PracticeUpdate: Conference Series - The Best of ICIEM 2017

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. 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. " Elevated aspartate

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

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ICIEM 2017 • PRACTICEUPDATE CONFERENCE SERIES 21