Clinical and Muscle MRI Findings in Late-Onset MADD Patients

0
0
0

Clinical and Muscle Magnetic Resonance Image Findings in Patients with Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency

Introduction

Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder predominantly caused by defects in the electron transfer flavoprotein dehydrogenase (ETFDH) gene, though mutations in ETFA and ETFB genes are also implicated. This condition disrupts mitochondrial fatty acid oxidation and branched-chain amino acid metabolism, leading to a heterogeneous clinical presentation characterized by muscle weakness, exercise intolerance, metabolic acidosis, and riboflavin responsiveness. While previous studies have described proximal muscle involvement in late-onset MADD, the distal lower limb muscle magnetic resonance imaging (MRI) patterns before and after treatment remain poorly characterized. This study aims to delineate the clinical, genetic, and MRI features of 25 patients with late-onset MADD, with a focus on identifying diagnostic imaging patterns and evaluating treatment-related changes.

Clinical and Genetic Characteristics

The cohort included 25 patients (15 males, 10 females) with a median age of onset at 34 years (range: 11–64 years). Key clinical features included proximal muscle weakness (88%), exercise intolerance (64%), neck weakness (60%), myalgia (32%), and dysphagia (16%). Extramuscular manifestations included fatty liver (40%), digestive symptoms (36%), sensory disturbances (20%), and hyperhomocysteinemia (median: 76 mmol/L, range: 41–126 mmol/L). Serum creatine kinase (CK) levels were elevated (median: 773 U/L, range: 163–27,090 U/L), and blood acylcarnitine profiles revealed combined elevations of short-, medium-, and long-chain species. Urine organic acid analysis detected abnormal metabolites in 7/16 patients. Electromyography (EMG) showed myopathic patterns in 3/9 patients, while nerve conduction studies indicated axonal sensory neuropathy in 4 cases.

Genetic analysis confirmed ETFDH mutations in all patients, including 17 compound heterozygotes and 8 single heterozygotes. Twenty-nine distinct variants were identified, 21 previously reported and 8 novel (c.34G>C, c.35-2A>C, c.176-1G>T, c.265_266delCA, c.542G>A, c.740G>T, c.1468+2T>G, c.1827_1828insCAC). Pathogenicity of novel variants was assessed using ACMG criteria, with splice-site and frameshift mutations classified as pathogenic and missense variants as likely pathogenic. No mutations were found in ETFA, ETFB, FLAD1, or SLC25A32.

Muscle MRI Findings

Pre-Treatment Imaging

Muscle MRI of the thigh and leg in all 25 patients revealed a distinct pattern of edema-like changes (STIR hyperintensity) and fat infiltration (T1 hyperintensity) with selective muscle involvement:

  1. Leg Muscles

    • Soleus (SO): Edema-like changes (median score: 3.0) and fat infiltration (median score: 2.0) were most severe, followed by the tibialis posterior (TP; edema: 2.0, fat: 1.0) and tibialis anterior (TA; edema: 0, fat: 0).
    • Gastrocnemius (GA): Notably spared, with no edema or fat infiltration (scores: 0).
    • Other Muscles: Peroneus longus/brevis (PLB), flexor digitorum longus (FDL), and extensor hallucis longus (EHL) showed minimal involvement.

  2. Thigh Muscles

    • Biceps Femoris Longus (BFL): Highest edema (median score: 2.0) and fat infiltration (median score: 1.0).
    • Semimembranosus (SM) and Adductor Magnus (AM): Moderate edema (score: 2.0) and fat infiltration (score: 1.0).
    • Semitendinosus (ST): Completely spared (scores: 0).
    • Quadriceps Femoris (QF), Adductor Longus (AL), Sartorius (SA), Gracilis (GR): Minimal or no involvement.

Paraspinal muscles exhibited fat infiltration in cervical (6/6 patients) and lumbar regions (5/6 patients). Edema-like changes correlated strongly with fat infiltration in the SO (Spearman’s ρ = 0.896, P < 0.001) and BFL (ρ = 0.774, P < 0.001).

Diagnostic MRI Patterns

Two imaging signs were identified as highly specific for late-onset MADD:

  1. “SO+/GA–” Sign: Edema and fat infiltration in the soleus with sparing of the gastrocnemius.
  2. “BFL+/ST–” Sign: Involvement of the biceps femoris longus with sparing of the semitendinosus.

When combined, these signs demonstrated a sensitivity of 80.0% and specificity of 83.5% for distinguishing MADD from other myopathies (e.g., dystrophinopathies, mitochondrial myopathies). Logistic regression confirmed their diagnostic independence from age, gender, disease duration, and CK levels (P < 0.01).

Post-Treatment Imaging

Eight patients underwent follow-up MRI after riboflavin treatment (median duration: 1 month). Edema-like changes in the SO and BFL resolved completely within 1 month, correlating with clinical improvement in muscle strength and exercise tolerance. Fat infiltration showed no significant reduction at 1 month but resolved entirely after 1 year of treatment.

Discussion

Clinical and Genetic Insights

This study expands the phenotypic spectrum of late-onset MADD, highlighting hyperhomocysteinemia as a novel metabolic feature. The mechanism linking ETFDH defects to elevated homocysteine remains unclear but may involve riboflavin’s role in folate metabolism. The predominance of ETFDH mutations aligns with prior reports, though the high rate of single heterozygous variants (32%) suggests potential undetected deep intronic or regulatory mutations.

Diagnostic Value of Muscle MRI

The selective involvement of SO and BFL muscles contrasts with mitochondrial myopathies, which often affect the gastrocnemius, and dystrophinopathies, which spare the semitendinosus. The “SO+/GA–” and “BFL+/ST–” signs provide a reproducible framework for differentiating MADD from mimics. The rapid resolution of edema-like changes post-treatment supports their utility as biomarkers for monitoring therapeutic response.

Pathophysiological Implications

The coexistence of edema and fat infiltration in affected muscles suggests a two-phase disease process: acute metabolic stress causing cytotoxic edema (reversible with riboflavin) and chronic lipid accumulation due to mitochondrial dysfunction (resolving slowly). The sparing of GA and ST may reflect differences in fiber-type composition or metabolic demands.

Limitations

The retrospective design and small sample size limit generalizability. Heterogeneity in control groups (e.g., mitochondrial myopathies) may affect specificity estimates. Further studies are needed to validate the proposed MRI criteria and explore the genetic basis of single heterozygous cases.

Conclusion

Late-onset MADD exhibits a distinct MRI pattern characterized by selective edema and fat infiltration in the soleus and biceps femoris longus, with sparing of the gastrocnemius and semitendinosus. The “SO+/GA–” and “BFL+/ST–” signs offer high diagnostic specificity, while dynamic STIR changes correlate with treatment response. These findings enhance recognition of MADD and underscore the utility of muscle MRI in metabolic myopathies.

doi.org/10.1097/CM9.0000000000000032

Was this helpful?

0 / 0