Hiroaki Miyajima

Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration.

A 52-year-old woman had a newly recognized disorder of familial hypoceruloplasminemia, blepharospasm, retinal degeneration, and high-density areas in CT of the basal ganglia and liver scan. Immunofixation electrophoresis disclosed apoceruloplasmin deficiency. Kinetic, x-ray analysis, and histochemical study showed accumulation of iron in liver and brain, but not of copper. Intestinal copper absorption was reduced, but liver uptake was increased. Ceruloplasmin is involved in iron metabolism, and the findings suggest that hypoceruloplasminemia due to lack of apoceruloplasmin was causally linked to the iron deposition in basal ganglia and other organs, leading to blepharospasm and retinal degeneration.

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation

Background: Neurodegeneration with brain iron accumulation (NBIA) defines a group of genetic disorders characterized by brain iron deposition and associated with neuronal death. The known causes of NBIA include pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia. Objective: To define the radiologic features of each NBIA subtype. Methods: Brain MRIs from patients with molecularly confirmed PKAN (26 cases), neuroferritinopathy (21 cases), INAD (four cases), and aceruloplasminemia (10 cases) were analyzed blindly to delineate patterns of iron deposition and neurodegeneration. Results: In most cases of PKAN, abnormalities were restricted to globus pallidus and substantia nigra, with 100% having an eye of the tiger sign. In a minority of PKAN cases there was hypointensity of the dentate nuclei (1/5 on T2* sequences, 2/26 on fast spin echo [FSE]). In INAD, globus pallidus and substantia nigra were involved on T2* and FSE scans, with dentate involvement only seen on T2*. By contrast, neuroferritinopathy had consistent involvement of the dentate nuclei, globus pallidus, and putamen, with confluent areas of hyperintensity due to probable cavitation, involving the pallida and putamen in 52%, and a subset having lesions in caudate nuclei and thalami. More uniform involvement of all basal ganglia and the thalami was typical in aceruloplasminemia, but without cavitation. Conclusions: In the majority of cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2* and T2 fast spin echo brain MRI, leading to accurate clinical and subsequent molecular diagnosis.

Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

The Neurological Presentation of Ceruloplasmin Gene Mutations

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease.

Aceruloplasminemia, an inherited disorder of iron metabolism

Ceruloplasmin, a multi-copper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron. Aceruloplasminemia is an inherited disorder of iron metabolism due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurological disease, which include ataxia, involuntary movements, and dementia. These symptoms reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Twenty-one mutations in the ceruloplasmin gene have been reported in 24 families worldwide. In Japan, the incidence was estimated to be approximately one per 2,000,000 in the case of non-consanguineous marriages. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with increased levels of lipid peroxidation in the serum, cerebrospinal fluid, and erythrocyte membranes. The levels of malondialdehyde and 4-hydroxynonenals, indicators of lipid peroxidation, were also elevated in the basal ganglia and cerebral cortex. Positron emission tomography showed diminished brain metabolism of glucose and oxygen. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximate 45% and 42%, respectively, for complexes I and IV. These findings suggest that iron-mediated free radicals causes neuronal cell damage through lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains.

Aceruloplasminemia, an iron metabolic disorder

Aceruloplasminemia is an inherited disorder of iron metabolism caused by the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of adult‐onset neurologic disease, retinal degeneration and diabetes mellitus. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. Severe iron overload and extensive neuronal loss were observed in the basal ganglia, while iron deposition and neuronal cell loss were trivial in the frontal cortices. The cerebellar cortex showed marked loss of Purkinje cells. Iron deposition was more prominent in the astrocytes than in the neurons. Excess iron functions as a potent catalyst of biologic oxidation. Astrocytic deformity and globular structures are characteristic features in aceruloplasminemia brains. The globular structures in the astrocytes were seen in proportion to the degree of iron deposition and reacted positively to anti‐4‐hydroxynonenal, one of the indicators of lipid peroxidation,  and  anti‐ubiquitin  antibodies,  but  not to  anti‐α‐synuclein antibody. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemia brains through lipid peroxidation. Ceruloplasmin may play an essential role in neuronal survival in the central nervous system.

Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries

We screened LRRK2 mutations in exon 41 in 904 parkin‐negative Parkinsons disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single‐founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single‐founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac 123I‐metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.

Mutations in a Thiamine-Transporter Gene and Wernicke's-like Encephalopathy

To the Editor: We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernickes encephalopathy that developed in the second decade ...

Iron accumulation in the liver of male patients with Wilson's disease

OBJECTIVES:There is accumulating evidence that ceruloplasmin, a copper protein with ferroxidase activity, plays an important role in iron metabolism. The genetic disorder, aceruloplasminemia, can lead to tissue storage of iron as in hemochromatosis. Because most patients with Wilsons disease, a genetic copper toxicosis, have hypoceruloplasminemia, some could be affected by iron overload.METHODS:Four male patients with Wilsons disease were enrolled in this study of pre- and post-treatment iron metabolism.RESULTS:Pretreatment copper contents of the liver were high in all four male patients studied as diagnostic of Wilsons disease. Genetic analysis supported their clinical diagnosis of Wilsons disease without a background of hemochromatosis. Pretreatment serum ceruloplasmin levels were <20 mg/dl in all four patients. A standard penicillamine treatment for 3–8.5 yr further decreased their serum ceruloplasmin levels. Post-treatment serum ferroxidase activity was low as was the serum ceruloplasmin protein. Copper contents in the liver decreased after treatment in all subjects. In contrast, nonheme iron in the liver increased during treatment. Pretreatment liver specimens were positive for histochemical iron in two patients, and post-treatment specimens were positive in all four patients. In two patients, serum aminotransferase levels rebounded with elevation of serum ferritin concentration during the treatment period. Subsequent iron reduction by phlebotomy ameliorated their biochemical liver damage.CONCLUSION:Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilsons disease.