miyajima et al first characterized an adult - onset , autosomal recessive , neurodegenerative disorder resembling parkinson disease ( pd ) associated with near - absent circulating serum ceruloplasmin levels in 1987 . this new disease , aceruloplasminemia , revealed 1 role of ceruloplasmin as an essential ferroxidase critical for iron homeostasis . aceruloplasminemia is an autosomal recessive iron metabolism disorder caused by mutations in the ceruloplasmin gene . while all aceruloplasminemia patients have evidence of abnormal iron homeostasis with marked parenchymal iron metabolism , most have a mild normochromic , normocytic anemia with a decreased serum iron concentration . the elevated serum ferritin suggests a systemic iron overload syndrome , yet affected patients had low transferrin saturation and mild anemia . diabetes mellitus ( dm ) , retinitis pigmentosa , and central nervous symptoms are the main symptoms of aceruloplasminemia . patients usually present in the fourth or fifth decade of life with neurologic signs . these neurologic features are advanced in most patients and associated with significant iron accumulation in the basal ganglia and dentate nucleus of the brain . aceruloplasminemia is one of the disorders causing neurodegeneration with brain iron accumulation ( nbia ) . the diagnosis of nbia is made on the basis of the combination of representative clinical features along with mri evidence of iron accumulation . pathophysiologic hallmarks of nbia include the disease - defining deposition of iron , presence of neuroaxonal spheroids , and variable accumulation of -synuclein - positive lewy bodies and/or tau pathology . some studies have included neurodegenerative disorders including alzheimer diseases ( ad ) , parkinson disease ( pd ) , amyotrophic lateral sclerosis ( als ) , and multiple sclerosis ( ms ) , which are known to feature brain accumulation of iron or associated with altered iron metabolism . iron deposition has been observed in the cortex and amyloid plaques of patients with ad , substantia nigra in pd , and spinal cord in als . the overlap of nbia disorders with common neurodegenerative disorders has generated significant interest and suggests an element of shared pathophysiology . the administration of an iron chelator , before onset or in the early stages of this disorder , is considered to be effective in treatment of aceruloplasminemia . the intravenous administration of deferoxamine has been proposed as a method of inhibiting the iron accumulation . deferoxamine is a high - affinity iron chelator that combines with a ferric iron molecule in 1:1 molar ratio . after crossing the blood brain barrier , deferoxamine has been shown to promote the excretion of excess iron in patients . in this report , we describe a female patient with aceruloplasminemia presenting as psychomotor excitement and neurological symptoms . an antibiotic , minocycline at 150  mg / day , successfully ameliorated the symptoms . to our knowledge , this is the first published case report of successful treatment of aceruloplasminemia with minocycline . one year later , insulin therapy was started for dm , and the insulin requirement gradually increased in a postpartum period . dm was caused by dysfunction of the pancreas due to iron accumulation , suggesting the replacement  cells by adipose tissue . her 1-year younger sister had been diagnosed aceruloplasminemia . based on a positive family history and identification of the homozygous mutation of the ceruloplasmin gene on exon 12 by a genetic study , the concentrations of serum ferritin and iron were 630  ng / ml and 42  g / dl , respectively . deferoxamine was administered for 6 months but was discontinued because of severe dizziness and hearing dysfunction . at the time , the serum ferritin and iron were 459  ng / ml and 42  g / dl , respectively . she had been unable to control her diet , and her blood sugar control had regressed since she was 40-year old . psychomotor excitement was acute in onset and psychotic features included dysphoria , delusional ideas , and thought disturbance . her family noted a decline in social functioning compared with that of 3 years prior . neuropsychiatric symptoms regressed gradually from 1 year previous . her mini mental state examination ( mmse ) general findings were as follows : her height and weight were 1.61 m and 60.5  kg ( bmi : 23.4 ) , her blood pressure was 129/83 mm hg and pulse was 90 bpm and regular . gait tests revealed that the patient was unable to stand with her feet together without falling backward . head mri on axial t2-weighted images showed low signal intensities in the bilateral lentiform nuclei , thalamus , caudate nuclei , cerebellar dentate nuclei , red nuclei , and substantia nigra in the midbrain . low intensities that looked like linear bodies were visible on the surfaces of the brain hemispheres ( figure 1 ) the extrapyramidal symptoms reflected the iron deposition in the basal ganglia ( figures 1 and 2 ) . ataxia and the wide - based gait reflected iron deposition in the dentate nuclei of the cerebellum ( figure 1 ) . magnetic resonance imaging ( t2/flair ) : iron deposition detected as a low - intensity signal . there were low - signal intensities in the bilateral lentiform nuclei , caudate nuclei , thalamus , and cerebellar dentate nuclei . in addition , linear low intensities were exhibited on the surfaces of the brain hemispheres . dopamine transporter scintigraphy : dat transporter imaging showed reduced uptake in the putamen on both the right and left sides . these findings include microcytic anemia , decreased serum iron and copper concentrations , and increased tibc , uibc , and serum ferritin concentrations . an elevated serum ferritin suggests a systemic iron overload syndrome , and the laboratory findings showed a marked decrease in ceruloplasmin . the neurological symptoms rated by the unified parkinson disease rating scale and the international cooperative ataxia rating scale ( icars ) were 32 and 62 , respectively . lithium carbonate ( 400  mg / day ) and aripiprazole ( 30  mg / day ) were started . a previous study reported that oral administration of deferasirox as iron chelation therapy improved the clinical symptoms . we considered the administration deferasirox to interrupt the cycle of iron overload and iron - induced tissue damage . however , her family refused because it is necessary to continue the medication for a long period , requires a large co - pay not covered by health insurance , and has adverse effects . acute bronchitis and sinusitis occurred , and a regimen of 150  mg / day minocycline was initiated with her consent . one week later , her mood was more stable than on admission , and the tendency toward aggression disappeared . minocycline is apparently effective for treatment of thought disturbance and psychiatric and neurological symptoms generally . her walk gradually became stable , and she could walk with the assistance of a walker . however , wearing a protective helmet was still needed . later on she was able to walk by herself , and staggering was also reduced . one year after discharge , the clinical improvement has been maintained , and there is no worsening of psychiatric and neurological symptoms . however , the mr imaging in the range of resolution was not improved despite the clinical improvement after minocycline administration ( figure 5 ) . written informed consent was obtained from the patient for the publication of this report . clinical course : an antibiotic , minocycline at 150  mg / day , ameliorated psychiatric and neurological symptoms . bprs  =  brief psychiatric rating scale , icars  =  international cooperative ataxia rating scale , updr  =  unified parkinson disease rating scale . magnetic resonance imaging ( t2w1/flair ) : 1 year after starting minocycline administration , the same low signal intensities are seen in the bilateral lentiform nuclei , caudate nuclei , thalamus , and cerebellar dentate nuclei as before treatment . the imaging sign that is a neuropathological hallmark of aceruloplasminemia is intracellular iron overload , which is thought to lead to neuronal cell death . in aceruloplasminemia abnormal low intensities reveal iron deposition in the brain . in this case , the finding that head mri on axial t2-weighted images showed low signal intensities in the basal ganglia and dentate nucleus and decreased striatal dat binding ( figure 2 ) indicate severe destruction of the basal ganglia . low intensities that look like linear bodies were also detected on the surfaces of the brain hemispheres ( figure 1 ) . it is supposed that the pathology may have been present for a long time , indicating that the neuropathologic process had worsened and extended beyond the basal ganglia to the cerebral cortex . this observation is consistent with the finding that patients with ad onset at an early age have a greater neocortical iron burden than late - onset patients . cortical iron elevation is a feature of ad and might contribute to the oxidative damage observed in ad brains . in this case , the changes in the serum ferritin level since she was diagnosed did not have a direct relationship with neurological and psychiatric symptoms ( figure 4 ) ; on the other hand , the csf ferritin level was abnormally elevated on admission . csf ferritin is supposed to be an index of the brain iron load , and an elevated csf ferritin in ad was reported to be an indication of cognitive decline . thus , lowering csf ferritin levels might be expected to be a treatment for neurodegenerative disorders , and deferoxamine has been used clinically to slow the progression associated with iron - induced ad and pd . minocycline is a semisynthetic , second - generation tetracycline analog that effectively crosses the blood  brain barrier , and is effective against gram - positive and gram - negative infections . minocycline , a second - generation tetracycline , has a direct radical scavenging property based on its chemical structure . administration of minocycline induced effects similar to those of deferoxamine , which was used 13 years ago in this case , but was abandoned due to side effects . iron is a bioactive metal essential for normal brain functions and an essential substance for the neural development in the central nervous system , myelination , neurotransmitter synthesis , catabolism , and the electron transport system in neuronal cells . on the other hand , iron is easily oxidized when it is not bound to protein , an unstable state that produces free radicals such as hydroxyl radicals by the fenton reaction . the brain is particularly vulnerable to oxidative damage because of its high oxygen utilization and its high concentration of oxidizable polyunsaturated fatty acids . therefore , the iron concentration in the brain is usually critically regulated by several iron metabolism molecules , including ferritin and ceruloplasmin against oxidative stress . ceruloplasmin , an amino oxidase , also known as ferroxidase oxidizes ferrous iron to ferric iron . therefore , ceruloplasmin is not only a ferroxidase but also a scavenger of ros ; in other words , the antioxidant activity of ceruloplasmin can be ascribed mainly to its ferroxidase activity , which inhibits ferrous ion - stimulated lipid peroxidation and formation of hydroxyl radicals in the fenton reaction . ultimately , this iron overload induces oxidative stress in the brain in aceruloplasminemia . oxidative stress and generation of reactive oxygen species ( ros ) are followed by lipid and protein peroxidation . previous studies demonstrated a marked excess in plasma lipid peroxidation in patients with aceruloplasminemia , which is consistent with a potential role for this process in iron - mediated tissue damage , an abnormality that was markedly decreased by deferoxamine therapy . minocycline has a direct radical scavenging property that is consistent with its chemical structure , which includes a multiply substituted phenol ring similar to a - tocopherol ( vitamin e ) . the effective reaction is of a phenol ring of radical scavengers with a phenol - derived free radical that is relatively stable and unreactive . it is also suggested that the direct antioxidant properties of minocycline may contribute to neuroprotective effects in this patient . there is enough evidence to show that enhanced oxidative stress is a major cause of neuronal cell death in aceruloplasminemia . the pathology of aceruloplasminemia , abnormal astrogliosis , and iron - loaded globular structures is observed and also seen in microglial cells . minocycline has been reported to inhibit microglial inflammatory responses in various neurodegenerative diseases such as hd , pd , and ms and has been shown to delay motor function alterations in models of hd , als , and pd . proinflammatory cytokines such as tnf- , il-1 , and il-6 are produced by microglial cells , astrocytes , neutrophils , and macrophages . this activity of minocycline could inhibit microglial activation , but could also prevent inflammatory mechanisms within astrocytes . the chronic inflammation is closely related to clinical symptoms of neurodegenerative diseases , which are associated with altered iron metabolism and free radical injury . the age - related increase in brain iron concentration occurs in conjunction with other risk factors , such as neuroinflammation and metabolic dysfunction . the anti - inflammatory effects of minocycline have been attributed to the compound 's antioxidant activity . the clinical improvement in this case may be related to reciprocal and synergic actions induced by minocycline . miyaoka et al reported the antipsychotic effects of minocycline in patients with schizophrenia and suggested that minocycline might be a safe and effective adjunct to antipsychotic medications , that is , that augmentation with minocycline may prove to be a viable strategy for  boosting  antipsychotic efficacy and for treating schizophrenia . in this case , minocycline is also considered to have a potential for treatment of major depression through its effects on neurogenesis and antiglutamate excitotoxicity because decreased neuronal survival and inflammatory reactions are important causative factors of major depression . it is noteworthy minocycline does not exert significant direct effects on different neuroreceptors , including monoaminergic and n - methyl - d - aspartic acid ( nmda ) receptors . however , it is reported that minocycline can regulate several processes involved in neurodevelopment and in neural plasticity . the clinical improvement in this case could be considered that minocycline provides a potential approach for preventing or treating neuropsychiatric symptoms associated with aceruloplasminemia and inhibiting the progress . despite controversies about the efficacy of minocycline , its relative safety and tolerability might lead to clinical improvements in patients of aceruloplasminemia .
abstractaceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin gene . 
 its prevalence is 1 in 2,000,000 people in japan . 
 this is a disorder of neurodegeneration with iron accumulation in the brain revealed by mri . 
 the iron overload induces oxidative stress and generation of reactive oxygen species , which triggers a cascade of pathological events that lead to neuronal death . 
 intravenous administration of an iron chelator , deferoxamine has been proposed as a method of inhibiting the accumulation of iron.the patient was a 46-year - old japanese woman . 
 she was diagnosed at the age of 33 years . 
 deferoxamine was administrated for 6 months but was discontinued due to adverse effects . 
 on admission at the age of 46 , psychomotor excitement was acute in onset . 
 the extrapyramidal symptoms reflected iron deposition in the basal ganglia and substantia nigra in the midbrain . 
 ataxia and a wide - based gate reflected iron deposition in the dentate nuclei of the cerebellum . 
 an antibiotic , minocycline at 150  mg / day successfully ameliorated the clinical symptoms.minocycline , a second generation tetracycline , has a direct radical scavenging property due to its chemical structure . 
 it has been reported that minocycline is similar to deferoxamine in its ability to chelate iron . 
 minocycline is also involved in preventing the upregulation of proinflammatory cytokines . 
 the iron - chelating , antioxidant , and anti - inflammatory effects of minocycline were involved in this case .