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44歳,男性,既往歴に糖尿病.緩徐進行性の自発性低下を主訴に入院.入院時は無関心・注意力低下と自発性消失,発語量の低下等の精神症状と動作緩慢,Gegenhaltenを認めた.高次機能検査では近時記憶障害,同じ色で同一部位を塗り続けるなど反復・常同動作を認めた.頭部MRIでは両側視床はT2強調画像で高信号を示し,同部位に造影効果を認めた.脳血管撮影静脈相では深部脳静脈が描出されず,また動脈相ではテント動脈より硬膜動静脈瘻(dural AVF)を認めたことより,dural AVF合併の深部脳静脈血栓症と診断した.本例は前頭葉症候で発症した点が特徴的であり,脳血流SPECT上両側前頭葉が低集積であったことより,視床―前頭葉間の連絡路障害による可能性を考えた.

Autosomal-dominant type of myotonia (Thomsen's disease) and autosomal-recessive one (Becker's disease) are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Clinical manifestation of the diseases ranges from minimum to severely disabling myotonia. We report a Japanese family with Thomsen's disease, featuring an index female young patient who possesses two dominantly-inherited mutated CLCN1 alleles. She showed severe myotonic symptoms from 18 months of age, associated with moderate muscle hypertrophy. Her mother had mild myotonic signs without muscle hypertrophy. Her father was quite normal by both clinical and electromyographic examinations. With genomic DNA extracted from blood leukocytes, all 23 exons of the CLCN1 gene were analyzed by direct sequencing of PCR products. The analysis revealed compound heterozygous mutations of T539A and M560T in the index patient, a heterozygous mutation of T539A in her mother, and a heterozygous mutation of M560T in her father. Since both mutations were previously described in families of Thomsen's disease, her father was regarded as a non-symptomatic carrier. The family reveals that compound heterozygosity of two dominantly inheritable disease mutations exacerbates the myotonia, suggesting the dosage effect of CLCN1 mutation responsible for myotonia congenita of Thomsen type.

A woman aged 59 years with adult-onset progressive myopathy had anti-Golgi (giantin) autoantibody in the serum. Limb-muscle biopsy revealed chronic myopathy with paucity of cellular reactions and reduced immunostaining for alpha-dystroglycan. The similarity of the current patient with cases of hereditary alpha-dystroglycanopathies (Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, muscle-eye-brain disease, congenital muscular dystrophy type 1C, and limb-girdle muscular dystrophy type 2I) suggests that the Golgi apparatus is the target organelle in a subset of myopathies.

58歳,女性.緩徐進行性の歩行障害.高度の変形性頸椎症と脊柱管狭窄,頸髄MRIでT2高信号変化より頸椎症性頸髄症を疑ったが,胸部X線で肺門部拡大あり.他のサルコイドーシス(サ症)の身体・血清学的所見は陰性.しかし縦隔内リンパ節生検でサ症を確認.診断治療を目的に副腎皮質ステロイドを投与し,神経・画像所見は寛解した.頸椎症性頸髄病変の存在例に一つでもサ症の所見が陽性時は,サ症の内科的治療を優先すべき点を強調した.

Five familial cases (in two families) and one sporadic case of a new congenital myasthenic syndrome were investigated. Symptoms arise in infancy or later life. Typically, one finds selective involvement of cervical, scapular, and finger extensor muscles, ophthalmoparesis, and variable involvement of other muscles. There is a repetitive muscle action potential to single nerve stimulus in all muscles and a decremental response at 2 to 3 Hz stimulation in clinical affected muscles. Microelectrode studies reveal markedly prolonged end-plate potential (epp), miniature end-plate potential (mepp), and miniature end-plate current; normal quantum content of the epp; and a smaller than normal or low-normal mepp amplitude. Light microscopy demonstrates predominance of type I fibers, small groups of atrophic fibers, tubular aggregates and vacuoles near end-plates, abnormal end-plate configuration, and nonspecific myopathic changes. Abundant acetylcholinesterase activity is present at all end-plates, and the activity and kinetic properties of this enzyme in muscle are normal. Calcium accumulated at the end-plate in one patient. Quantitative electron microscopy shows decrease in the size of nerve terminals, increase in the density of synaptic vesicles, and reduction in the length of postsynaptic membranes. There is focal degeneration of junctional folds with corresponding loss of acetylcholine receptor, most marked in cases with the lowest mepp amplitude. There are no immune complexes at the end-plate. Fiber regions near end-plates display dilation, proliferation, and degeneration of the sarcoplasmic reticulum; nuclear, mitochondrial, and myofibrillar degeneration; and vacuoles resembling those found in periodic paralysis. A prolonged open time of the acetylcholine-induced ion channel is considered to be the basic abnormality and may account for the physiological, morphological, and clinical alterations.

Rats immunized with purified torpedo acetylcholine receptor (AChR) plus adjuvants developed chronic experimental autoimmune myasthenia gravis (EAMG) after day 28. Forelimb muscles from EAMG rats 29 to 103 days after immunization and from control animals were used for the ultrastructural localization of IgG and C3. IgG was demonstrated with rabbit anti-rat IgG followed by treatment with peroxidase-labeled staphylococcal protein A; and C3 with peroxidase-labeled rabbit anti-rat C3, or with unlabeled rabbit anti-rat C3 followed by peroxidase-labeled protein A. In EAMG rats both IgG and C3 were localized on the terminal expansions of the junctional folds, where AChR is known to be located, and on detached, degenerated parts of the folds in the synaptic space. Background staining was negligible. The findings provide unambiguous evidence for a destructive autoimmune reaction involving the postsynaptic membrane in EAMG, implicate the complement system in this reaction and show that detachment of the tips of the junctional folds is one way by which immune complexes, and AChR, are eliminated from the postsynaptic membrane. The immuno-electron microscopic findings in chronic EAMG closely resemble those described in human myasthenia gravis.

Using a morphometric method, we studied ventral spinal roots and anterior horn neurons of the fourth lumbar segment in 17 patients with ALS. Both populations of large myelinated fibers and anterior horn cells had significantly high correlations to muscle strength in the legs and duration of symptoms. However, active axonal degeneration was consistently, present in terms of either large myelinated fibers or anterior horn cells.

Specific probes (alpha-bungarotoxin for acetylcholine receptor (AChR), staphylococcal protein A for IgG, monospecific antibodies against C3 and C9) labelled with peroxidase were applied to study of the ultrastructure of the MG end plate. In each case of MG there was postsynaptic AChR deficiency, usually greatest at end plates with marked degeneration of junctional folds. Morphometric estimates of postsynaptic AChR correlated linearly with the MEPP amplitude. In each case of MG, IgG was localized on the postsynaptic membrane where AChR is known to be located and on debris in the synaptic space. The abundance of antibody was proportionate to the amount of AChR remaining at the end plate. The localization of C3 was essentially identical with that of IgG. For most cases of MG it can be inferred that binding of IgG and C3 to AChR does not interfere with receptor function. C9, the terminal lytic complement component, was localized on debris in the synaptic space and on remnants of junctional folds. This proves that complement mediated destruction of junctional folds occurs in human MG. Studies in experimental auto-immune MG indicate that antibody-dependent internalization of AChR occurs in subclinical, mild and more severe diseases but increased AChR synthesis can compensate for this in subclinical and mild myasthenia. Complement-mediated injury of the postsynaptic membrane appears to be a requirement for induction of more severe MG.

The restriction endonuclease SmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993T--G mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F(0)F(1)-ATPase. Our ultimate goal is to apply SmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed the SmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by the SmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targeted EcoRI induced a decrease in cytochrome c oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases.