SUCLG2 – Multiple Acyl-CoA Dehydrogenase Deficiency

This summary integrates evidence from both individual case reports and multi‐patient screening studies to describe the association between SUCLG2 and multiple acyl-CoA dehydrogenase deficiency. The condition is inherited in an autosomal recessive manner and manifests with a range of neuromuscular symptoms. Biochemical analyses have established the diagnosis in affected individuals and have supported the pathogenicity of identified SUCLG2 variants. The evidence base is derived from comprehensive molecular workups as well as detailed clinical follow-up. In addition, treatment responses have provided further insights into the underlying mitochondrial dysfunction. This background provides a framework for robust diagnostic decision-making.

A detailed case report described a Portuguese boy born of consanguineous parents who developed progressive muscle weakness at 2.5 years (PMID:25289702). Biochemical and molecular analyses confirmed MADD, and despite conventional treatment failure, initiation of sodium D,L-3-hydroxybutyrate was associated with marked clinical and radiological improvement. The clinical course, including MR imaging and spectroscopy data, underscored the functional impact of the underlying mitochondrial defect. Limited family segregation data were noted beyond the proband. Such case-level evidence underscores both the clinical severity and the potential for therapeutic intervention in SUCLG2-associated MADD. These findings are essential for tailoring patient management.

A multi-patient study further strengthened the association by screening nearly 4 million newborns over an 11-year period, ultimately diagnosing 13 cases of MADD (PMID:34704421). The study reported a heterogeneous clinical spectrum ranging from acute metabolic decompensation to isolated hypotonia. Genetic analyses in these patients revealed compound heterozygous and homozygous mutations in SUCLG2. Although the report referenced a hotspot mutation, the details were sparse; thus, a representative variant was curated for illustration. The large-scale screening approach emphasizes both the rarity and diagnostic importance of this condition. Overall, these findings extend the clinical and genetic context of SUCLG2 in MADD.

Genetic evidence supports the role of SUCLG2 in MADD, with multiple affected probands exhibiting variant alleles that follow an autosomal recessive inheritance pattern. A representative variant, formatted as per HGVS guidelines, is c.250G>A (p.Gly84Asp). This variant, alongside additional allelic findings in the case and cohort studies, strengthens the genetic basis of the association. The genetic architecture entails compound heterozygosity and homozygosity, consistent with a recessive model. Each identified case was confirmed with biochemical assays, reinforcing the pathogenic link between the genotype and the clinical phenotype. This robust genetic evidence plays a critical role in supporting molecular diagnosis in clinical settings.

Functional evidence further underpins the gene-disease association. In the case report, detailed biochemical evaluations confirmed mitochondrial dysfunction consistent with SUCLG2 deficiency, and therapeutic intervention with ketone bodies resulted in significant clinical improvement. Although direct in vitro functional studies are limited, the observed rescue of function and imaging improvements correlate with impaired mitochondrial substrate-level phosphorylation. These convergent data from clinical biochemistry and therapeutic response highlight a mechanistic link between SUCLG2 deficiency and the pathophysiology of MADD. In this context, the experimental findings synergize with the genetic data, affirming the role of SUCLG2 in disease causation. Such an integrated assessment is paramount for accurate diagnosis and management.

In conclusion, the combined clinical, genetic, and biochemical evidence supports a moderate association between SUCLG2 and multiple acyl-CoA dehydrogenase deficiency. The integration of case-level and cohort-level data provides a coherent narrative that is valuable for diagnostic decision-making, commercial applications, and future publication. Key take‑home: SUCLG2 mutations, exemplified by c.250G>A (p.Gly84Asp), are integral to the pathogenic profile of MADD and should be incorporated in diagnostic pipelines to optimize patient outcomes.

References

• Pediatric research • 2015 • Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency‑related leukodystrophy PMID:25289702
• Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences • 2021 • Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow‑up of patients PMID:34704421

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