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  • Margaret P Adam
  • Holly H Ardinger
  • Roberta A Pagon
  • Stephanie E Wallace
  • Lora JH Bean
  • Karen Stephens
  • Anne Amemiya
  • Pankaj Prasun
PMID: 32550677




CLINICAL CHARACTERISTICS: Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI. Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy.



DIAGNOSIS/TESTING: The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine and/or by identification of biallelic pathogenic variants in , , or .


日常的な治療としては、タンパク質と脂肪の食事制限、長期絶食の回避、高用量リボフラビン(100-300mg/日)、カルニチン欠乏症の方へのカルニチン補給(50-100mg/kg/日を3回に分けて投与)、コエンザイムQサプリメント(60-240mg/日を2回に分けて投与)などがあります。その他の治療としては、発育遅延、心機能障害、感覚神経障害に対する標準治療のほか、発育不全者には胃瘻チューブを考慮した摂食療法が行われます。軽度の重症化に対する救急外来では、絶食間隔の短縮、発熱に対する解熱剤の投与、嘔吐に対する制吐剤の投与などが行われる。急性期治療としては、10%以上のブドウ糖を含む点滴液による入院、代謝状態に応じた重炭酸塩療法などが行われる。 また、絶食を避け、リボフラビン、L-カルニチン、コエンザイムQの補給を行う;重症度に応じて、脂肪とタンパク質を制限した食事療法を行う。肝不全、横紋筋融解症、脳症、昏睡などの合併症を避けるためには、ブドウ糖を含む点滴液の迅速な開始が不可欠である。緊急時の処置のためのプロトコルは、保護者、プライマリケアプロバイダー/小児科医、および教師と学校のスタッフに提供されるべきである。血漿遊離および総カルニチン、アシルカルニチンプロファイル、血清クレアチンキナーゼ(CK)、尿中有機酸、頭囲(乳児と子供の)、および各訪問時の成長と発達のマイルストーンの測定、神経心理学的テストと必要に応じて影響を受けた個人と両親/介護者のための標準化された生活の質の評価ツール、心電図と心エコー図は、MADDの重度のフォームを持つ個人のために毎年、軽度のプレゼンテーションを持つ個人のためにあまり頻繁に。ストレス要因(ワクチン接種後を含む)時の不十分なカロリー補給、長時間の絶食、脱水、高脂肪、高タンパクの食事、揮発性の麻酔薬や長鎖脂肪酸を多量に含むもの、急性代謝危機時のアリピドの静脈内投与。任意の年齢のすべてのリスクのある兄弟のテストは、早期診断とMADDの治療を可能にするために(家族性病原性変異体は、血漿アシルカルニチンプロファイル、血漿遊離および総カルニチン、尿有機酸アッセイと並行して知られている場合は、標的分子遺伝学的検査)が保証されています。: 後期発症MADDにおける低脂肪・高炭水化物食での妊娠成功例が発表されています。妊娠中にカルニチンのサプリメントを摂取することで、胎児に悪影響を及ぼすことを示唆するエビデンスはありません。リボフラビンはビタミンB群の一つであり、排泄物や尿を介して排除される可能性が高い必須栄養素と考えられており、過剰な組織吸収にはつながりません。

MANAGEMENT: Routine daily treatment includes limitation of protein and fat in the diet, avoidance of prolonged fasting, high-dose riboflavin (100-300 mg daily), carnitine supplementation (50-100 mg/kg daily in 3 divided doses) in those with carnitine deficiency, and coenzyme Q supplements (60-240 mg daily in 2 divided doses). Further treatments include feeding therapy with consideration of gastrostomy tube for those with failure to thrive, as well as standard treatment for developmental delay, cardiac dysfunction, and sensory neuropathy. Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy depending on the metabolic status. Avoidance of fasting and supplementation with riboflavin, L-carnitine, and coenzyme Q; a diet restricted in fat and protein is prescribed for some affected individuals based on the severity of the disorder. : Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment should be provided to parents and primary care providers/pediatricians, and to teachers and school staff. : Measurement of plasma free and total carnitine, acylcarnitine profile, serum creatine kinase (CK), urine organic acids, head circumference (in infants and children), and growth and developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessment tools for affected individuals and parents/caregivers as needed; EKG and echocardiogram annually for individuals with severe forms of MADD and less frequently for individuals with milder presentations. : Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids during an acute metabolic crisis. : Testing of all at-risk sibs of any age is warranted (targeted molecular genetic testing if the familial pathogenic variants are known in parallel with plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid assay) to allow for early diagnosis and treatment of MADD. : Successful pregnancy with low-fat, high-carbohydrate diet in late-onset MADD has been published. There is no evidence to suggest that taking supplemental carnitine during pregnancy leads to adverse fetal effects. Riboflavin is a B vitamin and is considered an essential nutrient that is likely eliminated through feces and urine and does not result in excessive tissue absorption.



GENETIC COUNSELING: MADD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being unaffected and a carrier, and a 25% change of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

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