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Iron-sulfur cluster assembly 2 (ISCA2) is a mitochondrial protein essential for the biogenesis of [4Fe-4S] clusters. It forms part of the late-acting multimeric machinery that converts [2Fe-2S] intermediates into [4Fe-4S] clusters. Biallelic variants in ISCA2 disrupt mitochondrial respiratory chain complexes I and II, enzyme activities in the Krebs cycle, and lipoic acid biosynthesis. These molecular defects underlie multiple mitochondrial dysfunctions syndrome 4 (MMDS4), an autosomal recessive neurodegenerative disorder in infancy. Patients typically exhibit leukodystrophy, optic atrophy, and progressive developmental regression. ISCA2 is encoded by the gene HGNC:19857 and is recognized under MONDO:0014611 as MMDS4.
Genetic evidence for ISCA2 in MMDS4 includes 23 probands (PMID:31106229) across 18 unrelated families (PMID:31106229), providing strong genetic support. Inheritance is autosomal recessive, with both homozygous and compound heterozygous presentations confirmed by segregation analyses in consanguineous pedigrees. Variants include missense changes, splice-site alterations, and frameshift mutations distributed throughout the gene. A Saudi Arabian founder missense variant, c.229G>A (p.Gly77Ser), has been identified in multiple cases (PMID:39544370). Other recurrent alleles such as c.297del (p.Phe99fs) have been observed in founder populations. Segregation in affected families confirms co-segregation with disease phenotype and rules out alternative genetic causes.
MMDS4 manifests in early infancy, typically between two and seven months of age, with rapid neurodevelopmental regression. Developmental regression (HP:0002376), diffuse leukodystrophy (HP:0002415), optic atrophy (HP:0007754), and nystagmus (HP:0000639) are consistent features. Magnetic resonance imaging shows cerebellar and spinal cord white matter abnormalities in most patients. Magnetic resonance spectroscopy may reveal elevated glycine or lactate peaks in a subset of cases. Biochemical analyses often demonstrate elevated glycine and lactate levels in cerebrospinal fluid and plasma, though with variable penetrance. Optic nerve involvement may lead to early nystagmus and visual impairment.
A case report described a 7-month-old Iranian boy with progressive neurodegeneration harboring the novel homozygous variant c.355G>A (p.Ala119Thr) (PMID:31279336). Segregation was confirmed by Sanger sequencing in the consanguineous family. A Korean patient presented at 13 months with post-febrile regression and leukodystrophy, carrying compound heterozygous variants c.166T>G (p.Cys56Gly) and c.422A>C (p.Gln141Pro) (PMID:37915614). No additional mitochondrial defects were noted beyond bilateral optic atrophy in that case. Recently, a novel homozygous splice-affecting variant, c.70A>G (p.Arg24Gly), was shown to cause aberrant splicing and segregate fully in a wider family (PMID:39544370).
Functional assays in patient-derived fibroblasts demonstrate that ISCA2 deficiency leads to mitochondrial depletion and reduced complex I activity. The founder missense variant p.Gly77Ser and the frameshift variant p.Phe99fs cause decreased expression of ISCA2, ISCA1, and IBA57 proteins, along with impaired mitochondrial morphology (PMID:25539947). Biochemical dipstick assays confirm decreased respiratory chain enzyme activity, while confocal and electron microscopy reveal altered mitochondrial ultrastructure. Splicing analysis of c.70A>G shows intron retention and a truncated transcript, with Seahorse XFp measurements indicating significantly reduced basal and maximal respiration in patient cells (PMID:39544370). These data support a loss-of-function mechanism leading to multisystem mitochondrial dysfunction consistent with the human phenotype.
The convergence of genetic segregation, diverse biallelic variant classes, and robust functional data establishes a Strong clinical validity classification for ISCA2-MMDS4. The autosomal recessive inheritance and early phenotypic presentation enable targeted genetic testing in infants with leukodystrophy and regression. Functional studies corroborate the pathogenicity of novel variants and clarify the molecular basis of ISCA2 deficiency. Additional case series and functional work are likely to further refine genotype–phenotype correlations but exceed the current ClinGen scoring cap. Key Take-home: Biallelic loss-of-function variants in ISCA2 should be considered in the diagnostic evaluation of early-onset neurodegeneration with leukodystrophy.
Gene–Disease AssociationStrong23 probands, 18 families with segregation and concordant functional data Genetic EvidenceStrong23 biallelic variants across multiple consanguineous families with confirmed autosomal recessive segregation Functional EvidenceModerateMultiple cellular and biochemical assays demonstrate mitochondrial complex I deficiency and impaired respiration due to ISCA2 variants |