Minocycline-associated rimmed vacuolar myopathy in a patient with rheumatoid arthritis.

BACKGROUND: The autophagic vacuolar myopathies (AVM) are a group of inherited myopathies defined by the presence of autophagic vacuoles in pathological muscle specimens. AVM can be categorized into three groups: acid maltase deficiency, myopathies characterized by autophagic vacuoles with unique sarcolemmal features, and rimmed vacuolar myopathies (RVM). While the pathogeneses of these conditions are still being elucidated, some drugs (e.g., chloroquine, its analog, hydroxychloroquine, and colchicine) can also cause AVM. Minocycline is a disease-modifying anti-rheumatic drug that may be used in the treatment of rheumatoid arthritis (RA). Here, we describe the first case of minocycline-associated AVM with rimmed vacuole formation. CASE PRESENTATION: A 75-year-old woman suffering from RA has been continuously treated with minocycline (200 mg/day) for the past 7 years. During this time, she developed a myopathy that predominantly affected her lower limbs. Histological studies of biopsied muscle revealed scattered atrophic myofibers with rimmed vacuoles that contained pigment granules. Histochemical staining revealed that the pigment comprised both iron and melanin, which is consistent with type II minocycline-induced cutaneous pigmentation. Under electron microscopy, autophagic vacuoles were consistently observed in association with numerous collections of pigment granules. CONCLUSIONS: This is the first report of minocycline-induced pigmentation in skeletal muscle. The strong association between autophagic vacuoles and the accumulation of minocycline-induced pigments suggest that long-term minocycline treatment induced pigment accumulation, leading to elevation of autophagic activity and RVM. It might also be possible that minocycline directly activated autophagy, as the observed pigments are known to form complexes containing minocycline and/or its metabolites. As long-term minocycline treatment is expected to be used more widely in the future, we must draw attention to this adverse effect.

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Saccharopinuria accompanied by hyperammonemia and hypercitrullinemia presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia.

We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.

Mild form of Danon disease: two case reports.

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness. Muscle pathology showed autophagic vacuoles with sarcolemmal features. Genetic testing revealed a hemizygous mutation in exon 9b, an alternatively spliced exon, of lysosome-associated membrane protein-2 (LAMP-2) (c.1097_1098delAA). Cardiac testing showed asymptomatic mild left ventricular hypertrophy. He had borderline intelligence. Early stage of retinopathy was detected. Another male patient, currently 53-year-old, had asymptomatic supraventricular extrasystole and muscle weakness but no intellectual disability, harboring the same mutation. He also had retinopathy. The present patients commonly carry a mutation in exon 9b of LAMP-2, suggesting that mutations in the exon are associated with a mild form of Danon disease.

Immunoglobulin G4-related Disease Accompanied by Peripheral Neuropathy: A Report of Two Cases.

Due to its rarity and the limited literature, the clinicopathological characteristics of peripheral nerve involvement in immunoglobulin G4 (IgG4)-related disease are unknown. We present two cases of IgG4-related disease, accompanied by peripheral neuropathy, presenting as unilateral ptosis (case 1) and sclerosing cholangitis (case 2), respectively. In both cases, sural nerve biopsy indicated vasculitis as the underlying pathophysiology; the peripheral neuropathy was refractory to corticosteroid therapy. In contrast to the previously proposed pathomechanism of IgG4-related neuropathy (direct lymphoplasmacytic infiltration), the pathological findings in our cases suggest that vasculitis occurs secondary to systemic autoimmune conditions.

Mitophagy in three cases of immune-mediated necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: ultrastructural and immunohistochemical studies.

Immune-mediated necrotizing myopathy (IMNM) associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies occurs in patients both with and without history of statin-intake. The mechanisms of muscle fiber degeneration in this condition remain unknown. We studied pathological changes in muscle biopsies from three patients lacking history of statin-intake. Ultrastructural observations showed accumulation of degenerating mitochondria, glycogen granules and autophagic vacuoles, forming large composites in three cases, along with various nonspecific changes. The autophagic vacuoles often contained remnants of mitochondria, indicating mitophagy. Furthermore, upregulation of B-cell lymphoma 2/adenovirus E1B 19 kD-interacting protein 3 (BNIP3), a protein involved in mitophagy, was observed in two cases examined. In three cases of sporadic inclusion body myositis, two polymyositis, and three IMNM with anti-signal recognition particle antibody, BNIP3 was upregulated less frequently, and ultrastructural change of mitophagy was rarely seen. These findings suggested that mitophagy plays an important role in muscle fiber degeneration in IMNM with anti-HMGCR autoantibodies.

An aggregate-prone conformational epitope in trinucleotide repeat diseases.

A broad range of neurodegenerative disorders is associated with accumulation of misfolded protein that is toxic to the cells. Knowledge of the conformational structure of the protein implicated is essential for understanding how an aggregate-prone protein causes disease. Here we show that a conformational epitope associated with aggregation property and cell toxicity is preserved in homopolymeric amino acid stretches implicated in oculopharyngeal muscular dystrophy (OPMD) and polyglutamine diseases. These disorders are characterized by the nuclear inclusions and a genetic gain of function. This is the first report of a candidate pathogenic structure, which may trigger aggregation of the proteins in trinucleotide repeat diseases including OPMD and polyglutamine diseases. It provides a possible therapeutic target useful for these disorders.

[A case of agnosia for streets without visual memory disturbance].

A 70-year-old, right-handed man was admitted to our hospital for his sudden-onset topographical disorientation. He failed to find his way to familiar places, but he knew distance and direction to the places. Neurological examination revealed homonymous left-upper quadrantanopsia on Goldmann perimeter and hypoesthesia over the left side of his body. Magnetic resonance imaging showed an abnormal intensity area at the right medial temporo-occipital region, due to the infarct of the right posterior cerebral arterial territory. The neuropsychological examination revealed agnosia for streets, and prosopagnosia without any other disturbance of visual perception. Both visual and topographical memories were intact. It is suggested that, in this case, the agnosia for streets was caused by impairment of recognizing familiar streets and houses or disconnection between their recognition and memory.

[Appearance of numerous lobulated fibers after a protracted course of 18 years in a case of dermatomyositis].

A woman aged 47 first noticed weakness in her proximal muscles of all four limbs at the age of 29. After the initial investigation at our hospital, she was diagnosed as having dermatomyositis associated with primary biliary cirrhosis. In the following 18 years, she was kept on steroids. Although she responded to this treatment, weakness progressed slowly necessitating re-investigation including a second muscle biopsy. It was remarkable that in her first muscle biopsy, no lobulated fiber had been, while they were numerous in the second one. As a result of these studies, possibilities of limb-girdle muscle dystrophy (LGMD) and other myopathies remained but were ultimately ruled out after immunohistochemical/and genetic studies, and the original diagnosis was confirmed. Her weakness responded to an increased dose of steroids. Lobulated fibers were originally described in LGMD, and were reported also in the facioscapulohumeral muscular dytrophy and other hereditary myopathies. They have been rarely described in the inflammatory myopathies. Based on the observation of the present case, we concluded that lobulated fibers have little disease specificity and can newly appear in the course of any chronic myopathies including acquired myopathies like dermatomyositis.

[A case of sensory ataxic neuropathy and polymyositis of perivascular type associated with Sjögren's syndrome].

A 53-year old woman was admitted with of sensory disturbance and weakness of lower limbs which had progressed slowly in the previous ten years. A diagnosis of sensory ataxic neuropathy associated with Sjögren's syndrome was made. A sural nerve biopsy showed marked loss of myelinated fibers. A muscle biopsy revealed atrophy of muscle fibers along with perivascular cellular infiltration. The dorsal root ganglia have been considered to be the main site affected in the ataxic neuropathy in Sjögren's syndrome. However, the evidence for that was meager. The perivascular inflammatory change observed in the muscle may also have existed in the peripheral nervous system including the dorsal root ganglia.

Neuromelanin MRI in a family with mitochondrial parkinsonism harboring a Y955C mutation in POLG1.

BACKGROUND: Progressive external ophthalmoplegia (PEO) and parkinsonism can be caused by genetic mutations that affect mitochondrial DNA (mtDNA) maintenance. We characterized parkinsonism in a family with dominantly inherited PEO. METHODS: We conducted clinical, histological and genetic analyses on two affected members suffering from PEO and parkinsonism, and reviewed the cases in the literature. To clarify parkinsonism related to multiple mtDNA deletions, we used 3-T neuromelanin magnetic resonance imaging (MRI) to assess signal changes in the substantia nigra (SN) and locus ceruleus (LC) in our patients, and compared the results to those observed in idiopathic Parkinson's disease (iPD) (n = 35). RESULTS: We report the first case of a Japanese family harboring a heterozygous p.Y955C mutation in POLG1. The clinical features of parkinsonism related to the Y955C mutation in a total of 16 patients, including our two cases, are indistinguishable from iPD. However, neuromelanin MRI showed a distinct pattern in our cases compared to iPD. The neuromelanin imaging results were consistent with the neuropathological findings reported in cases of POLG1 mutations, in which neurons of the SN were profoundly affected while those in the LC were preserved. CONCLUSIONS: Our results suggest that 3-T neuromelanin MRI may be useful for differentiating POLG1 mutation-associated parkinsonism from iPD, and that POLG1 mutations may cause selective neuronal loss in the SN via a mechanism different from that of iPD.

Effects of tacrolimus on dermatomyositis and polymyositis: a prospective, open, non-randomized study of nine patients and a review of the literature.

Dermatomyositis (DM) and polymyositis (PM) are often refractory to conventional therapy with corticosteroids sometimes combined with immune-suppressing agents and can lead to severe disability if these treatments are unsuccessful. In this prospective, open, non-randomized study, we examined the efficacy of tacrolimus (FK506), an immunosuppressant, in nine patients with DM (n = 5) or PM (n = 4) who did not respond to previous therapy. Outcomes included compound muscle strength, ambulatory status, and serum creatine kinase activity measured at intervals after starting tacrolimus. At 6 months after the introduction of tacrolimus, all five patients with DM and three patients with PM showed clinical improvements. Patients with a disease duration of <4 years and those with trough level of tacrolimus >5 ng/ml tended to have better outcomes than those with longer disease duration or lower trough levels. There were no side effects other than moderate hypertension and aggravation of diabetes mellitus. Tacrolimus was beneficial in the majority of patients with PM or DM refractory to corticosteroid therapy. It was also effective in four patients who were previously treated with other immunosuppressants or intravenous immunoglobulin combined with corticosteroids. These results warrant further studies as to the efficacy of tacrolimus compared to other immunosuppressing agents.

MERRF syndrome presenting with multiple symmetric lipomatosis in a Japanese patient.

Myoclonic epilepsy with ragged red fibers (MERRF), also called Fukuhara's disease, is sometimes accompanied by the rare symptom of multiple symmetric lipomatosis (MSL). MSL associated with MERRF has been reported mainly in Caucasians; such cases have not been reported in Japanese patients. We report the case of a 59-year-old Japanese woman with MERRF syndrome associated with A-->G substitution at nucleotide 8,344 of mtDNA. This case suggests that differences in lifestyle and gene polymorphism among races may be related to the prevalence of MSL due to mitochondrial abnormality, and that mitochondrial abnormalities should be considered as a cause of MSL even in Japanese patients.