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Autosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.

Unlabelled: This study investigated alterations in regional cerebral blood flow (rCBF) in patients with Parkinson's disease using statistical parametric mapping (SPM)., Methods: Noninvasive rCBF measurements using 99mTc-ethyl cysteinate dimer (ECD) SPECT were performed on 28 patients with Parkinson's disease and 48 age-matched healthy volunteers. The Parkinson's disease patients were divided into two groups, 16 patients with Hoehn and Yahr stage I or II and 12 patients with Hoehn and Yahr stage III or IV. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images in relative flow distribution (normalization of global CBF for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM., Results: In patients with stage I or II Parkinson's disease, we found a diffuse decrease in absolute rCBF in the whole brain with sparing of the central gray matter, hippocampus and right lower temporal lobe compared with healthy volunteers. Adjusted rCBF increased in both putamina and the right hippocampus. In patients with stage III or IV disease, rCBF decreased throughout the whole brain. Adjusted rCBF increased bilaterally in the putamina, globi pallidi, hippocampi and cerebellar hemispheres (dentate nuclei) and in the left ventrolateral thalamus, right insula and right inferior temporal gyrus., Conclusion: SPM analysis showed that significant rCBF changes in Parkinson's disease accompanied disease progression and related to disease pathophysiology in the functional architecture of thalamocortex-basal ganglia circuits and related systems.

We studied whether nicergoline, clinically active in chronic cerebrovascular insufficiency, influences nerve growth factor (NGF) levels in the rat brain. In young Fischer rats, repeated intraperitoneal injections of nicergoline (0.3 and 1.0 mg/kg body weight) did not show any effects on frontal NGF contents determined by a highly sensitive enzyme immunoassay. In aged rats, 22-month-old, however, repeated injections of nicergoline (1.0 mg/kg body weight) induced a significant increase in the NGF level in the frontal region.

Myotonic dystrophy (DM) is genetically characterized by abnormal expansion of an unstable CTG trinucleotide repeat, located in the 3'-untranslated region of mRNA encoding the family of serine-threonine protein kinases. DNA extracted from various organs of patients with DM was analyzed by the Southern blotting method. We identified differently expanded bands in DNAs from various tissues from patients with DM. In studying the length of the CTG repeat in different regions of the brain, we found a noticeably small increase in repeat length in the cerebellum compared with other tissues. While this phenomenon has been reported in other triplet repeat diseases such as Huntington disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy, we are the first to describe it in DM. Although the mechanism of expansion of the triplet repeat remains to be defined, the tissue-dependent somatic mosaicism suggests that its occurrence may depend on the differentiated state of each tissue.

A sporadic Japanese case of myotonia congenita with painful muscle cramps is reported. Electromyographic examinations disclosed myotonic discharge with dive bomber sounds at insertion, and high-amplitude, high-frequency motor unit potentials during the muscle cramps. Biopsied muscle specimens and EMG findings showed non-specific mild myopathic changes. There was no abnormal expansion of CTG repeat within the myotonic dystrophy gene. This patient's disorder closely resembles Becker's myotonia congenita Type II though the family history of was non contributory.

The cytogenetic analysis of 23 Japanese patients with amyotrophic lateral sclerosis is reported. G-banded chromosomes of cultured peripheral blood lymphocytes of one subject had a constitutional chromosomal translocation, t(7;13)(p22;q21). No constitutional chromosome abnormality was found in any of the other 22 Japanese patients with amyotrophic lateral sclerosis tested.

Clinical, neurophysiological and neuropathological investigations were performed on five patients from two families with autosomal dominant distal amyotrophy followed by spastic paraplegia and with a positive history in two generations of these two families. All cases in the two families had a benign clinical course, although two mothers could not walk without support at around 60 years old. Neurophysiological studies revealed normal maximum conduction velocities of peripheral sensory and motor nerves, and the central spinal sensory pathway. Distribution of motor nerve conduction velocities in the ulnar nerve had a normal pattern except for one patient who had severe deformities of the cervical vertebrae. The biopsied sural nerve disclosed no distinct abnormalities in any cases. From these results, we confirmed preservation of the myelinated nerve fibers of motor and sensory peripheral nerves.

Site-specific mutants of human myoglobin (Mb) have been prepared, in which Leu29 (B10) is replaced by Ala(L29A) or Ile(L29I), in order to examine the influence of this highly conserved residue in the hydrophobic clusters of the heme distal site on the heme environmental structure and ligand binding properties of Mb. Structural characterizations of these recombinant Mbs are studied by electronic absorption, infrared (IR), one- and two-dimensional proton nuclear magnetic resonance spectroscopies, and ligand-binding kinetics by laser photolysis measurements under ambient and high pressures (up to 2000 bar). Multiple split carbon monoxide (CO) stretch bands in the IR spectra of mutant Mbs exhibit a relative decrease of the 1945 cm-1 band (approximately 50%) which is associated with an upright binding geometry of CO, accompanied by an increase of the tilted CO conformer at 1932 cm-1. On the basis of these results, replacement of Leu29(B10) by Ala or Ile appears to allow bound CO to rotate from a conformation pointing toward the beta meso carbon of the heme group to the one pointing toward the alpha meso carbon atom, presumably filling the space left by removal of the delta 2 carbon atom of Leu29(B10). These substitutions cause the rate constants for CO and O2 association to decrease almost 3-5-fold. Present results show that CO and O2 bindings to the heme iron of Mb are controlled by Leu29(B10) by influencing the structure of close vicinity of the heme and the geometry of iron-bound ligand. Further, mutant Mbs (Leu72(E15)----Ala and Leu104 (G5)----Ala) which have altered residues in another hydrophobic clusters around proximal and distal site are also examined.

Immunoblot characterization and immunofluorescence localization of dystrophin are presented for 76 human patients with various neuromuscular diseases. Normal dystrophin (shown by immunoblotting) was invariably visualized as a continuous, peripheral membrane immunostaining of myofibers. Biochemical abnormalities of dystrophin (either lower or higher molecular weight dystrophin) resulted in patchy, discontinuous immunostaining, suggesting that the abnormal dystrophin proteins are not capable of creating a complete membrane cytoskeleton network. There was a very strong correlation of clinical diagnoses with the type of dystrophin abnormality; all Duchenne muscular dystrophy patient muscle contained no detectable dystrophin, Becker muscular dystrophy patient muscle had clearly abnormal dystrophin, and unrelated diseases showed normal dystrophin. However, a single patient of five carrying the diagnosis of Fukuyama dystrophy showed no detectable dystrophin and thus appeared to be a Duchenne dystrophy patient by the biochemical assays. We know of no other case of a patient with a disease thought to be unrelated to Duchenne/Becker dystrophy yet demonstrating dystrophin deficiency. Based on the data presented, we conclude that immunofluorescence is the best technique for the detection of female carriers of Duchenne dystrophy, whereas immunoblotting appears superior for the prognostic diagnosis of Becker muscular dystrophy.

We report a case of amyotrophic lateral sclerosis (ALS) in which the ability to close the eyes on command or voluntarily, was lost in spite of retention of reflex activity. A electrophysiological study of the blink reflex revealed a prominent R1 component with normal latency, which confirmed that the blink reflex was exactly preserved and also suggested a hemispherical lesion. Postmortem examination disclosed prominent cortical and subcortical lesions of the precentral areas on both sides. These lesions seem to be very closely related to the inability to initiate lid closing.