Miglustat in a Child With Niemann-Pick Disease
Miglustat in a Child With Niemann-Pick Disease
Introduction Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear.
Case presentation Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, who died at eight years and seven months of age, had a history of prolonged neonatal jaundice and subsequently displayed progressive neurological manifestations that started with delayed speech, ataxia, and gelastic cataplexy. A regimen of 100mg of miglustat three times a day was initiated when she was four years and 11 months old. She showed decreased neurological deterioration during about three and a half years of treatment. However, she displayed periods of distinct worsening that coincided with frequent epileptic seizures. Anti-epileptic therapy reduced seizure frequency and severity and allowed re-stabilization of her neurological function. Prior to her death, which was possibly due to acute cardiac arrest, seizure activity was well controlled.
Conclusions Miglustat delayed the expected deterioration of neurological function in this patient with p.S940L-homozygous late-infantile-onset Niemann-Pick disease type C and provided important quality-of-life benefits. This case demonstrates the importance of effective seizure control therapy in achieving and maintaining neurological stabilization in Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a potentially devastating progressive neurodegenerative disease currently estimated to occur in 1:100,000 to 1:120,000 live births. NP-C is caused by autosomal recessive mutations in both alleles of either the NPC1 gene, which is detected in 95% of cases, or the NPC2 gene. These mutations give rise to impaired intracellular lipid trafficking and subsequent accumulation of unesterified cholesterol, sphingosine, and a range of glycosphingolipids in various tissues, including the brain.
NP-C has an extremely heterogeneous clinical presentation characterized by a wide range of systemic, neurological, and psychiatric symptoms, many of which are not specific to the disease. This makes it difficult to establish an early diagnosis. Patients may present during infancy, but many cases present during adolescence or adulthood. Clinical NP-C phenotypes can be broadly defined on the basis of age at disease onset.
Until recently, no disease-modifying therapy was available for NP-C. In 2009, miglustat (Zavesca, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland) was approved in Europe for the treatment of adults and children with NP-C on the basis of clinical trial data and a retrospective observational cohort study showing improvements or stabilization of neurological disease manifestations. To date, no published reports have assessed the influence of seizure activity on disease course in NP-C or the possible impact of seizures on patient responses to miglustat therapy. We report the case of a young patient who had late-infantile NP-C and significant seizure activity and was treated with miglustat and anti-epileptic therapy.
Abstract and Introduction
Abstract
Introduction Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear.
Case presentation Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, who died at eight years and seven months of age, had a history of prolonged neonatal jaundice and subsequently displayed progressive neurological manifestations that started with delayed speech, ataxia, and gelastic cataplexy. A regimen of 100mg of miglustat three times a day was initiated when she was four years and 11 months old. She showed decreased neurological deterioration during about three and a half years of treatment. However, she displayed periods of distinct worsening that coincided with frequent epileptic seizures. Anti-epileptic therapy reduced seizure frequency and severity and allowed re-stabilization of her neurological function. Prior to her death, which was possibly due to acute cardiac arrest, seizure activity was well controlled.
Conclusions Miglustat delayed the expected deterioration of neurological function in this patient with p.S940L-homozygous late-infantile-onset Niemann-Pick disease type C and provided important quality-of-life benefits. This case demonstrates the importance of effective seizure control therapy in achieving and maintaining neurological stabilization in Niemann-Pick disease type C.
Introduction
Niemann-Pick disease type C (NP-C) is a potentially devastating progressive neurodegenerative disease currently estimated to occur in 1:100,000 to 1:120,000 live births. NP-C is caused by autosomal recessive mutations in both alleles of either the NPC1 gene, which is detected in 95% of cases, or the NPC2 gene. These mutations give rise to impaired intracellular lipid trafficking and subsequent accumulation of unesterified cholesterol, sphingosine, and a range of glycosphingolipids in various tissues, including the brain.
NP-C has an extremely heterogeneous clinical presentation characterized by a wide range of systemic, neurological, and psychiatric symptoms, many of which are not specific to the disease. This makes it difficult to establish an early diagnosis. Patients may present during infancy, but many cases present during adolescence or adulthood. Clinical NP-C phenotypes can be broadly defined on the basis of age at disease onset.
Until recently, no disease-modifying therapy was available for NP-C. In 2009, miglustat (Zavesca, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland) was approved in Europe for the treatment of adults and children with NP-C on the basis of clinical trial data and a retrospective observational cohort study showing improvements or stabilization of neurological disease manifestations. To date, no published reports have assessed the influence of seizure activity on disease course in NP-C or the possible impact of seizures on patient responses to miglustat therapy. We report the case of a young patient who had late-infantile NP-C and significant seizure activity and was treated with miglustat and anti-epileptic therapy.
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