Adult Batten Disease: New Genes, Better Diagnosis

1. What is adult Batten disease?
Adult Batten disease (also known as adult onset neuronal ceroid
lipofuscinosis or ANCL) is a diverse group of diseases with
different genetic causes. The age of onset can range from the late
teens to the sixties; symptoms include seizures, poor balance
(ataxia) and intellectual decline. Some forms involve blindness,
while others, known as Kufs disease, do not. Some forms show
recessive inheritance, where disease is caused by mistakes
(mutations) in two copies of a gene, while others show dominant
inheritance, in which mistakes in a single copy of a gene suffices
to cause disease.
How is it diagnosed?
ANCL is much more difficult to diagnose using skin biopsies or
other accessible tissues than childhood forms of Batten disease.
This is because the diagnostic findings may be sparse and difficult
to distinguish from normal changes of ageing. Reliable diagnosis
using microscopy may require examination of a small piece of
brain tissue surgically removed from the patient (a brain biopsy).
If a patient has a form of ANCL for which the genetic basis has
been discovered, then diagnosis can be performed by simply
examining the patient’s DNA from a blood sample.
Adult Batten Disease: New Genes, Better Diagnosis
Katherine R Smith1, Hans-Henrik Dahl2, John Damiano2, Melanie Bahlo1, Samuel F Berkovic2
(1) Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne VIC 3052, Australia
(2) Epilepsy Research Centre, University of Melbourne, Melbourne VIC 3084, Australia. Contact s.berkovic@unimelb.edu.au BDSRA 2012
At the start of 2010, the genetic basis of ANCL was completely
unknown, so genetic testing was not an option for patients
suspected to have ANCL. Fortunately, great progress has been
made since that time; the genetic basis of at least four different
types of ANCL have been discovered (Figure 1 and Table 1). Our
research group has identified three such genes. One is not yet
published and is described as ‘Gene B’ in this poster. The other
two genes are:
The CLN6 gene - recessive Kufs disease, type A
We have identified mutations in the CLN6 gene as the major cause
of Type A Kufs disease. It has been known since 2002 that
mutations in both copies of CLN6 can cause a form of childhood
Batten disease called variant late infantile NCL. We discovered
that mutations in both copies of this gene can also cause ANCL - a
surprising finding, since the two forms of Batten disease have
different ages of onset, and only the childhood form involves
blindness.
The progranulin gene (GRN) - recessive ANCL with blindness
So far, mutations in this gene have only been detected in two
ANCL patients, a pair of siblings, so mutations in this gene do not
appear to be a common cause of ANCL. The siblings developed
symptoms at the ages of 22 and 23, including visual problems.
They were found to have mutations in both copies of the GRN
gene.
It has been known since 2006 that mutations in a single copy of
the GRN gene can cause a form of late onset intellectual decline
called frontotemporal lobar degeneration (FTLD). This research
finding provides an unexpected link between ANCL, which is a
rare disease, and FTLD, which is relatively common.
What does this mean for patients?
The recent advances in ANCL mutation identification means that
most patients with a form of ANCL caused by mutations in CLN6,
DNAJC5, ‘Gene B’ or GRN can now be diagnosed by examining
DNA obtained from a blood sample. These patients will be able to
avoid surgery to remove brain tissue to be used for diagnosis.
A genetic diagnosis will inform genetic counseling of patients and
their relatives, helping them to understand the risk of disease
faced by themselves and any children they might have.
We hope that these findings will encourage research into the
function of the proteins produced by these four genes, and
ultimately lead to therapies being developed for these types of
ANCL.
Conclusion
Our research has revealed unexpected connections between a
form of ANCL and a form of childhood onset Batten disease, and
between a second form of ANCL and a relatively common late
onset cognitive impairment. ANCL is rare compared to childhood
onset Batten disease, which is itself a rare disease. We hope that
the links we have discovered will allow ANCL patients to benefit
from research being undertaken into these other conditions.
Great progress has been made in identifying genes in which
mutations cause ANCL. However, it is thought that several genes
still remain to be discovered.
References
1. Arsov T, Smith KR, Damiano J, et al. The American Journal
of Human Genetics 2011;88:566-73.
2. Benitez BA, Alvarado D, Cai Y, et al. PLoS ONE
2011;6:e26741.
3. Nosková L, Stránecký V, Hartmannová H, et al. The
American Journal of Human Genetics 2011;89:241-52.
4. Velinov M, Dolzhanskaya N, Gonzalez M, et al. PLoS ONE
2012;7:e29729.
5. Smith KR, Damiano J, Franceschetti S, et al. The American
Journal of Human Genetics 2012;90:1102-7.
Figure 1. Different forms of adult Batten disease and their
genetic basis (where known )
Gene Ages of onset No. families or
unrelated
patients with
mutations in this
gene
No. patients with
mutations in this
gene (can be
related)
No. different
mutations
discovered
CLN61 16-51 7 10 9
DNAJC52-4 24-46 9 >=23 2
GRN5 22-23 1 2 1
‘Gene B’ 20-35 3 4 5
Table 1. Summary of genes implicated in ANCL - age of onset,
number of patients and number of mutations