Serial electrophysiologic studies in rhesus monkeys with Krabbe disease

Weimer, Maria B.; Gutierrez, Amparo; Baskin, Gary B.; Borda, Juan T.; Veazey, Ronald S.; Myers, Leann; Phillippi-Falkenstein, Kathrine; Bunnell, Bruce A.; Ratterree, Marion S.; England, John D.

doi:10.1002/mus.20350

Cited by 11 publications

(14 citation statements)

References 17 publications

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“…By contrast, the motor conduction velocity (MCV) in monkey N416 was not different from that in aged, adult, or child monkeys. The MCV measured in our study was similar to that reported in rhesus and long-tailed monkeys [23], [24]. Further investigations are needed to clarify whether demyelination of the sensory nerve may occur in monkey N416 and whether the discrepancy between the SCV and the MCV may be ascribed to demyelination.…”

Section: Discussionsupporting

confidence: 84%

Sporadic Premature Aging in a Japanese Monkey: A Primate Model for Progeria

Oishi

Imai

et al. 2014

PLoS ONE

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In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

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Section: Discussionsupporting

confidence: 84%

Sporadic Premature Aging in a Japanese Monkey: A Primate Model for Progeria

Oishi

Imai

et al. 2014

PLoS ONE

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“…Importantly, the severity of the demyelination on NCV studies correlated well with the clinical severity of the disease (Siddiqi et al, ). Similarly, conduction velocities of the median, ulnar, and tibial nerves were significantly slower in GLD‐affected rhesus macaques compared with normal monkeys and also correlated with disease progression (Weimer et al, ). Comparably, motor NCVs of pelvic (tibial and sciatic nerves) and thoracic limbs (ulnar nerve) were a sensitive indicator of peripheral nerve dysfunction in the canine model of GLD, with all conduction velocities significantly lower than normal by 12–16 weeks of age.…”

Section: Discussionmentioning

confidence: 93%

Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease)

Bradbury

Bagel

Jiang

et al. 2016

J of Neuroscience Research

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Globoid cell leukodystrophy (GLD), or Krabbe disease, is a debilitating and always fatal pediatric neurodegenerative disease caused by a mutation in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). In the absence of GALC, progressive loss of myelin and accumulation of a neurotoxic substrate lead to incapacitating loss of motor and cognitive function and death typically by two years of age. To date there is no cure. Recent convincing evidence of the therapeutic potential of combining gene and cell therapies in the murine model of GLD has accelerated the need for validated markers of disease in order to evaluate therapeutic efficacy. Herein we demonstrate clinically relevant and quantifiable measures of central and peripheral nervous system (CNS, PNS) disease progression in the naturally-occurring canine model of GLD. As measured by brainstem auditory evoked response (BAER) testing, GLD dogs demonstrated a significant increase in I–V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCV) were significantly lower than normal by 12–16 weeks of age and sensory NCV by 8–12 weeks of age, serving as a sensitive indicator of peripheral nerve dysfunction. Post mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and PNS. Additionally, cerebrospinal fluid (CSF) psychosine concentrations were significantly elevated in GLD dogs, demonstrating potential as a biochemical marker of disease. These data demonstrate that CNS and PNS disease progression can be quantified over time in the canine model of GLD using identical tools as used to assess human patients.

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“…Initially, KD had been reported as a demyelinating disease in which progressive accumulation of PSY in OLs and myelin causes loss of OLs and myelin (Wenger et al, ; Suzuki, ). However, the presence of severe hypomyelination with a lack of large‐diameter axons in the PNS of twitcher (Twi)‐5J mice bearing missense mutation of galc (E130K; Potter et al, ) and the incomplete myelin pattern and associated decrease in conduction velocities of PNS nerves in a primate model of KD (Weimer et al, ) suggest that KD might also involve dysmyelination, formation of defective myelin, or failure of myelin development. Although the underlying mechanisms for dysmyelination under GALC‐deficient conditions are not currently known, PSY accumulation during OL differentiation and its inhibition of final maturation and survival of differentiating OLs have been described as factors contributing to myelin loss (Won et al, ; Fig.…”

Section: Pathological Role Of Psy In Oligodendrocytesmentioning

confidence: 99%

Biochemical, cell biological, pathological, and therapeutic aspects ofKrabbe's disease

Won

Singh

2016

J of Neuroscience Research

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Krabbe disease (KD; also called globoid cell leukodystrophy) is a genetic disorder involving demyelination of the central (CNS) and peripheral (PNS) nervous systems. The disease may be subdivided into three types; an infantile form which is most common and severe, a juvenile form, and a rare adult form. KD is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase (GALC) activity in lysosomes leading to accumulation of galactoceramide and neurotoxic galactosylsphingosine (psychosine) in macrophages (globoid cells) as well as neural cells especially in oligodendrocytes and Schwann cells. This ultimately results in damage to myelin in both CNS and PNS with associated morbidity and mortality. Accumulation of psychosine, a lysolipid with detergent-like properties, over a threshold level could trigger membrane destabilization leading to cell lysis. Moreover, sub-threshold concentrations of psychosine trigger cell signaling pathways that induce oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, endothelial/vascular dysfunctions, and neuronal and axonal damage. Since the proposed “psychosine hypothesis” considerable efforts have been made in search for effective therapy for lowering psychosine load using pharmacological, gene and stem cell approaches to attenuate psychosine-induced neurotoxicity. In this review, we focus on the recent advances and prospective research on understanding of disease mechanisms and therapeutic approaches for KD.

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Serial electrophysiologic studies in rhesus monkeys with Krabbe disease

Cited by 11 publications

References 17 publications

Sporadic Premature Aging in a Japanese Monkey: A Primate Model for Progeria

Sporadic Premature Aging in a Japanese Monkey: A Primate Model for Progeria

Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease)

Biochemical, cell biological, pathological, and therapeutic aspects ofKrabbe's disease

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