Neurite growth could be impaired by <i>ETFDH</i> mutation but restored by mitochondrial cofactors

Liang, Wen‐Chen; Lin, Ying-Ting; Liu, Ting-Yuan; Chang, Shin-Cheng; Chen, Bai-Hsiun; Nishino, Ichizo; Jong, Yuh Jyh

doi:10.1002/mus.25501

Cited by 8 publications

(4 citation statements)

References 32 publications

(40 reference statements)

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“…In an in vitro study, neurite growth was found to be impaired based on ETFDH mutation in mouse motor neurons due to enhanced reactive oxygen species production. 23 A zebrafish model of MADD displayed increased neural cell proliferation as well as hypomyelination of sensory axons in the PNS. MBP, the most abundant myelin-associated protein, decreased in the CNS (e.g.…”

Section: Discussionmentioning

confidence: 99%

Investigation of adult‐onset multiple acyl‐CoA dehydrogenase deficiency associated with peripheral neuropathy

Huang

Duan

et al. 2020

Neuropathology

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Multiple Acyl-CoA dehydrogenase deficiency (MADD), one of the most common lipid storage myopathies (LSMs), is a heterogeneous inherited muscular disorder that is pathologically characterized by numerous lipid droplets in muscle fibers due to lipid metabolism disturbance. MADD exhibits a wide range of clinical features, including skeletal muscle weakness and multisystem dysfunctions. However, MADD, as well as other types of LSM, associated with peripheral neuropathy has rarely been reported during the past four decades. Here, we present four Chinese patients affected by MADD with peripheral neuropathy in our neuromuscular center. Clinically, these four patients showed skeletal muscle weakness and prominent paresthesia. Muscle biopsy detected characteristic myopathological patterns of LSM, such as obvious lipid droplets in muscle fibers. Sural nerve biopsy revealed a severe reduction in number of myelinated nerve fibers, which is a typical neuropathological pattern of peripheral neuropathy. Causative ETFDH mutations were found in all four cases. The skeletal muscle weakness was rapidly improved after some treatments while paresthesia showed unsatisfactory improvement. The features of previously reported patients of this specific type are also summarized in this paper. We propose that MADD with peripheral neuropathy may be a new phenotypic subtype because the pathology and reaction to riboflavin treatment are different from those of traditional MADD, although further research on the precise pathogenesis and mechanisms is needed.

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Section: Discussionmentioning

confidence: 99%

Investigation of adult‐onset multiple acyl‐CoA dehydrogenase deficiency associated with peripheral neuropathy

Huang

Duan

et al. 2020

Neuropathology

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“…The underlying mechanism of peripheral nerve involvement in some MADD patients is unclear, and a possible explanation is that an aberrant lipid metabolism, such as accumulation of acylcarnitine lipid intermediates and reduction of myelin lipid components in Schwann cells can induce demyelination and axonal degeneration. Some studies on the zebrafish model of MADD showed dysregulation of neurogenesis with increased neural cell proliferation, reduced motor axon branching, and hypomyelination but the exacted pathomechanism has not been detailed ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Challenges in Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: Clinical, Morphological, and Genetic Aspects

et al. 2022

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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers. Most MADD patients greatly benefit from riboflavin supplementation.Patients and methodsA retrospective study was conducted on patients with a diagnosis of vacuolar myopathy with lipid storage followed in our neuromuscular unit in the last 20 years. We selected 10 unrelated patients with the diagnosis of MADD according to clinical, morphological, and biochemical aspects. Clinical features, blood tests including serum acylcarnitines, EMG, and ENG were revised. Muscle biopsy was performed in all, and one individual underwent also a sural nerve biopsy. Gene sequencing of ETFA, ETFB, and ETFDH was performed as a first-tier genetic analysis followed by next-generation sequencing of an hyperCKemia gene panel in patients with undefined genotypes.ResultsClinical evaluation at onset in all our patients showed fatigue and muscle weakness; four patients showed difficulties in chewing, three patients complained of dysphagia, two patients had a dropped head, and a patient had an unexpected ataxia with numbness and dysesthesia. Laboratory blood tests revealed a variable increase in serum CK (266–6,500) and LDH levels (500–2,000). Plasma acylcarnitine profile evidenced increased levels of different chains intermediates. EMG was either normal or showed myogenic or neurogenic patterns. NCS demonstrated sensory neuropathy in two patients. Muscle biopsies showed a vacuolar myopathy with a variable increase in lipid content. Nerve biopsy evidenced an axonal degeneration with the loss of myelinated fibers. ETFDH genetic analysis identifies 14 pathogenic variants. Patients were treated with high doses of riboflavin (400 mg/die). All of them showed a rapid muscle strength improvement and normalization of abnormal values in laboratory tests. Neuropathic symptoms did not improve.ConclusionOur data confirmed that clinical features in MADD patients are extremely variable in terms of disease onset and symptoms making diagnosis difficult. Laboratory investigations, such as serum acylcarnitine profile and muscle biopsy evaluation, may strongly address to a correct diagnosis. The favorable response to riboflavin supplementation strengthens the importance of an early diagnosis of these disorders among the spectrum of metabolic myopathies.

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“…Zebrafish model with defect of ETF:QO displayed a low response to touch stimulation and a disorganized sensory axonal tract with hypomyelination [18]. Marked neurite shortening were also observed in the cells expressing the ETFDH -mutant, but the neurite shortening could be restored by mitochondrial cofactor supplementation with carnitine, riboflavin, or coenzyme Q10 [19]. Intriguingly, sensory disturbances in the two cases showed significant improvements after long-term administration of riboflavin, coenzyme Q10 and vitamin B12, which attested the efficiency of mitochondrial cofactor supplementation to the neurite growth impaired by ETFDH -mutants.…”

Section: Discussionmentioning

confidence: 99%

Acute-onset multiple acyl-CoA dehydrogenase deficiency mimicking Guillain-Barré syndrome: two cases report

Hong

Wang

et al. 2018

BMC Neurol

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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) showed great clinical heterogeneity and poses a challenge to diagnosis. Guillain-Barré syndrome (GBS) is an acute-onset autoimmune-mediated peripheral neuropathy. However, no patients of acute-onset MADD mimicking the GBS phenotype are reported previously.Case presentationTwo patients displayed acute-onset limb weakness, areflexia, and length-dependent sensory disturbances, which clinically indicate the diagnosis of GBS, but electrophysiological and cerebrospinal fluid results threw doubtful points to the initial diagnosis. The muscle biopsy showed lipid storage disorder; and compound heterozygous mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene were found in the two patients through targeted next generation sequencing, which provided the definite diagnostic evidences of late-onset MADD. Muscle weakness was quickly improved by riboflavin supplementation, but sensory disturbances required a long-term treatment.DiscussionThe present two cases have demonstrated that MADD can mimic GBS. Taking into consideration the significant differences of therapeutic regimen and prognosis, MADD should be included in the differential diagnosis of GBS.

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Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors

Abstract: Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017.

Cited by 8 publications

References 32 publications

Investigation of adult‐onset multiple acyl‐CoA dehydrogenase deficiency associated with peripheral neuropathy

Investigation of adult‐onset multiple acyl‐CoA dehydrogenase deficiency associated with peripheral neuropathy

Diagnostic Challenges in Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: Clinical, Morphological, and Genetic Aspects

Acute-onset multiple acyl-CoA dehydrogenase deficiency mimicking Guillain-Barré syndrome: two cases report

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