White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology

Zerem, Ayelet; Ben-Sira, Liat; Vigdorovich, Nitzan; Leibovitz, Z.; Fisher, Yael; Schiffmann, Raphael; Grishchuk, Yulia; Misko, Albert L.; Orenstein, Naama; Lev, Dorit; Lerman‐Sagie, Tally; Kidron, Debora

doi:10.1007/s11011-021-00742-3

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…We further performed qRT-PCR analysis to examine astrocytosis and microgliosis that are early hallmarks of the MLIV brain pathology reported in the human tissue and the MLIV mouse model (28, 30, 31, 32). As expected, significant increases of mRNA transcripts of the astrocytosis marker Gfap and microgliosis marker Cd68 were observed in the cortical tissue of saline-treated Mcoln1 -/- mice compared to saline-treated WT litermates (Figure 5B) .…”

Section: Resultsmentioning

confidence: 99%

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

Sangster,

Bishop,

Yao

et al. 2023

Preprint

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Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits and progressive vision loss. Using AAV9 and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the humanMCOLN1gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-orientedMCOLN1gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1in adult symptomaticMcoln1-/-mice at a dose of 1e12 vg per mouse resulted inMCOLN1expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression ofMCOLN1transcripts was also detected in the retina of the mouse that had exhibited significant degeneration at the time of the treatment. However, no increase of retinal thickness was observed after the gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.

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Section: Resultsmentioning

confidence: 99%

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

Sangster,

Bishop,

Yao

et al. 2023

Preprint

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“…Proinflammatory activation of microglia and astrocytes, often referred to as microgliosis and astrocytosis, is a persistent feature of brain pathology in MLIV that is evident in MLIV mouse and human brain tissue starting from the early postnatal (mouse MLIV) and late prenatal (human MLIV) stages of development to the end-stage of disease ( Folkerth et al, 1995 ; Grishchuk et al, 2014 ; Weinstock et al, 2018 ; Cougnoux et al, 2019 ; Zerem et al, 2021 ). Increased levels of proinflammatory cytokines and chemokines previously reported in MLIV cortical homogenates and astrocyte cultures provide evidence of neuroinflammatory axis in MLIV ( Weinstock et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although it is not fully understood how early brain development is affected in MLIV, subcortical hypomyelination and iron accumulation in the basal ganglia have been reported in MLIV at gestational stage ( Zerem et al, 2021 ). Despite this early evidence of brain pathology, patients generally achieve their developmental motor milestones up to 6 months of age and present with hypotonia and delayed gross motor development around 1 year of age ( Chitayat et al, 1991 ; Altarescu et al, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

Sangster

Shahriar²,

Niziolek

et al. 2023

Front. Mol. Neurosci.

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Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model, Mcoln1−/− mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC–MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic Mcoln1−/− mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in Mcoln1−/− tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all Mcoln1−/− brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.

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“…In contrast, although some studies reported no improvement in the outcomes studied in relation to child cognitive or behavioural development following prenatal iron supplementation (Jayasinghe et al, 2018 ; Parsons et al, 2008 ; Zhou et al, 2006 ), the detrimental effect of high‐dose supplementation observed in the present study in children of mothers who started pregnancy with full iron stores was not so clear until now. One explanation for this finding is that giving high doses of prenatal iron to women who do not really need it could lead to excess iron, causing oxidative stress and even iron deposits that, in turn, could impair foetal brain development and lead to a poorer behavioural and psychological performance in infancy (Lavezzi et al, 2011 ; Zerem et al, 2021 ). Recent research has noted that epigenetics may also play a role in the association between maternal iron status and children's behavioural development by differential DNA methylation (Taeubert et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Prenatal iron supplementation adjusted to maternal iron stores reduces behavioural problems in 4‐year‐old children

Iglesias‐Vázquez,

Canals,

Hernández‐Martínez

et al. 2023

Maternal & Child Nutrition

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Prenatal iron supplementation improves children's health and cognitive performance, but few studies explore behavioural development. This study assessed the effects of adjusting prenatal iron supplementation to maternal iron stores during early pregnancy on children's behavioural problems. Randomized controlled trial conducted in Tarragona (Spain) involving 230 nonanaemic pregnant women and their children after a 4‐year follow‐up. Based on haemoglobin (Hb) levels before gestational week (GW) 12, women receive different iron doses: those with Hb = 110–130 g/L were randomized to receive 80 or 40 mg/day and those with Hb > 130 g/L were randomized to receive 20 or 40 mg/day. Maternal iron stores at GW12 were classified using serum ferritin (SF) as low (SF < 15 µg/L), normal (SF = 15–65 µg/L), and normal‐high (SF > 65 µg/L). Children's behaviour was assessed by parents using the Child Behaviour Checklist for ages 1.5–5 years and the Behaviour Rating Inventory of Executive Function‐Preschool Version, and by teachers using the Teacher's Report Form for ages 1.5–5 years. Multivariable regression models were performed. Taking 80 mg/day of iron improved child behaviour when women had low iron stores but worsened it when mothers had normal–high iron stores, except for depressive and attention/hyperactivity problems. Taking 20 mg/day of iron improved behaviour only in those children whose mothers had SF > 65 µg/L in early pregnancy. Additionally, executive functioning improved at high doses of prenatal iron when maternal baseline SF < 15 µg/L. Adjusting prenatal iron supplementation to both maternal baseline Hb levels and iron stores reduces behavioural problems in 4‐year‐old children.

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White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology

Cited by 9 publications

References 41 publications

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

Prenatal iron supplementation adjusted to maternal iron stores reduces behavioural problems in 4‐year‐old children

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