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Neuroimaging showed cerebellar atrophy
and claval hypertrophy to be the common-
est and earliest signs. Cerebellar cortex
hyperintensity and pallidal iron deposition
were later findings.
Motor or sensory motor axonal neurop-
athy was frequent (20 of 29 patients).
Fifteen patients from 10 families shared
the same mutation (p.V691del).
Neuroimaging showed cerebellar atro-
phy and claval hypertrophy to be the
commonest and earliest signs. Cerebellar
cortex hyperintensity and pallidal iron
deposition were later findings. Motor or
sensory motor axonal neuropathy was
frequent (20 of 29 patients).
Fifteen patients from 10 families shared
the same mutation (p.V691del). One
patient fitted the diagnosis of the much
rarer childhood-onset PLAN.
The following finding seems specific to
PLAN: 21 patients with neurodegenera-
tion with brain iron accumulation mutated
in other genes (16 PANK2, two C19orf12,
two COASY, one WDR45) and 56 patients
with distinct neurological conditions such
as mental retardation, dystonia, cerebral
palsy, epilepsy, mitochondrial encepha-
lopathy. All exhibited normal aspartate
transaminase values, while lactate dehy-
drogenase was mildly elevated in nine
only.
Different from alanine transaminase
and creatine phosphokinase, aspartate
transaminase is widely expressed also
in neuronal cells. It exists in two main
isoforms, cytoplasmic and mitochondrial.
Intriguingly, besides its enzymatic activ-
ity, mitochondrial aspartate transaminase
was found to be a plasma membrane
binding protein essential for free fatty
acid uptake. This finding led to specu-
lation that, in PLA2G6-mutated patients,
widespread mitochondrial damage and/
or the dysfunctional metabolism of free
fatty acids may result in abnormal release
of mitochondrial aspartate transaminase
from damaged cells.
Lactate dehydrogenase is a widespread
cytoplasmic enzyme that catalyzes the
anaerobic conversion of pyruvate to
lactate, whose levels usually increase in
the presence of tissue and cellular dam-
age and in many cancers. Thus, its rise
in PLAN may be less related to diffuse
neuronal damage specifically.
The diagnostic workup of patients sus-
pected of suffering from PLAN includes
brain imaging, neurophysiological, and
ophthalmological assessment. All these
tests can be inconclusive at onset. In
this light, the observation of an elevated
aspartate transaminase/alanine transam-
inase ratio and lactate dehydrogenase
may represent a potential supportive
biomarker of PLAN, prompting PLA2G6
genetic testing even in early stages of
disease or in atypical forms.
One patient fitted the diagnosis of the
much rarer childhood-onset PLAN.
Despite early onset (18 months of age),
clinical progression of this patient was
slower, with behavioral disturbances and
dystonia. The patient carried a missense
variant predicted to be less deleterious.
Dr. Kraoua concluded that elevated aspar-
tate transaminase/alanine transaminase
ratio associated with high lactate dehy-
drogenase values may be considered a
potential supportive biomarker to point
toward a diagnosis of PLAN, even in very
early stages of the disease. The p.V691del
mutation is founder and should be con-
sidered a priority in North African patients.
www.practiceupdate.com/c/58925"
Elevated aspartate
transaminase/alanine
transaminase ratio
associated with high
lactate dehydrogenase
values may be
considered a potential
supportive biomarker
to point toward a
diagnosis of PLAN,
even in very early
stages of the disease.
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