Neuronal ceroid lipofuscinoses (NCLs) are
a group of genotypically and
phenotypically variable lysosomal storage
disorders, characterized by
neurodegeneration and accumulation of
autofluorescent lipopigment within the
lysosomes of cells1,2.
The NCLs are historically categorized by
age of onset (infantile, late infantile,
juvenile, and adult onset disease).
Specific genes were thought to be
associated with specific phenotypes, i.e.,
CLN1 and infantile onset disease1,2.
Significant phenotypic heterogeneity may
be observed in individuals with mutations
in the various genes associated with NCL.
It is now recommended that the NCLs be
primarily classified by gene (or protein)
with secondary classifications based upon
age of onset and clinical features1.
Further molecular genetic characterization
has identified at least 10 genes associated
with NCL3. CLN10 disease is the result of
mutations in the lysosomal aspartic
protease cathepsin D gene (CTSD) 1.
CLN10 disease is classically associated
with severe, congenital neurologic disease,
including microcephaly, brain atrophy,
seizures, spasticity, and respiratory
insufficiency, with death occurring in the
first few weeks of life 1,4.
Here we present two Caucasian first
cousins (Figure 1) demonstrating a
similar, juvenile onset, neurodegenerative
phenotype due to compound heterozygous
missense mutations (G256A; T685A) in
CTSD. These cases provide further insight
the degree of genotypic and phenotypic
heterogeneity in the NCLs, particularly in
individuals with mutations in the same
Case 1: 13 year old Male
Reported to be normal until age 6
Significant academic challenges by ~ age 9
Behavioral concerns include immaturity,
impulsivity, uncontrollable outbursts and
compulsive behaviors; followed by a
psychiatrist and successfully treated with
Currently meeting goals of IEP with
modifications of assignments and scribe
Visual impairment reported at age 6 years;
diagnosed with pigmentary retinopathy
with subtle macular bull’s eye lesions
Currently legally blind with significant
limitations in central vision and ability to
see in dim light
Progressive tremor starting at age ~ 9 years,
limiting ability to read Braille; difficulties
with speech, including stammering and
word repetition. Balance issues followed.
Currently walks independently but with
poor balance and frequent falls.
Parents report occasional full body jerks;
staring spells noted by teachers
Based upon clinical features NCL panel was
performed; identified compound
heterozygous missense mutations (G256A;
T685A) in CTSD
Case 2: 19 year old Male
Mild delays in early development
Reads at approximately the 2nd grade level
and has challenges counting past 3-4
Experiences obsessive tendencies and
occasionally has outbursts
Progressive visual impairment beginning at
age 5 years; diagnosed with pigmentary
Total vision loss at approximately 8 years
Decline in motor skills beginning at age 6
years. Previously able to ambulate with
walker. Currently unable to walk
independently, primarily uses wheelchair
Fine motor exam concerning for
dysdiadochokinesia. Absent reflexes; no
Recent development of seizures consisting
of focal, unilateral upper extremity jerking;
treated with antiepileptic medication
Initially diagnosed in childhood with a
complex III mitochondrial defect based
upon results of electron transport chain
enzyme testing of muscle
NCL was subsequently suspected based
upon similarities to his cousin, and genetic
testing identified compound heterozygous
missense mutations (G256A; T685A) in
1 Mink JW, Augustine EF, Adams HR, Marshall FJ, Kwon JM. Classification and
Natural History of the Neuronal Ceroid Lipofuscinoses. J Child Neurol. 2013.
2 The Neuronal Ceroid Lipofuscinoses (Batten Disease), Second Edition, Edited
by Sara Mole, Ruth Williams and Hans Goebel . Oxford University Press, 2011.
3 Bennet MJ, Rakheja D. The Neuronal Ceroid-Lipofuscinoses. Dev Disabil Res
Rev. 2013. 17:254-9.
4 Siintola, E., Partanen, S., Stromme, P., Haapanen, A., Haltia, M., Maehlen, J.,
Lehesjoki, A.-E., Tyynela, J. Cathepsin D deficiency underlies congenital human
neuronal ceroid-lipofuscinosis. Brain. 2006. 129:1438-45.
5 Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W,
Saftig P, Gartner J. Cathepsin D Deficiency is Associated with a Human
Neurodegenerative Disorder. Am J Hum Genet. 2006. 78:988-98
These cases highlight the similarity
of phenotypes that may exist from a
specific genotype, and significant
phenotypic variability that can be
observed with different mutations in
specific NCL genes
Long-term registry data is needed to
further characterize phenotypic
and understand the reasons for this
Juvenile Onset Presentation Of Neuronal Ceroid Lipofuscinosis Due
to Mutations in CTSD
T. Andrew Burrow, M.D., Christine G. Spaeth, M.S., Robert Sisk, M.D., Barbara Hallinan, M.D., Ph.D.
Mutations in CTSD (CLN10) are classically
associated with severe, congenital neurologic
Here we present two related individuals with
mutations in CLN10 demonstrating juvenile
onset disease. Steinfeld and colleagues
previously described a 17-year-old female
with a childhood onset disease phenotype,
associated with progressive visual, motor,
and cognitive impairment5.
These cases provide further evidence for
significant genotypic / phenotypic variability
within a gene, which may also be observed
in individuals with mutations in other genes
associated with NCL, such as CLN11,2.
Pedigree of family