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1.
Mol Genet Genomic Med ; 8(10): e1371, 2020 10.
Article in English | MEDLINE | ID: mdl-32779865

ABSTRACT

BACKGROUND: In GM1 gangliosidosis the lack of function of ß-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce. METHODS: We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases. CONCLUSION: This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Gangliosidosis, GM1/drug therapy , Glycoside Hydrolase Inhibitors/therapeutic use , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/pharmacology , 1-Deoxynojirimycin/therapeutic use , Adolescent , Central Nervous System/diagnostic imaging , Central Nervous System/drug effects , Child , Child, Preschool , Drug Tolerance , Female , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Glycoside Hydrolase Inhibitors/adverse effects , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Infant , Male
2.
J Child Neurol ; 32(3): 316-321, 2017 03.
Article in English | MEDLINE | ID: mdl-27920268

ABSTRACT

We evaluated whether perfusion brain abnormalities by single-photon emission computed tomography (SPECT) imaging improves diagnostic and prognostic assessment in Sydenham chorea. Twenty-three children with acute autoimmune chorea underwent technetium-99m hexamethylpropyleneamine oxime brain SPECT imaging. In 16 children, SPECT was repeated during the follow-up. A pattern of basal ganglia hyperperfusion was observed in 20 (87%) patients. In 4 of 10 patients with generalized chorea, perfusion was comparable in right and left striatum and right and left thalamus. In 13 patients with hemi-chorea and in 3 with generalized chorea, unilateral hyperperfusion was detected. Three patients with generalized chorea had normal perfusion. Tracer uptake of basal ganglia of the patients at the acute phase was higher than at the follow-up ( P < .001). SPECT seems a useful noninvasive tool in pediatric patients with Sydenham chorea to support the clinicians during the acute phase of disease and to monitor the course of autoimmune chorea.


Subject(s)
Brain/diagnostic imaging , Chorea/diagnostic imaging , Adolescent , Basal Ganglia/diagnostic imaging , Child , Female , Humans , Male , Thalamus/diagnostic imaging , Tomography, Emission-Computed, Single-Photon
3.
Orphanet J Rare Dis ; 10: 22, 2015 Feb 27.
Article in English | MEDLINE | ID: mdl-25888393

ABSTRACT

BACKGROUND: Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. METHODS: Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. RESULTS: We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. CONCLUSIONS: The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. TRIAL REGISTRATION: EudraCT number 2006-005842-35.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/therapeutic use , Niemann-Pick Disease, Type C/drug therapy , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Female , Humans , Infant , Italy/epidemiology , Male , Niemann-Pick Disease, Type C/epidemiology , Young Adult
4.
Mol Ther ; 22(11): 2004-12, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25052852

ABSTRACT

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Glycogen Storage Disease Type II/blood , Glycogen Storage Disease Type II/drug therapy , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/pharmacology , 1-Deoxynojirimycin/pharmacology , Adolescent , Adult , Animals , Child , Child, Preschool , Disease Models, Animal , Dried Blood Spot Testing , Drug Synergism , Enzyme Replacement Therapy/methods , Enzyme Stability , Female , Humans , Male , Mice , Middle Aged , Young Adult , alpha-Glucosidases/blood , alpha-Glucosidases/therapeutic use
5.
Am J Med Genet A ; 155A(3): 540-7, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21344635

ABSTRACT

Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder characterized by defective intracellular lipid trafficking, with secondary accumulation of free cholesterol, sphingosine, and glycosphingolipids. NPC is clinically characterized by a wide spectrum of manifestations with progressive visceral and neurological involvement, including dysphagia. Neurological manifestations represent the most debilitating findings. Swallowing impairment is a frequent cause of morbidity and disability in NPC patients and progressive dysphagia may be considered a marker of neurological progression. Recently substrate reduction therapy with miglustat has been proposed for the treatment of neurological manifestations in NPC patients. This observational study reports on the long-term use of miglustat in four pediatric patients with NPC and shows the efficacy of the treatment to improve or prevent dysphagia, and persistence after 3 years of treatment or more. We used a videofluoroscopic analysis of liquid barium swallowing to provide additional information on patterns of impairment of the swallowing mechanism and to detect aspiration. In three patients showing dysphagia and aspiration we observed the improvement of the swallowing function and the sustained absence of barium aspiration in the airways after miglustat treatment, while the patient with normal swallowing function at baseline did not show any deterioration. We suggest that the videofluoroscopic study of swallowing should be routinely used to monitor the effects of treatment on swallowing ability in NPC patients.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Deglutition Disorders/drug therapy , Deglutition Disorders/physiopathology , Deglutition/physiology , Enzyme Inhibitors/therapeutic use , Niemann-Pick Disease, Type C/diagnostic imaging , Niemann-Pick Disease, Type C/drug therapy , Video Recording , 1-Deoxynojirimycin/therapeutic use , Child , Deglutition Disorders/complications , Deglutition Disorders/diagnostic imaging , Demography , Female , Fluoroscopy , Humans , Infant , Male , Niemann-Pick Disease, Type C/complications , Niemann-Pick Disease, Type C/physiopathology
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