Expanding the genotype-phenotype spectrum of ISCA2 -related multiple mitochondrial dysfunction syndrome-cavitating leuko
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ORIGINAL ARTICLE
Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival Tamar Gur Hartman 1,2 & Keren Yosovich 3 & Hila Gur Michaeli 3 & Lubov Blumkin 1,4 & Liat Ben-Sira 4,5 & Dorit Lev 3,4 & Tally Lerman-Sagie 1,4 & Ayelet Zerem 1,4,6 Received: 15 January 2020 / Accepted: 1 April 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Iron-sulfur cluster assembly 2 (ISCA2)-related multiple mitochondrial dysfunction syndrome 4 (MMDS4) is a fatal autosomal recessive mitochondrial leukoencephalopathy. The disease typically manifests with rapid neurodevelopmental deterioration during the first months of life leading to a vegetative state and early death. MRI demonstrates a demyelinating leukodystrophy. We describe an eleven-year-old boy with a milder phenotype of ISCA2 related disorder manifesting as: normal early development, acute infantile neurologic deterioration leading to stable spastic quadriparesis, optic atrophy and mild cognitive impairment. The first MRI demonstrated a diffuse demyelinating leukodystrophy. A sequential MRI revealed white matter rarefaction with well-delineated cysts. The patient harbors two novel bi-allelic variants (p.Ala2Asp and p.Pro138Arg) in ISCA2 inherited from heterozygous carrier parents. This report expands the clinical spectrum of ISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation. Keywords Leukodystrophy . Multiple mitochondrial dysfunction syndrome . White matter rarefaction . Spastic quadriparesis
Introduction Multiple mitochondrial dysfunction syndromes (MMDS) are a group of mitochondrial energy metabolism disorders that present early in life with severe neurodegeneration and leukodystrophy [12, 14, 17].
* Ayelet Zerem [email protected] 1
Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel
2
School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
3
Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
4
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
5
Pediatric Radiology Unit, TASMC, Tel Aviv, Israel
6
Pediatric Neurology Unit, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
To date, there are six known MMDS genes: NFU1, BOLA3, IBA57, ISCA2, ISCA1, and PMPCB [4,10,11,14,17,21,23]. These genes encode proteins with a role in iron-sulfur (Fe-S) cluster biosynthesis. Defects in this pathway lead to abnormal function of proteins containing Fe-S centers, including mitochondrial respiratory chain (MRC) complexes I, II, and III and lipoic acid synthase. Consequently, a systemic energy failure occurs and manifests as a severe early-onset neurometabolic disease [19, 22]. In 2015, Al-Hassan [5] published the first report of a mitochondrial neurodegenerative disorder due to iron-sulfur
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