November 2011
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Niemann-Pick disease type C – Latest Evidence
Niemann-Pick disease type C
Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disorder,
characterized by organomegaly and progressive neurodegeneration. The excess storage of
cholesterol and glycosphingolipides in the viscera and central nervous system is caused by
impaired intracellular lipid trafficking.
1,3,4
Most cases of NPC, approximately 95%, are associated with mutations in the NPC1 gene (located at
chromosome 18q11) which leads to NP type C1 (MIM 257220). About 4% are attributable to
mutations in the NPC2 gene (located at chromosome 14q24.3) causing NP type C2 (MIM
607625).
3,5-7
The remainder of patients are biochemically proven cases who do not have identified
mutations.
8
The identical biochemical pattern and clinical manifestations observed in NPC1 and
NPC2 phenotypes suggest that the two proteins participate together in mediating in egress of
cholesterol from late endosomes or lysosomes. Still the precise mechanism by which these
proteins act remains unknown.
7
The prevalence has been estimated to be between 1:120.000 and 1:150.000, although is probably
an underestimate due to the fact that atypical phenotypes may not be recognized.
3
Clinical features
NPC can develop at any age and has a wide spectrum of clinical phenotype. Both the
symptomatology and the rate of disease progression are heavily influenced by age of the patient at
onset.
8
The late childhood and juvenile neurologic onset forms are most common (60-70%). The
continuous and unbroken neurologic progression in NPC is consistently more rapid in patients
diagnosed in early childhood, compared with those diagnosed later on. The NPC disability scale is a
representative
tool for measuring the neurological progression regarding ambulation,
manipulation, language and swallowing.
1
Classification can be made from the age of onset:
1,3,8-10
Perinatal presentation
:
In the perinatal period liver disease is predominant with occurrence of
prolonged cholestatic icterus and progressive hepatosplenomegaly. In about 10% this may lead to
a rapidly fatal liver failure and death before the age of 6 months. In those patients who survive the
neonatal liver disease, this is generally followed by supranuclear gaze palsy, ataxia, increasing
spasticity, seizures and dementia. The onset of these neurological problems can occur at any time
over years or even decades in this group of patients. Occasional occurrence of fetal ascites or fetal
hydrops and rare cases with severe neonatal respiratory failure have been described.
Early infantile presentation (< 2 years)
:
Less-frequently a severe infant neurological
phenotype occurs with hepatosplenomegaly, hypotonia, delay of developmental motor milestones,
loss of acquired motor skills and mental regression followed by spasticity and pyramidal tract
involvement. Most of these patients die before the age of 5 years.
Late infantile presentation (2-6 years)
:
In children with a neurologic onset by the age of 3-5
years the first manifestation is often ataxic gait accompanied by spleno- or hepatomegaly. Isolated
hepatosplenomegaly may initially be the only sign in children of this age, followed later by
development of neurological symptoms.
Late childhood presentation (6-12 years)
:
In patients with neurologic onset between 6-12
years mild learning difficulties due to intellectual impairment and impaired fine motor function are
often the first symptoms, although seizure or cataplexy can be presenting symptoms. Transient
neonatal icterus and hepatosplenomegaly may have occurred previously. Later symptoms include
slowly progressive supranuclear gaze palsy, ataxia, dysartria, chorea and dystonia. Seizures or
(
gelastic) cataplexy often occur in this group of patients and are difficult to control. As disease
progresses spasticity and pyramidal signs develop. The motor impairment is prominent, intellectual