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Effects of intracerebroventricular administration of 2-hydroxypropyl- β -cyclodextrin in a patient with Niemann – Pick Type C disease

View Article: PubMed Central - PubMed

ABSTRACT

Niemann–Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD) in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood–brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF) was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

No MeSH data available.


Related in: MedlinePlus

(A) Changes in the choline to creatine ratio (Cho/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum. (B) Changes in the N-acetylaspartate to creatine ratio (NAA/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum.
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f0015: (A) Changes in the choline to creatine ratio (Cho/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum. (B) Changes in the N-acetylaspartate to creatine ratio (NAA/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum.

Mentions: Frontal dominant, irregular, high-voltage, slow activities on the awake EEG were significantly decreased after two years of treatment with intrathecal HPB-CD (Fig. 1), although there were no significant changes on brain MRI (Fig. 2). MRS of the cerebral white matter, basal ganglia, and cerebellum showed a decreased choline to creatine ratio (Cho/Cr), indicating decreased myelin destruction, and an increase in the N-acetylaspartate to creatine ratio (NAA/Cr), indicating decreased neuronal and axonal damage in all areas (Fig. 3A,B). The standardized uptake values on PET were slightly increased in all areas after two years (Fig. 4A, B), indicating increased metabolism and activities of the patient's brain. There were no changes in ABR.


Effects of intracerebroventricular administration of 2-hydroxypropyl- β -cyclodextrin in a patient with Niemann – Pick Type C disease
(A) Changes in the choline to creatine ratio (Cho/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum. (B) Changes in the N-acetylaspartate to creatine ratio (NAA/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum.
© Copyright Policy - CC BY-NC-SA
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121362&req=5

f0015: (A) Changes in the choline to creatine ratio (Cho/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum. (B) Changes in the N-acetylaspartate to creatine ratio (NAA/Cr) of MRS in the cerebral white matter, basal ganglia, and cerebellum.
Mentions: Frontal dominant, irregular, high-voltage, slow activities on the awake EEG were significantly decreased after two years of treatment with intrathecal HPB-CD (Fig. 1), although there were no significant changes on brain MRI (Fig. 2). MRS of the cerebral white matter, basal ganglia, and cerebellum showed a decreased choline to creatine ratio (Cho/Cr), indicating decreased myelin destruction, and an increase in the N-acetylaspartate to creatine ratio (NAA/Cr), indicating decreased neuronal and axonal damage in all areas (Fig. 3A,B). The standardized uptake values on PET were slightly increased in all areas after two years (Fig. 4A, B), indicating increased metabolism and activities of the patient's brain. There were no changes in ABR.

View Article: PubMed Central - PubMed

ABSTRACT

Niemann–Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD) in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood–brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF) was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

No MeSH data available.


Related in: MedlinePlus