Children with Infantile Neuronal Ceroid Lipofuscinosis Have an Increased Risk of Hypothermia and Bradycardia During Anesthesia

Miao, Ning; Levin, Sondra W.; Baker, Eva H.; Caruso, Rafael C.; Zhang, Zhongjian; Gropman, Andrea; Koziol, Deloris E.; Wesley, Robert; Mukherjee, Anil B.; Quezado, Zenaide M.N.

doi:10.1213/ane.0b013e3181aa6e95

Cited by 21 publications

(15 citation statements)

References 24 publications

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“…We found that these animals have thermoregulation defects akin to what has been previously reported in children with INCL [17]. Specifically, with aging, Ppt1 -KO mice drop basal body temperature and during acute cold exposure, these mice develop hypothermia compared with wild-type controls.…”

Section: Discussionsupporting

confidence: 75%

In a Model of Batten Disease, Palmitoyl Protein Thioesterase-1 Deficiency Is Associated with Brown Adipose Tissue and Thermoregulation Abnormalities

et al. 2012

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Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1α and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1α and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets) compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of neurodegenerative diseases that are linked to alterations in peripheral metabolic processes. In addition, extrapolating these findings clinically, impaired thermoregulation and hypothermia are potential risks in patients with INCL.

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Section: Discussionsupporting

confidence: 75%

In a Model of Batten Disease, Palmitoyl Protein Thioesterase-1 Deficiency Is Associated with Brown Adipose Tissue and Thermoregulation Abnormalities

et al. 2012

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“…Because all of the patients were young children, most examinations were performed under sedation with propofol 17 . Some late stage patients did not require sedation for the MRI exams.…”

Section: Methodsmentioning

confidence: 99%

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

Baker

Levin

Zhang

et al. 2016

AJNR Am J Neuroradiol

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Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. PPT1 deficiency impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood demise. As part of a project studying treatment benefits of a combination of cysteamine bitartrate and N-acetylcysteine, we made serial measurements of patients’ brain volumes using MRI. Methods Ten INCL patients participating in a treatment/follow-up study underwent brain MRI that included high resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brainstem, and thalamus. Patients’ brain volumes were compared to those of a normal population. Results Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss, and may never have been normal postnatally. The thalamus dropped out of the normal range around age 6 months, cerebellum around age 2 years, and brainstem around age 3 years. Discussion Rapid cerebral volume loss was expected based upon previous qualitative reports. Because our study did not include a non-treatment arm, and because progression of brain volumes in INCL has not previously been quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.

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“…General anesthesia was administered by staff anesthesiologists as previously reported 19 . Upon completion of the procedures and emergence from anesthesia, children were observed in the post-anesthesia care unit until ready to be transferred to the pediatric ward.…”

Section: Methodsmentioning

confidence: 99%

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Levin

Baker

Zein

et al. 2014

The Lancet Neurology

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Summary Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1-deficiency causes lysosomal ceroid accumulation leading to INCL pathogenesis. Previously, we reported that phosphocysteamine and N-acetylcysteine mediated ceroid depletion in cultured cells from INCL patients. We conducted a pilot study to determine whether a combination of cysteamine bitartrate and N-acetylcysteine is beneficial for these patients. Methods Patients (6-month to 3-years old) with any combination of 2 of the 7 most lethal PPT1 mutations were admitted. All patients were recruited from physician referrals and the PPT1 mutations were analyzed prior to admission. Patients were evaluated by electroretinography(ERG), brain MRI and MRS, electroencephalography (EEG), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Patients received oral cysteamine bitartrate (60mg/kg/day) and N-acetylcysteine (60mg/kg/day) and were evaluated every 6 to 12 months until they showed isoelectric EEG attesting to a vegetative state or were too sick to travel. Outcomes were compared with the reported INCL natural history. In two cases, the disease progression was compared with that of a sibling who was above the age limit for inclusion into the protocol. Findings Between March, 2001, and June, 2011, we recruited 10 children with INCL but one was lost to follow-up after the first visit. Thus, a total of 9 patients (5 females and 4 males) were studied. At the first follow-up visit, peripheral leukocytes in all 9 patients showed virtually complete depletion of GRODs and 7 of 9 patients manifested less irritability and/or improved alertness based upon parental and physician observations. Evaluation by Denver scale showed acquisition of no new developmental skills and retinal function assessed by ERG progressively declined. Most notably, average time to isoelectric EEG (indicating vegetative state) was significantly longer in our patients compared to that previously reported. MRI studies demonstrated signal abnormalities similar to previous reports. Brain volume and NAA declined steadily, but no published quantitative MRI or MRS studies of INCL patients are available for comparison on these measures. There were no adverse events related to therapy other than a mild gastrointestinal discomfort in 2 of 9 patients, which was eliminated when the liquid preparation of cysteamine bitatrate was replaced with capsules. Interpretation The objectively demonstrated benefits in our study are the depletion of GRODs and delay of isoelectric EEG in all patients; in addition, several subjective benefits were suggested, all of which warrant further study. Nevertheless, this report systematically and quantitatively documents the natural history of 9 INCL patients with the most lethal CLN1/PPT1 mutations and thereby provides a benchmark for evaluating future experimental therapies. Fu...

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Children with Infantile Neuronal Ceroid Lipofuscinosis Have an Increased Risk of Hypothermia and Bradycardia During Anesthesia

Cited by 21 publications

References 24 publications

In a Model of Batten Disease, Palmitoyl Protein Thioesterase-1 Deficiency Is Associated with Brown Adipose Tissue and Thermoregulation Abnormalities

In a Model of Batten Disease, Palmitoyl Protein Thioesterase-1 Deficiency Is Associated with Brown Adipose Tissue and Thermoregulation Abnormalities

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

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