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Phenotypic continuum of NFU1-related disorders.

ABSTRACT: Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

SUBMITTER: Kaiyrzhanov R

PROVIDER: S-EPMC9735368 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Phenotypic continuum of NFU1-related disorders.

Kaiyrzhanov Rauan R Zaki Maha S MS Lau Tracy T Sen Sambuddha S Azizimalamiri Reza R Zamani Mina M Sayin Gözde Yeşil GY Hilander Taru T Efthymiou Stephanie S Chelban Viorica V Brown Ruth R Thompson Kyle K Scarano Maria Irene MI Ganesh Jaya J Koneev Kairgali K Gülaçar Ismail Musab IM Person Richard R Sadykova Dinara D Maidyrov Yerdan Y Seifi Tahereh T Zadagali Aizhan A Bernard Geneviève G Allis Katrina K Elloumi Houda Zghal HZ Lindy Amanda A Taghiabadi Ehsan E Verma Sumit S Logan Rachel R Kirmse Brian B Bai Renkui R Khalaf Shaimaa M SM Abdel-Hamid Mohamed S MS Sedaghat Alireza A Shariati Gholamreza G Issa Mahmoud M Zeighami Jawaher J Elbendary Hasnaa M HM Brown Garry G Taylor Robert W RW Galehdari Hamid H Gleeson Joseph J JJ Carroll Christopher J CJ Cowan James A JA Moreno-De-Luca Andres A Houlden Henry H Maroofian Reza R

Annals of clinical and translational neurology 20221018 12

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental del ...[more]

PMID: 36256512

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Project description:BackgroundHeterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date.MethodsWe identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data.ResultsCASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein.ConclusionsBased on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups.

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Phenotypic continuum of NFU1-related disorders.

Publications

Phenotypic continuum of NFU1-related disorders.

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