MCADD, we see a combination of two effects: a substantial reduction in pathway flux and severe CoASH depletion. […] We hypothesised that clinically asymptomatic MCADD patients may implement compensatory mechanisms that increase pathway flux and CoASH concentration.
#43 Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients | BMC Biology | Full Text
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01652-9
The isoenzymes SCAD and VLCAD catalyse the same reaction as MCAD, but with a preference for shorter or longer acyl-chain lengths, respectively. […] MCADD poses a threat to mitochondrial metabolism because it simultaneously causes the loss of about 35% of pathway flux relative to the control, as well as a 40% drop in CoASH. […] In summary, the upregulation of SCAD, MTP and the ACOTs, as well as the downregulation of CPT2, were found to have a positive effect on flux and CoASH concentration in MCADD under overload conditions. […] This was also the first time that patient data were directly employed to personalise computational models for the investigation of MCADD.
#44 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560837/
MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood. […] A clinical trial testing MCAD activity in the lymphocytes of patients with MCADD reported increased enzyme activity after riboflavin supplementation. […] These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. […] 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.
#45 Medium-chain Acyl-CoA dehydrogenase deficiency presenting with neonatal pulmonary haemorrhage | Maternal Health, Neonatology and Perinatology | Full Text
https://mhnpjournal.biomedcentral.com/articles/10.1186/s40748-015-0010-9
Medium-chain Acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited disorder of fatty acid beta-oxidation. […] Medium-chain Acyl-CoA dehydrogenase deficiency (MCADD) is a rare metabolic disorder in which patients have problems breaking down fatty acids for energy. […] The prognosis of MCADD is excellent once the diagnosis is established and frequent feedings to avoid fasting are instituted. […] The key towards successful management of severe pulmonary haemorrhage in newborns with a coagulopathy and suspicion of an underlying metabolic disorder consists of adequate mechanical ventilation and aggressive use of fresh frozen plasma, while treating the metabolic decompensation and initiating an early diagnostic work-up. MCADD can lead to acute decompensation and present with complications such as pulmonary haemorrhage independent of cardiac function.
#46 SciELO Brazil – Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence
https://www.scielo.br/j/jiems/a/5CCSBv6vW4LtKwSWCS35sRv/
Medium chain acyl-coA dehydrogenase deficiency (MCADD) is the most common disorder of fatty acid oxidation with a varied prevalence depending on ethnicity. MCADD is an autosomal recessively inherited condition due to genetic mutations in the ACADM gene on chromosome 1p31, which codes for the enzyme responsible for medium chain fatty acid catabolism. The most common associated genotype is a homozygous missense mutation of 985AG in ACADM, which results in lysine being substituted for glutamic acid in the protein in position 304 (p.Lys304Glu); this is found in approximately 80% of patients. This results in protein misfolding, loss of function, insufficient medium chain acyl-CoA dehydrogenase enzyme production and ultimately accumulation of medium chain acylcarnitines. […] Patients with MCADD are at risk of several life-threatening issues should they develop metabolic decompensation. In previously undiagnosed patients, case series have quoted mortality rates as high as 50% in adults with acute presentations, compared to approximately 25% in the infantile population.
#47 SciELO Brazil – Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence
https://www.scielo.br/j/jiems/a/5CCSBv6vW4LtKwSWCS35sRv/
The hallmark of metabolic instability in MCADD is hypoglycaemia with relative hypoketosis secondary to impaired fatty acid oxidation and thus inadequate ketogenesis. It should be noted that ketosis may not be absent, rather inappropriate for the degree of hypoglycaemia. Hypoglycaemic seizures can result, leading rapidly to metabolic decompensation with risk of death. […] The management of MCADD focuses primarily on preventative measures with avoidance of fasting to prevent catabolism and hypoglycaemia. Lifelong dietary management is prescribed with recommendations for adequate carbohydrate intake. […] The development of obesity is a risk for patients with MCADD, presumably owing to the reiteration of recommendations to avoid fasting and increase carbohydrate intake, particularly when unwell. Long term outcome studies have demonstrated that these patients are prone not only to excessive weight gain but also to type 2 diabetes.
#48 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine
https://www.nature.com/articles/gim200638
The reduced ability to metabolize medium-chain fatty acids becomes problematic when individuals are faced with extra metabolic demands or reduced dietary inputs. Most often, stress induced by fasting or infection, during which the demands on fatty acid oxidation are particularly high, leads to symptomatic presentation. […] Information on long-term outcomes in children with MCADD detected through newborn screening is still lacking. […] Newborn screening for MCADD clearly prevents death and disability in many children with the disorder.
#49 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid -oxidation in humans. […] The pathogenesis of the wide range of metabolic disturbances in MCAD deficiency is poorly understood and certain aspects of patient management are controversial. An animal model for MCAD deficiency is essential to better understand the pathogenesis of MCAD deficiency and to develop better management regimens for human patients. […] Successfully targeting Acadm produced a mouse model for MCAD deficiency with features that mimic the clinical, biochemical, and pathologic phenotype found in human patients. […] The microvesicular and macrovesicular hepatic steatosis seen in fasted MCAD/ mice is consistent with the primary pathological finding seen in human MCAD patients with fasting stress.
#50 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023
Sporadic cardiac lesions in MCAD/ mice, however, were an interesting and unexpected finding. The diffuse cardiomyopathy with multifocal myocyte degeneration and necrosis observed in MCAD/ mice has not been reported in human MCAD patients, however, cardiac arrhythmias and dysfunction have been reported in MCAD-deficient patients. […] The MCAD-deficient mouse offers new insights into the pathogenesis of mitochondrial -oxidation deficiencies and will provide a robust tool to better understand the role of fatty acids in other relevant diseases.
#51
https://link.springer.com/article/10.1007/s11154-020-09568-3
FAOD are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. […] In patients with FAOD, reduced or loss of function of one of the mitochondrial proteins involved in fatty acid transport or metabolism can lead to tissue accumulation of fatty acids and/or their intermediate metabolites, as well as metabolic decompensation due primarily to the resulting depletion of tricarboxylic acid cycle intermediates such as acetyl-CoA. […] The current review focuses primarily on the clinical manifestations associated with LC-FAOD and (to a lesser extent) MCADD, which affects a narrower group of organ systems compared with LC-FAOD. […] The pathogenesis of rhabdomyolysis among individuals with FAOD is poorly understood. However, it is known that rhabdomyolysis can be triggered by periods of fasting or exercise, resulting in deficient delivery of adenosine triphosphate to the muscle cells, which disrupts cellular integrity, ultimately leading to cellular disintegration.
#52
https://link.springer.com/article/10.1007/s11154-020-09568-3
In FAOD, depleted glycogen stores in conjunction with the inability to process fatty acids results in deficiency of adenosine triphosphate in muscle cells leading to rhabdomyolysis. […] The pathophysiology of retinopathy secondary to FAOD has yet to be elucidated; however, several theories have been proposed. Findings from studies have indicated that the number of metabolic decompensations is positively correlated with vision loss in patients with FAOD, suggesting that elevated levels of metabolic by-products during these crises may cause the observed retinopathy.
#53 SciELO Brazil – Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence
https://www.scielo.br/j/jiems/a/5CCSBv6vW4LtKwSWCS35sRv/
Interestingly, despite the risk-taking behaviour displayed by these patients, none developed severe sequelae of restricting carbohydrate intake, with the lowest glucose recorded at 3.8mmol/L. This is higher than the level of 3.0mmol/L, documented to be accepted as the threshold for hypoglycaemia in adults with inherited metabolic disease. […] The potential cardiac stress, often multifactorial in nature, that could arise in patients with both MCADD and disordered eating is of significant concern. Furthermore, a state of starvation regardless of disordered eating, impacts psychologically leading to symptoms of depression and anxiety. The resulting loss of concentration with these psychological states could theoretically exacerbate the risk taking behaviour and inability to follow or institute management plans. […] The coexistence of these pathologies may amplify the risk of several sequelae placing the patient at significant risk of poor outcome.