Late onset lipid storage myopathy due to multiple acyl CoA dehydrogenase deficiency triggered by valproate

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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Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations

BMC Neurology ◽

10.1186/s12883-019-1562-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Wei Chen ◽

Youqiao Zhang ◽

Yifeng Ni ◽

Shaoyu Cai ◽

Xin Zheng ◽

...

Keyword(s):

Dehydrogenase Deficiency ◽

Late Onset ◽

Southern China ◽

Case Reports ◽

Lipid Storage ◽

Chinese Family ◽

Homozygous Mutation ◽

Muscle Enzymes ◽

Lipid Storage Myopathy ◽

Southern Min

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation. Case presentation Both siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries. Conclusions Mutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

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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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