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.

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.

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.

[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.

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.

[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.