Niedobór dehydrogenazy acyl-coa o łańcuchu średnim

Niedobór dehydrogenazy acyl-coa o łańcuchu średnim
Diagnostyka i diagnoza

Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim (MCAD deficiency) to autosomalne recesywne zaburzenie metabolizmu kwasów tłuszczowych, z częstością występowania około 1:15 000-17 000 żywych urodzeń. Diagnostyka przesiewowa noworodków opiera się na spektrometrii masowej (MS/MS) wykrywającej podwyższone stężenia oktanoilokarnityny (C8), heksanoilokarnityny (C6), dekanoilokarnityny (C10) i decenoilokarnityny (C10:1), a także zwiększone stosunki C8/C2 i C8/C10. Pozytywny wynik wymaga dalszej diagnostyki biochemicznej (analiza acylokarnityn w osoczu, kwasów organicznych i acyloglicyn w moczu), najlepiej podczas epizodu dekompensacji metabolicznej, oraz potwierdzenia molekularnego poprzez sekwencjonowanie genu ACADM, ze szczególnym uwzględnieniem mutacji c.985A>G (p.Lys304Glu), obecnej u około 85% pacjentów europejskich. Alternatywnie, pomiar aktywności enzymu MCAD w leukocytach lub fibroblastach z użyciem fenylopropionyl-CoA jako substratu stanowi złoty standard diagnostyczny, zwłaszcza w przypadkach niejednoznacznych wyników genetycznych.

Diagnostyka niedoboru dehydrogenazy acyl-CoA o łańcuchu średnim

Niedobór dehydrogenazy acyl-CoA o łańcuchu średnim (MCAD deficiency) to zaburzenie metaboliczne dziedziczone w sposób autosomalny recesywny, które uniemożliwia organizmowi prawidłowe przetwarzanie tłuszczów o średniej długości łańcucha w energię. Jest to najczęstszy zaburzenie oksydacji kwasów tłuszczowych, występujący z częstością około 1 na 15000-17000 żywych urodzeń.¹² Wczesna diagnostyka tego schorzenia ma kluczowe znaczenie dla zapobiegania poważnym powikłaniom, w tym nagłej śmierci, która może być pierwszym objawem choroby.³

Badania przesiewowe noworodków

W większości krajów wysoko rozwiniętych, w tym we wszystkich stanach USA, niedobór MCAD jest rutynowo wykrywany w ramach obowiązkowych badań przesiewowych noworodków.⁴⁵ Procedura obejmuje pobranie kilku kropli krwi z pięty noworodka zwykle między 1 a 8 dniem życia.

Test przesiewowy wykorzystuje spektrometrię masową (tandem mass spectrometry, MS/MS) do wykrycia charakterystycznego wzorca acylokarnityn we krwi:⁶

Podwyższony poziom oktanoilokarnityny (C8) – najbardziej specyficzny marker dla niedoboru MCAD
Podwyższone stężenia heksanoilokarnityny (C6), dekanoilokarnityny (C10) i decenoilokarnityny (C10:1)
Zwiększony stosunek C8/C2 i C8/C10⁷⁸

Wynik pozytywny badania przesiewowego nie oznacza rozpoznania choroby, ale wymaga dalszej diagnostyki potwierdzającej.⁹ Należy podkreślić, że choć badania przesiewowe znacząco zmniejszyły zachorowalność i śmiertelność związaną z niedoborem MCAD, w rzadkich przypadkach profil acylokarnityn może być prawidłowy mimo obecności choroby.¹⁰

Badania biochemiczne potwierdzające

Po uzyskaniu dodatniego wyniku badania przesiewowego wykonuje się następujące badania biochemiczne:¹¹¹²

Analiza acylokarnityn w osoczu – potwierdzająca podwyższone poziomy C6, C8, C10 i C10:1
Analiza kwasów organicznych w moczu – wykazująca zwiększone wydalanie kwasów dikarboksylowych o średniej długości łańcucha (C6-C10)
Analiza acyloglicyn w moczu – charakterystyczne podwyższone stężenia heksanoiloglicyny i suberyloglicyny¹³¹⁴

Optymalne jest pobranie próbek do badań biochemicznych podczas epizodu dekompensacji metabolicznej, ponieważ wyniki tych testów mogą normalizować się w okresie stabilnym.¹⁵ Same badania biochemiczne mają wysoką czułość diagnostyczną, ale nie powinny być jedynym sposobem potwierdzenia diagnozy.¹⁶

Diagnostyka molekularna

Ostateczne potwierdzenie diagnozy niedoboru MCAD opiera się na badaniach genetycznych genu ACADM, który koduje enzym dehydrogenazę acyl-CoA o średniej długości łańcucha. Gen ACADM znajduje się na chromosomie 1p31 i składa się z 12 eksonów.¹⁷

Najczęstsze podejścia w diagnostyce molekularnej obejmują:¹⁸

Badanie pojedynczego genu (sekwencjonowanie genu ACADM)
Wykorzystanie paneli wielogenowych (w przypadku diagnostyki różnicowej zaburzeń oksydacji kwasów tłuszczowych)
W pierwszej kolejności poszukiwanie najczęstszej mutacji c.985A>G (p.Lys304Glu, K304E), która odpowiada za około 85% przypadków niedoboru MCAD w populacji europejskiej¹⁹

Około 50% osób z niedoborem MCAD jest homozygotycznych dla mutacji c.985A>G, a około 40% to heterozygoty złożone z jednym allelem c.985A>G i inną, rzadszą mutacją.²⁰ Sekwencjonowanie genu ACADM wykrywa 95-100% mutacji u osób chorych.²¹

Badanie aktywności enzymatycznej

Alternatywną metodą diagnostyczną jest pomiar aktywności enzymu MCAD w:

Leukocytach lub limfocytach krwi obwodowej
Hodowlach fibroblastów skóry²²

Za złoty standard w potwierdzaniu niedoboru MCAD po dodatnim wyniku testu przesiewowego uważa się pomiar aktywności MCAD w leukocytach lub limfocytach z wykorzystaniem fenylopropionyl-CoA jako substratu.²³ Znaczące zmniejszenie aktywności enzymu poniżej 50% wartości prawidłowych potwierdza diagnozę.²⁴

Badanie aktywności enzymatycznej może być szczególnie przydatne w przypadkach, gdy wyniki badań genetycznych są niejednoznaczne, jednak dostępność tego badania jest ograniczona do wyspecjalizowanych ośrodków akademickich.²⁵

Diagnostyka prenatalna i badania rodzinne

W rodzinach, w których wcześniej zdiagnozowano niedobór MCAD, możliwe jest wykonanie badań prenatalnych oraz badań nosicielstwa:²⁶²⁷

Diagnostyka prenatalna – możliwa poprzez analizę DNA z komórek płynu owodniowego (amniocenteza) lub z biopsji kosmówki (CVS)
Badania nosicielstwa – analiza DNA w celu identyfikacji nosicieli mutacji w genie ACADM wśród członków rodziny
Badania rodzeństwa – zalecane nawet jeśli nie wystąpiły objawy, ze względu na niepełną penetrację genotypu²⁸

Poradnictwo genetyczne jest istotnym elementem diagnostyki, pomagającym rodzinom zrozumieć wyniki testów oraz ryzyko wystąpienia choroby u przyszłego potomstwa (25% przy obojgu rodzicach będących nosicielami).²⁹

Diagnostyka różnicowa

Niedobór MCAD należy rozważyć w diagnostyce różnicowej następujących stanów:³⁰³¹

Hipoglikemia hipoketotyczna
Ostra niewydolność wątroby
Zespół Reye’a
Niewyjaśniona encefalopatia i drgawki
Nagła niewyjaśniona śmierć niemowląt (SIDS)
Inne zaburzenia oksydacji kwasów tłuszczowych

Rozpoznanie niedoboru MCAD powinno być brane pod uwagę szczególnie w przypadku dzieci z nawracającymi epizodami dekompensacji metabolicznej po infekcjach lub głodzeniu.³²

Diagnostyka u osób dorosłych

Choć niedobór MCAD najczęściej diagnozowany jest w okresie niemowlęcym lub wczesnego dzieciństwa, w rzadkich przypadkach pierwsze objawy mogą wystąpić w wieku dorosłym.³³ U pacjentów dorosłych diagnostyka może być utrudniona, ponieważ niedobór MCAD nie jest zwykle rozważany jako potencjalna przyczyna objawów. Diagnoza jest zwykle stawiana po wykluczeniu innych przyczyn i opiera się na badaniach genetycznych.³⁴

Badania pośmiertne

W przypadkach nagłej, niewyjaśnionej śmierci, szczególnie poprzedzonej łagodną chorobą, która zwykle nie prowadzi do śmierci, należy rozważyć niedobór MCAD jako przyczynę.³⁵ Sekcja zwłok może wykazać złogi tłuszczowe w wątrobie, ale diagnoza wymaga analizy molekularnej DNA z tkanek pobranych pośmiertnie.³⁶³⁷

Postępowanie po rozpoznaniu niedoboru MCAD

Po potwierdzeniu diagnozy, pacjent powinien zostać skierowany do specjalisty chorób metabolicznych oraz dietetyka.³⁸ Kluczowe znaczenie ma wdrożenie odpowiedniego postępowania dietetycznego i prewencyjnego, aby zapobiec epizodom dekompensacji metabolicznej.³⁹

Główne zasady leczenia obejmują:⁴⁰

Unikanie długich okresów głodzenia
Regularne przyjmowanie posiłków bogatych w węglowodany złożone
Stosowanie skrobi kukurydzianej przed snem u starszych dzieci i dorosłych
Wdrożenie protokołu postępowania w sytuacjach awaryjnych podczas chorób lub przedłużonego głodzenia
W niektórych przypadkach suplementacja L-karnityny⁴¹

Wczesna diagnoza i odpowiednie leczenie umożliwiają większości pacjentów z niedoborem MCAD prowadzenie normalnego życia z dobrym rokowaniem.⁴²

Wyzwania diagnostyczne

Pomimo postępów w diagnostyce niedoboru MCAD, istnieją pewne wyzwania:⁴³⁴⁴

Możliwość fałszywie ujemnych wyników badań przesiewowych, szczególnie u pacjentów z rzadszymi mutacjami⁴⁵
Zmienność fenotypowa nawet w obrębie tej samej rodziny
Niepełna penetracja – niektóre osoby z defektem genetycznym mogą nigdy nie rozwinąć objawów klinicznych
Trudności diagnostyczne u pacjentów dorosłych z nietypową prezentacją kliniczną
Ograniczona dostępność testów enzymatycznych w wielu ośrodkach

Obserwowana częstość występowania niedoboru MCAD jest niższa niż oczekiwana na podstawie częstości nosicielstwa mutacji, co może wskazywać zarówno na niedodiagnozowanie, jak i na niepełną penetrację choroby.⁴⁶

Większość przypadków niedoboru MCAD jest obecnie rozpoznawana dzięki badaniom przesiewowym noworodków, co znacząco poprawiło rokowanie pacjentów z tym zaburzeniem. Algorytm diagnostyczny obejmujący analizę profilu acylokarnityn, kwasów organicznych w moczu oraz badania genetyczne pozwala na wiarygodne potwierdzenie diagnozy i wdrożenie odpowiedniego leczenia zapobiegającego poważnym powikłaniom tej choroby metabolicznej.

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Materiały źródłowe

#1 MCAD Deficiency
https://my.clevelandclinic.org/health/diseases/21973-mcad-deficiency
MCAD deficiency is a genetic condition when your body can’t convert certain fats into energy. […] MCAD deficiency is a condition that prevents your body from turning fats into energy. […] People who have MCAD deficiency don’t have enough of this enzyme and are unable to metabolize medium-chain fatty acids. […] MCAD deficiency is a genetic condition that you inherit when both of your parents carry a copy of the mutated ACADM gene, and you inherit the mutated copy from each of your parents (autosomal recessive). […] MCAD deficiency occurs in about 1 out of every 15,000 individuals. […] MCAD deficiency is a condition your healthcare provider will test for during a newborn screening, which means a diagnosis is possible before your baby shows any symptoms of the condition. […] Your healthcare provider might order additional tests, including genetic testing, where they will take a small sample of your baby’s blood, urine or tissue to verify the diagnosis.
#2 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). […] Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood glucose (hypoglycemia). In rare cases, symptoms of this disorder are not recognized early in life, and the condition is not diagnosed until adulthood. People with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death. […] Problems related to MCAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections. […] In the United States, the estimated incidence of MCAD deficiency is 1 in 17,000 people.
#3 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. […] Prior to expanded newborn screening, MCADD was an underdiagnosed cause of sudden death in infants. Individuals who have been identified prior to the onset of symptoms have an excellent prognosis. […] Clinically, MCADD or another fatty acid oxidation disorder is suspected in individuals who present with lethargy, seizures, coma and hypoketotic hypoglycemia, particularly if triggered by a minor illness. MCADD can also present with acute liver disease and hepatomegaly, which can lead to a misdiagnosis of Reye syndrome. In some individuals, the only manifestation of MCADD is sudden, unexplained death often preceded by a minor illness that would not usually be fatal.
#4 MCAD deficiency – Diagnosis and treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/diagnosis-treatment/drc-20353747
MCAD deficiency is diagnosed through newborn screening followed by genetic testing. […] Many countries, including all states in the United States, screen for MCAD deficiency at birth. Using a heel prick, a few drops of your baby’s blood are taken and analyzed. If screening levels are outside the standard range, additional testing can be done. […] Genetic testing can reveal the changed gene that causes MCAD deficiency. Depending on the type of test, a sample of blood or saliva or cells from the inside of the cheek, the skin or other tissue is collected and sent to a lab to be tested. Your health care provider may also recommend testing family members for this gene. Genetic counseling can help you understand the testing process and what the results mean.
#5 MCAD deficiency – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/symptoms-causes/syc-20353745
MCAD deficiency is present from birth and is a lifelong condition. […] In the United States, all states test for MCAD deficiency at birth as part of newborn screening. […] If MCAD deficiency is diagnosed and treated early, the disorder can be well managed through diet and lifestyle. […] In the United States and many other countries, newborn screening programs test for MCAD deficiency. After your first evaluation, you may be referred to a specialist in evaluating and treating 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. […] If you inherit only one changed gene, you won’t develop MCAD deficiency. […] A child is at risk of MCAD deficiency if both parents are carriers of a gene known to cause it. […] If metabolic crisis caused by MCAD deficiency is left untreated, it can lead to: Seizures, Liver problems, Brain damage, Coma, Sudden death.
#6 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency | New York State Department of Health, Wadsworth Center
https://www.wadsworth.org/public-health-programs/newborn-screening/newborn-screening-program/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency
MCAD deficiency is inherited in an autosomal recessive pattern. […] Screening for MCAD deficiency is accomplished by measuring acylcarnitines (C6 and C8) by tandem mass spectrometry (MS/MS). […] If an elevation of C8 is identified, DNA testing is performed for a single common mutation, p.K329E. […] Diagnostic testing includes quantification of plasma acylcarnitines, urine organic acids, and urine acylglycines. Molecular genetic testing of the ACADM gene may be used for confirmation of the diagnosis.
#7 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. […] 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. […] The diagnosis of MCAD deficiency is established in a proband by confirmatory biochemical testing AND/OR by identification of biallelic pathogenic (or likely pathogenic) variants in ACADM by molecular genetic testing OR by significantly reduced medium-chain acyl-CoA dehydrogenase enzyme activity in blood or cultured skin fibroblasts.
#8 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1424/
Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. […] 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. […] Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers. […] The diagnosis of MCAD deficiency is established in a proband by confirmatory biochemical testing AND/OR by identification of biallelic pathogenic (or likely pathogenic) variants in ACADM by molecular genetic testing OR by significantly reduced medium-chain acyl-CoA dehydrogenase enzyme activity in blood or cultured skin fibroblasts.
#9 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 babys newborn screening result for medium-chain acyl-CoA dehydrogenase deficiency (MCAD) was out of the normal range, your babys doctor or the state screening program will contact you to arrange for your baby to have additional testing. It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. […] Follow-up testing will involve checking your babys urine and blood samples for harmful levels of acids and toxins. […] A specific pattern of acylcarnitines in the blood and other organic acids in the urine might indicate that your baby has MCAD. […] 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.
#10 MCAD-Deficiency with Severe Neonatal Onset, Fatal Outcome and Normal Acylcarnitine Profile
https://www.mdpi.com/2409-515X/3/3/21
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessively inherited disorder of fatty acid oxidation with a potentially fatal outcome in undiagnosed patients. […] The introduction of tandem mass spectrometry into newborn screening (NBS) has led to the inclusion of MCADD in NBS in many countries, which has resulted in a significant reduction of morbidity and mortality. […] In addition, NBS for MCADD has resulted in a significant reduction of morbidity and mortality. […] However, acylcarnitines determined from stored EDTA blood were not suggestive of MCADD. […] This case report illustrates that (a) a normal acylcarnitine profile cannot exclude MCADD; and (b) that NBS for MCADD cannot always prevent a fatal neonatal outcome.
#11 Screening for medium-chain acyl CoA dehydrogenase deficiency: current | RRN
https://www.dovepress.com/screening-for-medium-chain-acyl-coa-dehydrogenase-deficiency-current-p-peer-reviewed-fulltext-article-RRN
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder associated with fatty acid oxidation. […] Newborn metabolic screening enables the early detection of MCAD deficiency in many countries worldwide. […] Tandem mass spectrometry newborn blood spot screening for MCAD deficiency is accurate and effective, and reduces morbidity and mortality in affected children. […] The biochemical diagnosis is based on plasma acylcarnitine profile characterized by increased levels of hexanoylcarnitine (C6), octanoylcarnitine (C8), decanoyl and decenoylcarnitines (C10 and C10:1) species, and prominent among them being octanoylcarnitine (C8). […] The diagnosis can be confirmed by molecular analysis of ACADM gene, which encodes for the MCAD enzyme. […] The goal of NBS is to identify affected infants before they have an acute episode and implement simple interventions such as avoidance of fasting as the mainstay of treatment.
#12 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1424/
Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. […] Testing should include plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis, ideally collected during an acute episode of metabolic decompensation, as any of these assays can normalize when the individual is not under metabolic stress. […] Sole reliance on plasma acylcarnitine analysis can lead to a missed diagnosis. […] When NBS results and other laboratory findings suggest the diagnosis of MCAD deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. […] If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis.
#13 Medium-chain acyl-CoA dehydrogenase deficiency – Genomics Education Programme
https://www.genomicseducation.hee.nhs.uk/documents/medium-chain-acyl-coa-dehydrogenase-deficiency/
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that prevents the conversion of fats to energy via hepatic ketogenesis. This impairs the supply of energy to peripheral tissues, causing a continual reliance on glucose to provide energy. […] In MCADD, plasma acylcarnitine analysis has a characteristic abnormal pattern of increased C6 to C10 acylcarnitine species; C8 is usually especially elevated. This can be detected by tandem mass-spectrometry performed on dried blood spots, which is used as part of the newborn blood spot screening programme in England to diagnose MCADD. However, acylcarnitine analysis can also be performed on plasma if investigations are required in older patients. […] Urine organic acid and urine acylglycine analyses are also used in diagnosis. In MCADD, these tests demonstrate elevated C6 to C10 dicarboxylic acids, elevated hexanoylglycine and elevated suberylglycine.
#14 Diagnosis and Discussion – Case 1076 | Department of Pathology
https://www.path.pitt.edu/diagnosis-and-discussion-case-1076
Urine organic acid and urine acyl glycine analysis can also provide supportive evidence of MCADD deficiency. Increased levels of hexanoylglycine (C6), octanoylglycine (C8), decanoylglycine (C10) along with low ketone are usual pattern on urine organic acid analysis. Our case showed a significantly elevated level of hexanoylglycine only with a low ketone level. Blood carnitine level can be low, because excess acylcarnitine binds with free carnitine and gets excreted; however, it was normal in our case.
#15 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1424/
Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. […] Testing should include plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis, ideally collected during an acute episode of metabolic decompensation, as any of these assays can normalize when the individual is not under metabolic stress. […] Sole reliance on plasma acylcarnitine analysis can lead to a missed diagnosis. […] When NBS results and other laboratory findings suggest the diagnosis of MCAD deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. […] If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis.
#16
https://gmdi.org/Resources/Nutrition-Guidelines/MCAD
Medium chain acyl CoA dehydrogenase deficiency (MCADD) is caused by mutations in the medium chain acyl CoA dehydrogenase (MCAD) gene leading to insufficient enzymatic activity to allow complete mitochondrial beta oxidation of fatty acids. […] It is possible to detect MCADD through tandem mass spectrometry newborn screening of blood spots. Although the definition of a positive screen is established by each state’s program, the minimum requirement is that the medium chain (C8 and possibly also C6, C10 and C10:1) acyl carnitines be elevated and the C8 acylcarnitine be greater than the C10. […] For any positive screen, further confirmatory testing is necessary before a diagnosis of MCADD can be made. This confirmatory testing usually includes a plasma acylcarnitine profile, urine organic acids, DNA mutation analysis and plasma carnitine. A repeat newborn screen, in and of itself, is not sufficient for confirmatory testing for MCADD.
#17 MCADZ – Overview: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency Full Gene Analysis, Varies
https://www.mayocliniclabs.com/test-catalog/overview/35478
The MCAD gene (ACADM) maps to 1p31 and has 12 exons, spanning 44 kb of DNA. […] A small percentage of individuals who are carriers or have a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency may have a variant that is not identified by this method (eg, large genomic deletions, promoter variants). […] Test results should be interpreted in the context of clinical findings, family history, and other laboratory data.
#18 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1424/
Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. […] Testing should include plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis, ideally collected during an acute episode of metabolic decompensation, as any of these assays can normalize when the individual is not under metabolic stress. […] Sole reliance on plasma acylcarnitine analysis can lead to a missed diagnosis. […] When NBS results and other laboratory findings suggest the diagnosis of MCAD deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. […] If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis.
#19 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 Î²-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 Î²-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). […] Newborn screening by tandem mass spectrometry of the heel stick dried blood spot identifies elevated levels of octanoylcarnitine (C8 acylcarnitine), usually accompanied by decanoyl (C10), hexanoyl (C6) and decenoyl (C10:1) carnitine esters. […] 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. […] Because the diagnosis and therapy of MCAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist.
#20 Medium Chain Acyl-CoA Dehydrogenase (MCAD) Gene Sequencing | Test Detail | Quest Diagnostics
https://testdirectory.questdiagnostics.com/test/test-detail/91284/medium-chain-acyl-coa-dehydrogenase-mcad-gene-sequencing?p=r&cc=MASTER
Medium Chain Acyl-CoA Dehydrogenase (MCAD) Gene Sequencing – Based upon newborn screening results, approximately 50% of affected individuals are homozygous for the common variant, p.Lys304Glu (K304E, c.985A>G)K304E, and approximately 40% are compound heterozygous for p.Lys304Glu (K304E, c.985A>G)K304E and one of the more than 40 other, previously described, rare alleles. Nucleotide sequence analysis can be used to detect these rare alleles and can also be used to detect novel, deleterious variants. Therefore, nucleotide sequence analysis can be used for confirmatory diagnosis detection. In addition, it can be used for carrier testing and prenatal diagnosis. […] This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by FDA. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes. […] Alternative Name(s): Fatty Acid Oxidation Defect, MCAD Deficiency, Mitochondrial B Oxidation Defect, MCAD Gene Sequencing.
#21 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency: ACADM Sequencing – Greenwood Genetic Center
https://ggc.org/test-finder-item/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency-acadm-sequencing
ACADM sequencing is a molecular test used to identify variants in the gene associated with Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. […] Molecular testing is useful to confirm the diagnosis and to identify the disease causing mutations within a family to allow for carrier testing and prenatal diagnosis. […] Sequencing of the ACADM gene should detect 95-100% of mutations in affected individuals.
#22 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK1424/
Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. […] 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. […] The diagnosis of MCAD deficiency is established in a proband by confirmatory biochemical testing AND/OR by identification of biallelic pathogenic (or likely pathogenic) variants in ACADM by molecular genetic testing OR by significantly reduced medium-chain acyl-CoA dehydrogenase enzyme activity in blood or cultured skin fibroblasts.
#23
https://link.springer.com/article/10.1007/s10545-007-0492-3
The outcome was determined of population-wide neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (MS/MS) in The Netherlands, between October 2003 and September 2005. […] In newborns with blood octanoylcarnitine (C8:0) concentrations 0.3 mol/L, clinical and laboratory follow-up was initiated, including MCAD enzymatic measurements which played a decisive role. […] True-positives (n=14) were identified based upon MCAD enzyme activity 50%, measured with hexanoyl-CoA as substrate. […] Measurement of MCAD activity using phenylpropionyl-CoA as a substrate further discriminated between newborns with MCAD deficiency and so-called mild MCAD deficiency. […] To summarize, neonatal screening for MCAD deficiency in the northern part of The Netherlands resulted in the predicted number of affected newborns. Measurement of MCAD activity in leukocytes or lymphocytes using phenylpropionyl-CoA as a substrate can be regarded as the gold standard to diagnose MCAD deficiency upon initial positive screening test results.
#24
https://link.springer.com/article/10.1007/s10545-007-0492-3
The outcome was determined of population-wide neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (MS/MS) in The Netherlands, between October 2003 and September 2005. […] In newborns with blood octanoylcarnitine (C8:0) concentrations 0.3 mol/L, clinical and laboratory follow-up was initiated, including MCAD enzymatic measurements which played a decisive role. […] True-positives (n=14) were identified based upon MCAD enzyme activity 50%, measured with hexanoyl-CoA as substrate. […] Measurement of MCAD activity using phenylpropionyl-CoA as a substrate further discriminated between newborns with MCAD deficiency and so-called mild MCAD deficiency. […] To summarize, neonatal screening for MCAD deficiency in the northern part of The Netherlands resulted in the predicted number of affected newborns. Measurement of MCAD activity in leukocytes or lymphocytes using phenylpropionyl-CoA as a substrate can be regarded as the gold standard to diagnose MCAD deficiency upon initial positive screening test results.
#25 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviewsÂ® – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1424/
Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. […] 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. […] Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers. […] The diagnosis of MCAD deficiency is established in a proband by confirmatory biochemical testing AND/OR by identification of biallelic pathogenic (or likely pathogenic) variants in ACADM by molecular genetic testing OR by significantly reduced medium-chain acyl-CoA dehydrogenase enzyme activity in blood or cultured skin fibroblasts.
#26 MCADD (medium chain acyl-CoA dehydrogenase deficiency) – newbornscreening.info
https://www.newbornscreening.info/mcadd-medium-chain-acyl-coa-dehydrogenase-deficiency/
MCADD occurs when an enzyme called medium chain acyl-CoA dehydrogenase (MCAD), is either missing or not working properly. This enzymes job is to break down certain fats in the food we eat into energy. It also breaks down fat already stored in the body. […] Genetic testing for MCADD can be done on a blood sample. Genetic testing, also called DNA testing, looks for changes in both copies of the ACADM genes. In many children with MCADD, both gene changes can be found. However, in other children, only one or neither of the two gene changes can be found, even though we know they are present. […] MCADD can also be confirmed either by a blood test called an acylcarnitine profile or an enzyme test on a skin sample. Talk to your doctor or your genetic counselor if you have questions about testing for MCADD.
#27 MCAD Deficiency Diagnosis and Treatment
https://informnetwork.org/mcad-deficiency/
If there is a family history of this deficiency or if the parents are known to carry genetic changes that cause the MCAD deficiency, prenatal diagnosis can be done during pregnancy using cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). If an ill child has not been screened for MCAD as a newborn, diagnostic testing may involve analysis of specific fats called acylcarnitine, the levels of free carnitine in the blood, and the medium carbon-chain-length fats in the urine.
#28
https://www.gov.uk/government/publications/mcadd-suspected-description-in-brief/mcadd-detailed-information
If your baby does have MCADD, the metabolic team will explain the condition in detail and answer any questions you might have. […] With prompt use of the emergency regimen and avoidance of prolonged fasting, the outcome is usually very good and most children will avoid any long-term health problems. […] Children from the same parents have a 1 in 4 chance of having MCADD. Your other children might be at risk of MCADD even if they have never shown any symptoms. It is therefore very important to get them tested if they have not been previously screened for MCADD. Your metabolic team will be able to arrange this testing. […] A new baby from the same parents will also have a 1 in 4 chance of having MCADD. When you find out that you are pregnant, you should tell your midwife and GP that there is a family history of MCADD. You should also inform your metabolic team early in the pregnancy.
#29 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
https://www.wadsworth.org/node/2638/printable/print
MCAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two ACADM genes. In people with MCAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MCAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%. […] Diagnostic testing includes quantification of plasma acylcarnitines, urine organic acids, and urine acylglycines. Molecular genetic testing of the ACADM gene may be used for confirmation of the diagnosis.
#30 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. […] Prior to expanded newborn screening, MCADD was an underdiagnosed cause of sudden death in infants. Individuals who have been identified prior to the onset of symptoms have an excellent prognosis. […] Clinically, MCADD or another fatty acid oxidation disorder is suspected in individuals who present with lethargy, seizures, coma and hypoketotic hypoglycemia, particularly if triggered by a minor illness. MCADD can also present with acute liver disease and hepatomegaly, which can lead to a misdiagnosis of Reye syndrome. In some individuals, the only manifestation of MCADD is sudden, unexplained death often preceded by a minor illness that would not usually be fatal.
#31 Screening for medium-chain acyl CoA dehydrogenase deficiency: current | RRN
https://www.dovepress.com/screening-for-medium-chain-acyl-coa-dehydrogenase-deficiency-current-p-peer-reviewed-fulltext-article-RRN
The availability of simple intervention such as avoidance of fasting makes MCAD deficiency an excellent candidate for early detection by NBS programs. […] Despite the issues during the neonatal period and childhood, future challenges are emerging with respect to the anticipation of serious episodes and deterioration of outcome in screened individuals entering adolescence and adulthood. […] MCAD deficiency should always be included in the differential diagnosis for neonatal hypoglycemia, particularly in infants with severe metabolic acidosis, liver dysfunction, and hyperammonemia.
#32 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. […] It would be prudent to evaluate any infant or child with a repetitive history of postinfectious decompensation for fatty acid oxidative disorders. […] Hepatomegaly is a cardinal feature of MCAD, as well as of other fatty acid oxidative disorders. […] 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.
#33 MCAD Deficiency: Symptoms, Treatment, Life Expectancy
https://www.verywellhealth.com/mcad-overview-4175022
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. […] Today, testing for MCAD deficiency is part of standard newborn screenings in the United States. […] The U.S. Department of Health and Human Services recommends MCAD deficiency testing as part of routine newborn screening. The primary benefit of screening is that an infant can be diagnosed before symptoms develop. […] If the screening indicates MCAD deficiency, additional testing can provide more information. […] Other tests used to confirm a diagnosis of MCAD deficiency include: genetic testing to look for specific ACADM gene mutations, blood tests to measure glucose, ammonia, liver enzymes, and other levels, and urine tests to rule out other conditions that cause low blood sugar. […] If a person doesn’t experience symptoms until adulthood, MCAD deficiency may not be at the top of the list of medical causes. It may only be after all other causes are excluded that MCAD deficiency is considered and genetic testing is performed.
#34 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. […] It would be prudent to evaluate any infant or child with a repetitive history of postinfectious decompensation for fatty acid oxidative disorders. […] Hepatomegaly is a cardinal feature of MCAD, as well as of other fatty acid oxidative disorders. […] 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.
#35 Medium-chain acyl-coenzyme A dehydrogenase deficiency – Wikipedia
https://en.wikipedia.org/wiki/Medium-chain_acyl-coenzyme_A_dehydrogenase_deficiency
In areas with expanded newborn screening using tandem mass spectrometry (MS/MS), MCADD is usually detected shortly after birth, by the analysis of blood spots collected on filter paper. […] After biochemical suspicion of MCADD, molecular genetic analysis of ACADM can be used to confirm the diagnosis. […] In cases of sudden death where the preceding illness would not usually have been fatal, MCADD is often suspected. The autopsy will often show fatty deposits in the liver. […] MCADD and other fatty acid oxidation disorders have been recognized in recent years as undiagnosed causes of sudden infant death syndrome.
#36 MCADZ – Overview: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency Full Gene Analysis, Varies
https://www.mayocliniclabs.com/test-catalog/overview/35478
Confirmation of diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (as a follow-up to biochemical analyses) […] Screening of at-risk carriers of MCAD deficiency when an affected relative has not had molecular testing […] Diagnosis of MCAD deficiency in autopsy specimens […] Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive inherited defect in the mitochondrial oxidation of fatty acids. […] Review of clinical features and biochemical analysis via plasma acylcarnitines (ACRN / Acylcarnitines, Quantitative, Plasma), fatty acid profile (FAO / Fatty Acid Oxidation Probe Assay, Fibroblast Culture), urine organic acids (OAU / Organic Acids Screen, Random, Urine), and urine acylglycines (ACYLG / Acylglycines, Quantitative, Urine) are always recommended as the initial evaluation for MCAD.
#37 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency Full Gene Analysis, Varies – Mayo Clinic Laboratories | Pediatric Catalog
https://pediatric.testcatalog.org/show/MCADZ
Confirmation of diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (as a follow-up to biochemical analyses) […] Diagnosis of MCAD deficiency in autopsy specimens […] Review of clinical features and biochemical analysis via plasma acylcarnitines (ACRN / Acylcarnitines, Quantitative, Plasma), fatty acid profile (FAO / Fatty Acid Oxidation Probe Assay, Fibroblast Culture), urine organic acids (OAU / Organic Acids Screen, Random, Urine), and urine acylglycines (ACYLG / Acylglycines, Quantitative, Urine) are always recommended as the initial evaluation for MCAD. […] A small percentage of individuals who are carriers or have a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency may have a variant that is not identified by this method (eg, large genomic deletions, promoter variants). The absence of a variant, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MCAD. […] Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
#38 MCAD deficiency | Altru Health System
https://www.altru.org/health-library/conditions/mcad-deficiency
MCAD deficiency is diagnosed through newborn screening followed by genetic testing. […] Many countries, including all states in the United States, screen for MCAD deficiency at birth. Using a heel prick, a few drops of your baby’s blood are taken and analyzed. If screening levels are outside the standard range, additional testing can be done. […] Genetic testing can reveal the changed gene that causes MCAD deficiency. Depending on the type of test, a sample of blood or saliva or cells from the inside of the cheek, the skin or other tissue is collected and sent to a lab to be tested. Your health care provider may also recommend testing family members for this gene. Genetic counseling can help you understand the testing process and what the results mean. […] A metabolic specialist, and often a registered dietitian, are usually included in your diagnosis and treatment. Lab tests can be done to help identify problems with your metabolism the processes your body uses to produce energy. Results can help treat or prevent complications.
#39 MCAD Deficiency
https://my.clevelandclinic.org/health/diseases/21973-mcad-deficiency
Treatment for MCAD deficiency focuses on meeting nutritional requirements for your child’s body and reducing long periods of time between meals, which may trigger symptoms of the condition. […] Dietary requirements for MCAD deficiency include scheduling meals more frequently throughout the day. […] There’s no way to prevent MCAD deficiency because it’s a genetic condition that passes from parents to children. […] Early diagnosis and treatment of MCAD deficiency significantly improve your baby’s quality of life, and offer a good prognosis. […] The majority of people diagnosed with MCAD deficiency live normal and healthy lives. […] The best way to take care of your child with MCAD deficiency is to minimize long periods when they go without eating by scheduling meals closer together and more frequently.
#40
https://gmdi.org/Resources/Nutrition-Guidelines/MCAD
The primary intervention goal for MCADD individuals is to avoid situations in which the cells must rely solely on stored fats for energy (i.e., avoid fasting). […] Emergency care must be initiated if symptoms are present. Caregivers should not rely solely on the blood glucose levels to initiate care. […] Discharge from the medical facility should not occur until the MCADD individual is able to consume sufficient oral intake to maintain normaglycemia.
#41 Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-102
Our study points to that the ACADM genotype most commonly seen in MCADD might be of particular relevance in refining a follow-up protocol, since plasma carnitine levels in patients homozygous for c.985AG tend to be lower and supplementation is required to maintain carnitine within the normal range. […] By demonstrating an association between carnitine levels and homozygosity for the c.985AG mutation, the current study also contributes to our understanding of the relationship between genotype/biochemical markers and phenotype in MCADD.
#42 MCAD Deficiency
https://my.clevelandclinic.org/health/diseases/21973-mcad-deficiency
Treatment for MCAD deficiency focuses on meeting nutritional requirements for your child’s body and reducing long periods of time between meals, which may trigger symptoms of the condition. […] Dietary requirements for MCAD deficiency include scheduling meals more frequently throughout the day. […] There’s no way to prevent MCAD deficiency because it’s a genetic condition that passes from parents to children. […] Early diagnosis and treatment of MCAD deficiency significantly improve your baby’s quality of life, and offer a good prognosis. […] The majority of people diagnosed with MCAD deficiency live normal and healthy lives. […] The best way to take care of your child with MCAD deficiency is to minimize long periods when they go without eating by scheduling meals closer together and more frequently.
#43 Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-102
This study contributes to a better understanding of the relationship between genotype and phenotype in newborn patients with MCADD detected through screening which could be useful in improving follow-up strategies and clinical outcome. […] The main goal of the present study was to evaluate any relationships between biochemical findings at diagnosis, genotype, free carnitine (C0) levels during follow-up, and clinical outcome, in patients with MCADD detected by NBS. […] Diagnosis was confirmed by mutation analysis of the ACADM gene. […] The average follow-up period was 3 years and 7 months (range 2 months-10 years 7 months). […] Following carnitine treatment, the average C0 levels were significantly lower in patients homozygous for the common mutation than in patients with other mutations (14 mol/L vs 22 mol/L, p0.001).
#44 The difference between observed and expected prevalence of MCAD deficiency in The Netherlands: a genetic epidemiological study | European Journal of Human Genetics
https://www.nature.com/articles/5201428
Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency is assumed to be the most common inherited disorder of mitochondrial fatty acid oxidation. […] The observed prevalence of MCAD deficiency in The Netherlands was 1/27400 (95% confidence interval (CI) 1/23000-1/33900), significantly different from the expected prevalence of 1/12100 (95% CI 1/8450-1/18500). […] From the patients in this cohort, it can be observed that underdiagnosis contributes to a larger extent to the difference between the expected and observed prevalences of MCAD deficiency in our country, than reduced penetrance. […] Previous studies have shown that the observed prevalence of patients with MCAD deficiency may be lower than the prevalence one must expect on the basis of observed carrier frequencies. […] Theoretically, underreporting or underdiagnosis, reduced penetrance with a lifelong clinical tolerance for the enzyme disorder, prenatal loss of affected offspring or abnormal segregation of alleles in heterozygous parents could explain this discrepancy.
#45 MCAD-Deficiency with Severe Neonatal Onset, Fatal Outcome and Normal Acylcarnitine Profile
https://www.mdpi.com/2409-515X/3/3/21
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessively inherited disorder of fatty acid oxidation with a potentially fatal outcome in undiagnosed patients. […] The introduction of tandem mass spectrometry into newborn screening (NBS) has led to the inclusion of MCADD in NBS in many countries, which has resulted in a significant reduction of morbidity and mortality. […] In addition, NBS for MCADD has resulted in a significant reduction of morbidity and mortality. […] However, acylcarnitines determined from stored EDTA blood were not suggestive of MCADD. […] This case report illustrates that (a) a normal acylcarnitine profile cannot exclude MCADD; and (b) that NBS for MCADD cannot always prevent a fatal neonatal outcome.
#46 The difference between observed and expected prevalence of MCAD deficiency in The Netherlands: a genetic epidemiological study | European Journal of Human Genetics
https://www.nature.com/articles/5201428
Knowledge about the prevalence of a disorder is of great importance for decision-making about population screening. […] In this study only directly or indirectly (through family members) diagnosed cases could be included, so no direct information about the cases that remain undiagnosed outside these families was available. […] The observed prevalence of MCAD deficiency in The Netherlands was 1/27400 (95% CI 1/23000-1/33900), significantly lower than expected, and the 985GA allele frequency was 94%, as was previously used in calculating the estimated prevalence. […] In conclusion, the results of this study show that in The Netherlands the diagnosed number of patients with MCAD deficiency is significantly lower than the expected number. This discrepancy is mainly explained by misdiagnosis but reduced penetrance is an important factor also.