Ak. Das et al., MOLECULAR-GENETICS OF PALMITOYL PROTEIN THIOESTERASE DEFICIENCY IN THE US, The Journal of clinical investigation, 102(2), 1998, pp. 361-370
Mutations in a newly described lysosomal enzyme, palmitoyl-protein thi
oesterase (PPT), were recently shown to be responsible for an autosoma
l recessive neurological disorder prevalent in Finland, infantile neur
onal ceroid lipofuscinosis. The disease results in blindness, motor an
d cognitive deterioration, and seizures. Characteristic inclusion bodi
es (granular osmiophilic deposits [GROD]) are found in the brain and o
ther tissues. The vast majority of Finnish cases are homozygous for a
missense mutation (R122W) that severely affects PPT enzyme activity, a
nd the clinical course in Finnish children is uniformly rapidly progre
ssive and fatal. To define the clinical, biochemical; and molecular ge
netic characteristics of subjects with PPT deficiency in a broader pop
ulation, we collected blood samples from U.S. and Canadian subjects re
presenting 32 unrelated families with neuronal ceroid lipofuscinosis w
ho had GROD documented morphologically. We measured PPT activity and s
creened the coding region of the PPT gene for mutations. In 29 of the
families, PPT deficiency was found to be responsible for the neurodege
nerative disorder, and mutations were identified in 57 out of 58 PPT a
lleles. One nonsense mutation (R151X) accounted for 40% of the alleles
and was associated with severe disease in the homozygous state. A sec
ond mutation (T75P) accounted for 13% of the alleles and was associate
d with a late onset and protracted clinical course. A total of 19 diff
erent mutations were found, resulting in a broader spectrum of clinica
l presentations than previously seen in the Finnish population. Sympto
ms first appeared at ages ranging from 3 mo to 9 yr, and about half of
the subjects have survived into the second or even third decades of l
ife.