Syndrome of inappropriate secretion of thyrotropin associated with thymoma-related peripheral nerve hyperexcitability.

Syndrome of inappropriate secretion of thyrotropin (SITSH) is a clinical state of inappropriately elevated secretion of thyrotropin (TSH) in the presence of elevated free thyroid hormones. Peripheral nerve hyperexcitability (PNH) is a rare disorder characterized by muscle twitching at rest. No relation between them is known. A 49-year-old man was referred to our hospital because of elevated serum free thyroxine (2.6 ng/dL; normal range, 0.9-1.7) and normal TSH (2.7 mIU/L; normal range, 0.5-5.0). Genetic analysis revealed no mutations of the thyroid hormone receptor ß gene. Magnetic resonance imaging visualized no pituitary adenoma. He complained of appetite loss, weight loss, myokymia, paraesthesia, hyperhydrosis and insomnia. Chest X ray and computed tomography (CT) scan showed a mediastinal tumor diagnosed as a thymoma by CT-guided biopsy. Electromyography disclosed fasciculations and myokymic discharges. Nerve conduction studies showed prolonged after-discharges following evoked compound muscle action potential. The patient was diagnosed with thymoma-associated PNH based on neurological manifestations and neurophysiological findings, and was treated with pulse therapy with methylprednisolone after thymectomy. Interestingly, the SITSH state became less prominent as his neurological manifestations improved. This is the first case of SITSH possibly caused by thymoma-associated PNH.

Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia.

BACKGROUND/AIMS: Aceruloplasminemia is an inherited iron overload disorder caused by a mutation in the ceruloplasmin gene and characterized by iron accumulation in both the liver and brain. The aim of this study was to elucidate the molecular pathogenesis of aceruloplasminemia by a functional analysis of mutant ceruloplasmin. METHODS: The effects of nonsense mutations including Y694ter, W858ter and R882ter were studied by the expression in cultured cells. RESULTS: A biogenesis study demonstrated that the Y694ter and W858ter mutants showed protein synthesis identical to that of wild type protein, however, the mutants were retained in the endoplasmic reticulum (ER), while R882ter mutant was secreted out. Site-directed mutagenesis analyses suggested that Cys-881 was necessary for the secretion of the truncated ceruloplasmin. The W858ter mutant decreased viability in the transfected cells. The expression and the promoter activity of glucose-regulated protein 78 that is an ER stress sensor protein, were up-regulated in the transfected cells. CONCLUSIONS: The truncated mutant containing Cys-881 was able to pass through the ER and was secreted, while the truncated mutant protein without Cys-881 appeared to accumulate in the ER thus leading to ER stress and eventually resulting in cell death.

Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier.

A clinical association between Gaucher disease and parkinsonism has been demonstrated. We herein report a Japanese patient with type 3 Gaucher disease who was compound heterozygous for F213I and L444P mutations in the glucocerebrosidase gene while his father was heterozygous for the L444P mutation. They both presented with parkinsonism characterized by a predominance of akinetic-rigid signs and a favorable response to anti-Parkinson therapies. We investigated the dopaminergic neuronal function using positron emission tomography (PET) with radioligands, [(11)C] CFT and [(11)C] raclopride. PET studies of both patients demonstrated the [(11)C] CFT uptake to be severely decreased in the putamen and the caudate nucleus, however, the [(11)C] raclopride uptake was normal in the basal ganglia. Although the majority of Gaucher disease patients with parkinsonism tend to be refractory to anti-Parkinson therapies. The clinical features and the findings of the PET studies suggest that patients with parkinsonism associated with the mutation in the glucocerebrosidase gene, even in heterozygosis, may be related to the presynaptic dopaminergic neuronal dysfunction reported in Parkinson's disease. A PET study to evaluate the dopaminergic neuronal function in Gaucher disease would provide both a better understanding of the effects of anti-Parkinson therapies and a help to improve our ability to make an early diagnosis of parkinsonism associated with Gaucher disease.

Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia.

BACKGROUND & AIMS: Aceruloplasminemia is a novel hereditary iron overload disease caused by a mutation in the ceruloplasmin gene and characterized by a complete deficiency of serum ceruloplasmin and iron accumulation in the liver and brain. METHODS: We herein studied a novel clinical type of aceruloplasminemia in which a low amount of ceruloplasmin was detected in the serum of a patient. The patient presented with an asymptomatic hepatic iron overload, retinal degeneration, and diabetes mellitus. Magnetic resonance imaging of the liver and basal ganglia showed T2-hypointensity signals associated with parenchymal iron accumulation because of an absence of the ferroxidase activity in ceruloplasmin. RESULTS: A gene analysis showed a novel G969S mutation in the ceruloplasmin gene. A biochemical analysis of the patients' serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity. CONCLUSIONS: This novel clinical type of aceruloplasminemia should therefore be considered in the differential diagnosis of unexplained hemochromatosis, which is associated with a decrease in the serum ceruloplasmin level.

Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia.

Aceruloplasminemia is a neurodegenerative disease characterized by parenchymal iron accumulation owing to mutations in the ceruloplasmin gene. Ceruloplasmin is expressed in the central nervous system in which most of the ceruloplasmin is located on the surface of astrocytes in a glycosylphosphatidylinositol (GPI)-anchored form. We herein describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. An overexpression of wild-type GPI-anchored ceruloplasmin in Chinese hamster ovary cells led to the formation of aggresome-like inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with gamma-tubulin and a disruption of microtubules using nocodazole blocked the formation of such inclusions. Aceruloplasminemia-linked mutant proteins failed to form such inclusions even after treatment with proteasomal inhibitors. An immunofluorescent analysis indicated that the mutant proteins were thus retained in the endoplasmic reticulum (ER), whereas the transfected cells showed a decreased viability. The expression of glucose-regulated protein 78 that is one of the ER stress sensor proteins, and the activity of glucose-regulated protein 78 promoter was upregulated in the cells transfected with the mutants. These findings indicated that when the overexpressed cytoplasmic wild-type ceruloplasmin was not subjected to degradation by the proteasome-ubiquitin system, then the wild-type protein was transported along the microtubules, thus forming inclusions at the microtubule organizing center, whereas the mutant ceruloplasmin failed to form any such inclusions, because the mutant protein might not have been translocated across the ER into the cytoplasm. Therefore, the mutant protein was considered to have accumulated in the ER thus leading to the ER stress, which resulted in cell death.

Intronic mutation in the PGK1 gene may cause recurrent myoglobinuria by aberrant splicing.

A 33-year-old man with mental retardation and recurrent myoglobinuria demonstrated a deficiency in the phosphoglycerate kinase 1 (PGK1) activity of his muscles and erythrocytes. His PGK1 gene had intronic G-to-A substitution 5 nucleotides downstream from the normal exon 7 5' splice site (IVS7 + 5 G>A). This novel mutation results in a frame shift due to the insertion of 52 bp of intron 7 in the mature mRNA by aberrant splicing.

Cytomegalovirus colitis following immunosuppressive therapy for lupus peritonitis and lupus nephritis.

We report a woman with lupus nephritis complicated with lupus peritonitis and cytomegalovirus (CMV) colitis. Diagnosis of lupus peritonitis was made by abdominal computed tomography scan, colonoscopy, and ascitic fluid analysis. Steroid and cyclophosphamide therapy resulted in the improvement of severe lupus nephritis and peritonitis. Thereafter, she developed multiple colonic ulcers as diagnosed by colonoscopy and positive CMV antigenemia assay. Treatment with ganciclovir resulted in the disappearance of colonic lesions. The low cluster of differentiation (CD)4+ lymphocyte count (41/mm3) suggested that the cell-mediated immunity of this patient was comparable to that seen in patients with acquired immunodeficiency syndrome (AIDS).