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  • We used MRI images taken to


    We used MRI images taken 1 to 8 weeks after a crisis to explore basal ganglion involvement and found restricted hiv integrase at the basal ganglion. This finding suggests that cytotoxic damage to the basal ganglion persists post-crisis. When MRI images were obtained much longer after crisis, restricted diffusion was not found at the basal ganglia, but rather atrophied changes were present (Table 3). The disappearance of restricted diffusion suggests that the acute insult affecting the basal ganglion has disappeared gradually, and this is accompanied by basal ganglion atrophy due to neural death. T2 hyperintensities in white matter were prevalent among older patients, both with or without encephalopathic crises. The neuropathological implications of the presence of white matter disease in relation to GA-1 seems to involve spongiform myelinopathy, which is supposed to be caused by toxins associated with GA-1 that cause desmyelination or demyelination. Our study suggests that the frequency of encephalopathic crisis decreases notably after newborn screening. This is compatible with previous reports. However, despite early treatment, 22% of patients still suffered from an encephalopathic crisis. This frequency is similar to that of presymptomatically diagnosed patients worldwide, which is around 25%. Among the nine patients diagnosed by newborn screening, the outcomes of cases 1–6 were much better than those of cases 7–9. Cases 7–9 had delayed emergency treatment, which is consistent with a German study showing that adherence to the maintenance treatment and early emergency treatment improves the neurological outcome, with all reported crises only occurring in patients when emergency treatment had been delayed for more than 24 hours after the initial symptoms. Additionally, different levels of disease severity were noted after an encephalopathic crisis. For example, Case 10 had an encephalopathic crisis at 2 months of age, but the diagnosis of GA-1 was delayed until 14 years of age. Despite some disability, she was still able to study at university. Her genotype included one Chinese hot spot mutation, IVS10-2A>C and one novel mutation N291K. We suspect that N291K is a milder mutation because of the more limited disease course. Nevertheless, recent studies suggest that there is no clear relationship between genotype and clinical phenotype. Interestingly, cases 1, 8, and 9, homozygous for IVS10-2A>C, had significantly different outcomes. Uniquely, two GA1 patients (cases 1, 2) had nystagmus; this has never been reported in pediatric GA1 patients. Nystagmus may be caused by cortical visual impairment and/or optic atrophy. Importantly, several inherited metabolic disorders cause cortical visual impairment or optic atrophy. Optic atrophy or nystagmus has been reported in patients with organic aciduria, such as cobalamin C defects, methylmalonic aciduria or isovaleric aciduria. We suggest that GA-1 might be a new etiology of nystagmus. Our examinations revealed optic atrophy affecting case 1 and the presence of T2 hyperintensity within the left occipital lobe in case 2, which might be related to the disease or unmyelination. Therefore, although cortical visual impairment was suspected as a cause of the nystagmus affecting case 2, the actual etiology of that case remains undetermined. Additionally, nystagmus had been reported in one patient with adult onset GA-1 who presented with leukoencephalopathy. Cataract, intraretinal hemorrhages, strabismus, gaze palsy, pigmentary retinopathy, and ametropia have also been reported in GA-1 patients. However, optic atrophy has never been reported in GA1 patients; ours is the first reported. Therefore, complete ophthalmological evaluations are suggested when examining patients with GA-1. The pathophysiology of the optic atrophy detected in case 1 remains unknown, but we suggest that it is similar to the white matter disease, namely spongiform myelinopathy, which is induced by toxins associated with GA-1. This suggestion is based on a GA-1 autopsy report, which demonstrated the presence of spongiform myelinopathy of the optic nerve. Furthermore, in vitro studies and animal studies also support the hypothesis that GA and its metabolites cause white matter disease in GA-1 patients. Although GA-1 nervous system damage starts prenatally, early treatment in case 1 was able to produces a gradual improvement in visual acuity.