respiratory disease

Niemann-Pick Disease, Types C1 (D)

Clinical Characteristics
Ocular Features: 

The predominant ocular sign in types C1 is difficulty in upgaze described as a supranuclear palsy.  Abnormal saccadic movements have been reported as well.  Retinal signs such as a cherry red spot are not common.

Systemic Features: 

Hepatosplenomegaly and cognitive decline are similar in nature to those found in Niemann-Pick disease types A and B.  Types C1 and C2 are clinically similar but discussed separately as they are caused by mutations in separate genes.  Type D is caused by the same mutation causing C1.  Onset of disease manifested by ataxia, seizures and spasticity is usually between 2 and 4 years.  Dystonia, intention tremor, dysarthria, and hepatosplenomegaly are other features but visceral involvement may be absent.  Ascites and jaundice are sometimes present.  Dementia and extrapyramidal signs are often seen later.  However, there is considerable variation in onset and progression of disease but the symptoms are generally milder than that in types A and B.

Genetics

Type C1 (and D) are caused by mutations in the NPC1 gene (18q11-q12), and type C2 (607625) by mutations in the NPC2 gene (14q24.3).  Mutations in C1 are far more common (95%) than C2 mutations.  The gene mutations reduce the efficiency of sphingosine efflux from lysosomes and late endosomes as a result of a defect in esterification of cholesterol.

Types A (257200) and B (607616) Niemann-Pick disease generally cause more severe clinical signs and are the result of a sphingomyelinase deficiency.  All types of Niemann-Pick disease follow autosomal recessive patterns of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has recently been reported that intrathecal 2-hydroxypropyl-beta-cyclodextrin slows progression of clinical symptoms and prolonged lifespan.

References
Article Title: 

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-v-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Aug 10. pii: S0140-6736(17)31465-4. doi: 10.1016/S0140-6736(17)31465-4. [Epub ahead of print].

PubMed ID: 
28803710

Niemann-Pick disease type C

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. Review.

PubMed ID: 
12974729

Niemann-Pick Disease, Types A and B

Clinical Characteristics
Ocular Features: 

Affected infants usually develop prominent cherry red spots during the first 12 months of life and the entire retina has an ‘opaque’ appearance.  Intracellular lipid accumulation has been seen in retinal neurons, amacrine cells, retinal pigment epithelial cells, and receptors.  The cornea has stromal haziness.  The lens has a brownish coloration on the anterior surface with white spots on the posterior capsule.  Lens opacification seems to progress.

Vision in the first year of life is likely normal as infants have normal fixation, pupillary reactions, and following movements with no nystagmus.  However, by about 2 years of age visual responsiveness may be lost.

Systemic Features: 

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.

Genetics

This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1.  This recessive gene has an unusual biology.  Only the maternally inherited allele is active in the homozygous condition.  Such parent-specific gene activation is called gene imprinting.

Types A and B are allelic disorders.  

Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625)  from mutations in the NPC2 gene (14q24.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy trials are underway.  Amniotic membrane, bone marrow, and stem cell transplantation have been tried with some improvement in visceral disease but the results are mixed and await further studies.

References
Article Title: 
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