Diagnosis, Treatment, and Long-Term Outcomes of Late-Onset (Type III) Multiple Acyl-CoA Dehydrogenase Deficiency

Pollard, Laura; Williams, Nolan; Espinoza, Lesby; Wood, Tim; Spector, Elaine; Schroer, Richard J.; Holden, Kenton R.

doi:10.1177/0883073809351984

Cited by 26 publications

(16 citation statements)

References 15 publications

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“…Making a biochemical diagnosis of late-onset MADD may be challenging in both symptomatic and asymptomatic individuals [[31]]. Most patients display a typical pattern of organic acids in urine and acylcarnitines in dried blood/plasma at least during metabolic decompensations.…”

Section: Discussionmentioning

confidence: 99%

“…Most patients display a typical pattern of organic acids in urine and acylcarnitines in dried blood/plasma at least during metabolic decompensations. However, organic acid and acylcarnitine results may be unremarkable especially during metabolically stable conditions and in some cases even during catabolism [[7],[9],[13],[19],[31]-[36]]. Others show only selected abnormal metabolites, but not a full diagnostic pattern.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

154

156

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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases.MethodsAll 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment.ResultsMean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. Diagnosis may be difficult as a relevant number of patients do not display typical biochemical patterns of urine organic acids and blood acylcarnitines during times of wellbeing. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions. Almost all patients with late-onset MADD (98%) are clearly responsive to riboflavin.ConclusionsLate-onset MADD is probably an underdiagnosed disease and should be considered in all patients with acute or chronic muscular symptoms or acute metabolic decompensation with hypoglycemia, acidosis, encephalopathy and hepatopathy. This may not only prevent patients from invasive diagnostic procedures such as muscle biopsies, but also help to avoid fatal metabolic decompensations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

154

156

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“…Our study indicates that this characteristic AC profile can be applied to diagnose MADD due to ETFDH mutations in adults, even during asymptomatic phases of the disease. However, some late‐onset MADD patients may show normal AC profile during asymptomatic period (16). Thus, MADD due to ETFA or ETFB mutations cannot be excluded for the patients without ETFDH mutation (patients 8 and 9), even though they had only mild change in AC profile.…”

Section: Discussionmentioning

confidence: 99%

High frequency of ETFDH c.250G>A mutation in Taiwanese patients with late‐onset lipid storage myopathy

et al. 2010

Clinical Genetics

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Lipid storage myopathies (LSMs) are characterized pathologically by the accumulation of lipid droplets in muscle fibers due to impaired cellular lipid metabolism. The purpose of this study was to determine etiologies and genetic mutations associated with LSMs in ethnic Han Taiwanese. The usefulness of the blood acylcarnitine (AC) profile for diagnosing LSMs in adult patients was also investigated. Nine patients were diagnosed with late-onset LSMs following a review of muscle biopsies and medical records and were recruited retrospectively. Genetic studies were performed to detect mutations in the SLC22A5 for primary carnitine deficiency, PNPLA2 for neutral lipid storage disease with myopathy, ABHD5 for neutral lipid storage disease with ichthyosis, ETFDH for multiple acyl-CoA dehydrogenation deficiency (MADD), and CPT2 for carnitine palmitoyltransferase II deficiency. Blood AC levels were measured by tandem mass spectrometry. The mutation c.250G>A in ETFDH was detected in seven (78%) patients, six of whom were homozygous for the variant. Patients with ETFDH mutations had elevated blood levels of ACs ranging from C8 to C16 species, a pattern consistent with MADD. ETFDH c.250G>A mutation is common in Taiwanese patients with late-onset LSMs. The blood AC profile is a sensitive biochemical marker for diagnosing MADD arising from ETFDH mutations in adults.

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“…There is a wide spectrum of clinical phenotypes, ranging from pre-and neonatal, rapidly fatal, forms (1) to later-onset forms manifesting from juvenile to adult age (2)(3)(4)(5). It may be severe or even fatal at any age (6,7).…”

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confidence: 99%

Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency–related leukodystrophy

et al. 2014

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Background: Multiple acyl-CoA dehydrogenase deficiency-(MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein-and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. Methods:We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. results: During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. conclusion: NaHB is a highly effective and safe treatment that needs further controlled studies.

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Diagnosis, Treatment, and Long-Term Outcomes of Late-Onset (Type III) Multiple Acyl-CoA Dehydrogenase Deficiency

Cited by 26 publications

References 15 publications

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

High frequency of ETFDH c.250G>A mutation in Taiwanese patients with late‐onset lipid storage myopathy

Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency–related leukodystrophy

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