Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy

Gramegna, Laura Ludovica; Pisano, Annalinda; Testa, Claudia; Manners, David Neil; D’Angelo, Roberto; Boschetti, Elisa; Giancola, Fiorella; Pironi, Loris; Caporali, Leonardo; Capristo, Mariantonietta; Valentino, Maria Lucia; Plazzi, Giuseppe; Casali, Carlo; Dotti, Maria Teresa; Cenacchi, Giovanna; Hirano, Michio; Giordano, Carla; Parchi, Piero; Rinaldi, Rita; Giorgio, Roberto De; Lodi, Raffaele; Carelli, Valerio; Tonon, Caterina

doi:10.3174/ajnr.a5507

Cited by 20 publications

(23 citation statements)

References 36 publications

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“…The acquisition protocol included the following sequences: volumetric FSPGR-T1 (voxel = 1 mm 3 ), axial FLAIR-T2, coronal FSE T2, diffusion weighted imaging, DWI, (25 gradient directions, b-value = 900 s mm −2 , voxel=1.25 × 1.25 × 4 mm). Moreover, water-suppressed proton MR spectra were acquired by the point-resolved spectroscopy single-voxel localization sequence (PROBE), as previously reported 58 , in the lateral ventricles in ten WS patients (TR/TE = 1500/288 ms, volume = 3.7-8.2 ml), in the left cerebellar hemisphere in 9 (TR/ TE = 4000/35 ms, volume = 6 ml), in the left POWM in 7 (TR/TE = 4000/35 ms, volume = 8 ml) and in the ventral pons in 5 (TR/TE = 1500/40 ms, volume = 1.2-1.5 ml).…”

Section: Muscle Biopsy Three Ws Patients Underwent Muscle Biopsy Stmentioning

confidence: 99%

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Morgia

Maresca

Amore

et al. 2020

Sci Rep

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Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria. Wolfram Syndrome (WS) is a rare genetic disorder also known as DIDMOAD, i.e. Diabetes Insipidus (DI), Diabetes Mellitus (DM), Optic Atrophy (OA) and Deafness 1. Additional neurological features include brainstem atrophy, cerebellar ataxia, peripheral neuropathy, cognitive deterioration and epilepsy 2. The onset of OA and DM, the minimal diagnostic criteria for WS, is typically within the second decade. The large majority of WS patients carry recessive mutations in the WFS1 gene encoding for the Wolframin (WFS1) protein 3. WFS1 is associated with the endoplasmic reticulum (ER) 4 and cellular and animal model studies involved Wolframin in the ER stress response, regulation of calcium homeostasis and Na/K ATPase function 5. Due to the clinical features resembling a mitochondrial disorder 6 and reports of mitochondrial DNA (mtDNA)

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Section: Muscle Biopsy Three Ws Patients Underwent Muscle Biopsy Stmentioning

confidence: 99%

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Morgia

Maresca

Amore

et al. 2020

Sci Rep

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“…Leukoencephalopathy is the hallmark feature of the pathology and its presence in combination with gastrointestinal and neuropathic symptoms significantly narrows the differential diagnosis to MNGIE. The leukoencephalopathy as identified by MRI, is initially patchy but progressively becomes more diffuse, appearing as hypointense on T1- and hyperintense on T2- weighted images and in fluid-attenuated inversion recovery (FLAIR) and fast spin echo (FSE) T2 sequences (Garone et al, 2011; Çoban et al, 2013; Scarpelli et al, 2013; Gramegna et al, 2018). The most involved region of the CNS in MNGIE is the subcortical white matter.…”

Section: Clinical Descriptionmentioning

confidence: 99%

“…Areas less frequently affected include the capsular white matter, and the white matter in the basal ganglia, thalami, midbrain, pons and cerebellum (Millar et al, 2004; Barragán-Campos et al, 2005; Scaglia et al, 2005; Petcharunpaisan and Castillo, 2010). The reasons why the leukoencephalopathy remains asymptomatic are yet to be elucidated, however it has been suggested that hyperintense lesions observed by MRI could be the result of alterations in the brain microvasculature causing vasogenic oedema and glial dysfunctions (Szigeti et al, 2004a; Scarpelli et al, 2013; Gramegna et al, 2018). Whether there are subtle neuropsychiatric or cognitive changes associated with the leukoencephalopathy remains an open question.…”

Section: Clinical Descriptionmentioning

confidence: 99%

“…Histopathological studies post mortem have failed to identify demyelination, neuronal loss or glial scarring in the areas of the brain white matter affected, as visualized by MRI (Szigeti et al, 2004a; Gramegna et al, 2018). However, the presence of albumin in the cytoplasm of reactive astrocytes was observed suggesting functional blood brain barrier alterations and consequent vasogenic oedema as a cause of leukoencephalopathy (Szigeti et al, 2004a).…”

Section: Clinical Descriptionmentioning

confidence: 99%

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Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

et al. 2018

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

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“…The segmental demyelination is thought to be a result of an uneven distribution of mtDNA abnormalities along the nerve [56] Asymptomatic leukoencephalopathy is a hallmark of MNGIE and its presence in combination with the gastrointestinal and neurological symptoms significantly narrows the diagnosis to MNGIE [16] . In the majority of patients, the leukoencephalopathy is initially patchy but becomes progressively more diffuse, appearing as hypointense on T1-and hyperintense on T2-weighted images and in fluid-attenuated inversion recovery and fast spin echo T2 sequences [16,43,57,58] .…”

Section: Clinical Investigationsmentioning

confidence: 99%

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

Bax¹

2019

JTGG

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2'-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a résumé of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.

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Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy

Cited by 20 publications

References 36 publications

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

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