029 Multiple-acyl-coa dehydrogenase deficiency (MADD): a rare but treatable genetic metabolic myopathy

IntroductionMultiple-acyl-CoA dehydrogenase deficiency or MADD is a rare autosomal recessive disorder caused by deficiency of electron transfer flavoprotein. Late onset form of MADD typically present with slowly progressive proximal weakness, myalgia, lethargy, vomiting, hypoglycaemia and metabolic acidosis. This condition is highly variable in age and symptoms at onset. The mean delay between onset of symptoms and diagnosis was 3.9 years. Confirmation of the diagnosis requires relatively complicated tests including muscle biopsy, Acylcarnitine profiling, urinary organic acid analysis and molecular gene testing. MADD responds dramatically to riboflavin supplementation and dietary treatment i.e. high carbohydrate, low fat and low protein diet. We report of a case of Multiple-Acyl-CoA Dehydrogenase Deficiency (MADD) and a review of the literature.CaseA 22 year old female presented with 3 year history of slowly progressive muscle weakness, fatigue and dyspnea on minimal exertion. Clinical examination revealed profound neck extension weakness (‘dropped head syndrome’), proximal muscle weakness (winged scapula and positive Gower’s sign), mild dysphagia and dysarthria. There was no obvious facial weakness, ptosis or ophthalmoplegia. Muscle biopsy showed prominent lipid and generalised hypotrophy of type I fibres. The diagnosis of MADD was suspected on the basis of clinical presentation. The patient was commenced on riboflavin, carnitine supplementation and low protein, low fat diet. Her symptoms improved significantly over 2 months (improvement in muscle strength and respiratory function, FVC improved from 42% to 89%). Acylcarnitine and amino acid screen results came back later showing elevated levels of C6, C8, C10 and C12 in keeping with the diagnosis of MADD.ConclusionMultiple-acyl-CoA dehydrogenase deficiency is a rare genetic metabolic myopathy. It is under-recognised and diagnosis of the adult onset form is often challenging. The majority of patients respond well to riboflavin and dietary modifications with excellent clinical outcome.References. Sharp LJ, Haller RG. Metabolic and mitochondrial myopathies. Neurol Clin2014Aug;32:777–99.. Grunert SC. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme: A dehydrogenase deficiency. Orphanet J Rare Dis2014Jul 22;9:117.. Angelini C. Spectrum of metabolic myopathies. Biochem Biophys Acta2015Apr;1852(4):615–21.. Yee WC. Two eminently treatable genetic metabolic myopathies. Neurol India2008Jul–Sep;56(3):333–8.

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Late-onset multiple acyl-CoA dehydrogenase deficiency mimicking myositis in an elderly patient: a case report

BMC Neurology ◽

10.1186/s12883-020-02010-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Yiming Zheng ◽

Yawen Zhao ◽

Wei Zhang ◽

Zhaoxia Wang ◽

Yun Yuan

Keyword(s):

Elderly Patient ◽

Muscle Weakness ◽

Dehydrogenase Deficiency ◽

Late Onset ◽

Lipid Storage ◽

Exercise Intolerance ◽

Lipid Storage Myopathy ◽

Case Presentation ◽

Acylcarnitine Profile ◽

Progressive Weakness

Abstract Background Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare and treatable inherited lipid storage myopathy. Here, we report an elderly patient with MADD mimicking myositis. Case presentation An 80-year-old woman had progressive weakness in her limbs, exercise intolerance, and no muscle pain for 3 months. The patient’s serum creatine kinase level was slightly elevated. The initial diagnosis was myositis. However, muscle biopsy showed many cytoplasmic vacuoles stained with oil red O, indicating the presence of lipid storage myopathy. The plasma acylcarnitine profile showed increased medium-chain and long-chain acylcarnitine species, consistent with the diagnosis of MADD. Riboflavin treatment dramatically improved muscle weakness. Conclusions MADD should be considered when evaluating elderly patients with subacute muscle weakness.

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Carnitine Palmitoyltransferase II deficiency, a Rare Cause of Rhabdomyolysis: A Case Report

Case Reports in Clinical Practice ◽

10.18502/crcp.v4i3.1715 ◽

2019 ◽

Author(s):

Parisa Farshchi ◽

Sahar Karimpour Reyhan ◽

Mahsa Abbaszadeh ◽

Shadi Shiva

Keyword(s):

Acute Kidney Injury ◽

Muscle Weakness ◽

Muscle Biopsy ◽

Kidney Injury ◽

Carnitine Palmitoyltransferase ◽

Metabolic Myopathy ◽

Dark Urine ◽

Recurrent Rhabdomyolysis ◽

Carnitine Palmitoyltransferase Ii ◽

Cpt Ii Deficiency

Introduction: Muscle weakness and rhabdomyolysis have a wide range of differential diagnosis. In many situations, they are induced by seizure, trauma, drugs, and toxins. They could also be due to inflammatory or metabolic myopathies. Identifying the exact cause is crucial and sometimes challenging. Case Presentation: A 23-year-old man was admitted to our hospital with muscle weakness, fatigue, dyspnea, and dark urine, all preceded by flu-like symptoms, myalgia, and fever. Due to reduced muscle strength, dark urine, elevated serum creatine kinase, and serum creatinine, he was diagnosed with rhabdomyolysis and acute kidney injury. Muscle biopsy was performed three years before for the patient, due to a history of similar episodes and exercise intolerance. Because of recurrent episodes of muscle weakness and rhabdomyolysis along with the negative muscle biopsy for inflammatory myopathies, we suspected metabolic myopathy as a cause. Therefore, metabolic screening was performed for the patient, and he was diagnosed with metabolic myopathy known as Carnitine Palmitoyltransferase II (CPT II) deficiency. Conclusion: In patients with recurrent rhabdomyolysis, we should consider inherited myopathies, especially carnitine palmitoyltransferase II deficiency and glycogen storage disease type V (McArdle disease) as likely causes. CPT II deficiency is regarded as a preventable cause of recurrent rhabdomyolysis. Therefore, by early diagnosis of this disorder we could prevent recurrent episodes of rhabdomyolysis and ultimately avoid life-threatening complications like acute kidney injury

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The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642558 ◽

1988 ◽

Vol 59 (01) ◽

pp. 018-022 ◽

Cited By ~ 139

Author(s):

C L Gladson ◽

I Scharrer ◽

V Hach ◽

K H Beck ◽

J H Griffin

Keyword(s):

Venous Thrombosis ◽

Protein C ◽

Antithrombin Iii ◽

Young Patients ◽

Protein S ◽

Type I ◽

Protein S Deficiency ◽

Protein C Deficiency ◽

Low Protein ◽

S Deficiency

SummaryThe frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

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AN ATYPICAL CASE OF LATE ONSET TYPE I INTERFERONOPATHY

10.26226/morressier.594a7d46d462b8028d8937fd ◽

2017 ◽

Author(s):

Kasinskaite Simona

Keyword(s):

Late Onset ◽

Type I ◽

Atypical Case ◽

Onset Type

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Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0694 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Yiming Lin ◽

Weifeng Zhang ◽

Zhixu Chen ◽

Chunmei Lin ◽

Weihua Lin ◽

...

Keyword(s):

Mass Spectrometry ◽

Genetic Analysis ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Late Onset ◽

False Negative ◽

Tandem Mass ◽

Lipid Storage Myopathy ◽

Molecular Features

Abstract Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

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CHIP control degradation of mutant ETF : QO through ubiquitylation in late‐onset multiple acyl‐CoA dehydrogenase deficiency

Journal of Inherited Metabolic Disease ◽

10.1002/jimd.12361 ◽

2021 ◽

Author(s):

Xin‐Yi Liu ◽

Xue‐Jiao Chen ◽

Miao Zhao ◽

Zhi‐qiang Wang ◽

Hai‐zhu Chen ◽

...

Keyword(s):

Dehydrogenase Deficiency ◽

Late Onset

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Late-onset multiple acyl-CoA dehydrogenase deficiency with breast cancer

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-020-00121-0 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Keechilat Pavithran ◽

Divya Pachat ◽

Dehannathparambil Kottarathil Vijaykumar

Keyword(s):

Dehydrogenase Deficiency ◽

Late Onset ◽

Acid Oxidation ◽

Successful Management ◽

Carcinoma Of The Breast ◽

Metabolic Complications ◽

Case Presentation ◽

Neonatal Onset ◽

Gene Mutation Analysis ◽

Rare Metabolic Disorder

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MAAD) is a rare metabolic disorder resulting from an abnormality in fatty acid oxidation. There are three types of presentations: neonatal onset with or without congenital anomalies and the late-onset type. There is much clinical heterogeneity in the presentation of late-onset variants; hence, the diagnosis is often delayed or missed. Case presentation Here, we report the successful management of a 41-year-old female with late-onset MAAD due to mutation in the ETFDH gene who presented with carcinoma of the breast. Chemotherapy was challenging because there were no previous reports regarding the treatment of such cases. Conclusion The diagnosis was made based on metabolic workup and gene mutation analysis. Unplanned surgery and chemotherapy can be fatal in these patients due to metabolic complications. With proper precautions and monitoring, the patient tolerated surgery and chemotherapy without any complications.

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