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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrhythmias. Because electrical signals are critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lead to disease. All of these diseases have prominent genetic components. Difficulty in understanding these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to exist. Therefore, early work in may laboratory was aimed at understanding the pathogenesis of rare disorders that are similar in their episodic nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal people. We, and others, have shown that hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) result from mutations in a gene encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a gene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other episodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels. Long QT syndrome, an episodic cardiac dysrhythmia syndrome, is known to result from mutations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (non-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a reflex epilepsy in mice. The similarities among all these disorders, including their episodic nature, precipitating factors, and therapeutic responses, are striking. Understanding gained from work in these rare monogenic episodic disorders is not only allowing characterization of the molecular and physiologic basis of these diseases, but may ultimately shed light on our understanding of the pathophysiology of more common and genetically complex disorders of the central nervous system.
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PMID:Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. 919 7

Shaking rat Kawasaki (SRK) is an autosomal recessive mutant rat that exhibits tremor, dystonia, and ataxia and that is characterized by abnormal lamination of the cerebral and cerebellar cortices and the hippocampus. To examine whether or not layer V neurons in the mutant neocortex are malpositioned in accordance with the aberrant laminar cytoarchitecture, horseradish peroxidase (HRP) was injected into the lumbar spinal cord of SRK mutant and normal control rats to label cortical pyramids projecting through the corticospinal tract (CST). HRP-labeled CST neurons of both normal and SRK rats were found mainly in the hindlimb area of the sensory-motor cortex, indicating a normal tangential distribution of labeled CST neurons in the SRK mutant. In the radial axis, however, labeled CST neurons were spread throughout all layers of the mutant cortex, whereas those in normal rats were restricted to layer V. In the mutant, most labeled CST neurons located in the inner third of the cortex had a typical pyramidal form with an upright apical dendrite, but many of those located near the pial surface displayed abnormal shapes and could be subdivided into inverted pyramidal, horizontal, and bipolar neurons on the basis of their dendritic morphology. The abnormal distribution pattern of labeled CST neurons in the mutant was quantified using a standardized measure of their depth distribution, where 0% = the level of the white matter and 100% = the pial surface. The mean value for the SRK cortex of 47.0% was significantly greater than the figure of 40.5% for normal rats (P < 0.01, Student's t test), indicating a spread of CST neurons toward the pial surface in SRK, but even more striking was the size of the standard deviation: 30.4 in SRK compared with 7.1 in controls. The distribution pattern of CST neurons of the SRK rat was also statistically identical with that of the reeler mouse, which is a well-known mutant that also exhibits an abnormal lamination pattern in the cerebral cortex. These results indicate that neuronal components of the neocortex of the SRK mutant are intermingled along the radial axis, but not in the tangential axis, and provide further evidence for a strong similarity between this spontaneous rat mutation and the reeler malformation.
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PMID:Corticospinal tract neurons are radially malpositioned in the sensory-motor cortex of the Shaking rat Kawasaki. 920 47

Ablation of the BPAG1 gene results in the dystonia musculorum mouse, exhibiting rapid spinal nerve degeneration, dystonic movements, and severe ataxia. By defining the developmental and tissue-specific expression of the neuronal form of BPAG1 (BPAG1-n) and by comparing the corresponding pathology in BPAG1 null mice, we seek here to understand how absence of BPAG1 results in this devastating phenotype in mice and in potentially related human neurological disorders. Throughout normal development, BPAG1-n was expressed in a variety of sensory and autonomic neuronal structures, but was absent or reduced in areas such as basal ganglia that are often affected in dystonias and ataxias. Interestingly, BPAG1-n was also expressed broadly in embryonic motor neurons, but expression declined dramatically after birth. Despite these complex developmental patterns, BPAG1-/- pathology was restricted largely to postnatal development. Moreover, gross neuronal degeneration was restricted to only a few regions where BPAG1-n was found, including dorsal root ganglion neurons and a small subset of motor neurons. Most notably, while skeletal muscle was normal, appearance of severe dystonic ataxia correlated with postnatal degeneration of muscle spindles. Collectively, our findings suggest a mechanism for the BPAG1 null phenotype and indicate that different neurons respond differently to the absence of BPAG1-n, a cytoskeletal linker protein.
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PMID:Developmental expression of BPAG1-n: insights into the spastic ataxia and gross neurologic degeneration in dystonia musculorum mice. 924 12

Infants with macrocephaly, young children with acute disease resembling encephalitis, and children with truncal hypotonia, ataxia, or dystonia may be affected by glutaric aciduria type I (GA 1, glutaryl-CoA-dehydrogenase deficiency), a not-so-rare autosomal recessive neurometabolic disease. Well-known features of GA1 are fronto-temporal brain atrophy with macrocephaly and acute encephalopathic episodes with striatal necrosis followed by dystonia, but some patients develop motor disease without overt crises and other biochemically affected individuals remain asymptomatic. Biochemical and molecular characterization is available and allows post- and prenatal diagnosis. The pathogenesis of fronto-temporal atrophy, macrocephaly, and basal ganglia necrosis is still not understood, and there is no close correlation between biochemical parameters and clinical outcome. There is, however, evidence suggesting that carnitine supplementation and anticatabolic treatment of intercurrent illness may arrest or prevent neurological deterioration, while the role of limitation of dietary lysine and tryptophane is not yet clear. Although pathogenetic aspects are poorly understood, the natural course of glutaric aciduria type 1 can be changed by early diagnosis and treatment. Coordinated research is needed to understand the pathogenesis of brain toxicity, to define the role of dietary therapy, and to explore the possibility of neonatal screening.
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PMID:Glutaric aciduria type 1 (glutaryl-CoA-dehydrogenase deficiency): advances and unanswered questions. Report from an international meeting. 939 91

Wilson's disease is an autosomal-recessive inherited disorder that results in predominantly hepatic and neurologic manifestations. Neurologic abnormalities include tremor, ataxia, bradykinesia, rigidity, chorea, and dystonia. We report the clinical, radiologic, and serial FDG PET findings in a 20-year-old woman who presented with an asymmetric upper limb tremor caused by Wilson's disease. Reduced striatal and cerebral cortical glucose metabolism was demonstrated on a FDG PET study performed before the commencement of D-penicillamine therapy. After 6 months of treatment, the patient had shown only minimal clinical improvement, despite an increase in striatal and cerebral cortical glucose metabolism on a repeat FDG PET study. After 14 months of treatment, however, a moderate clinical improvement was noted and there was further increase in glucose metabolism on FDG PET.
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PMID:Pretreatment and posttreatment positron emission tomographic scan imaging in a 20-year-old patient with Wilson's disease. 945 44

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.
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PMID:Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. 946 7

We report a 67-year-old hypertensive right-handed woman who developed severe pain and dystonia in her left upper and lower extremity after a thalamic infarction. She was well until 9 months prior to the present admission to our hospital, when she had an acute onset of left hemiparesis which turned out to have been caused by a thalamic infarct. Her hemiparesis showed nearly complete recovery during the next four months. She noted an onset of severe spontaneous pain and difficulty in using her left hand four months prior to the present admission. Neurologic examination on admission revealed an alert and well oriented Japanese woman. Cranial nerves were intact. Although she did not have weakness, her left hand showed thalamic posture, and upon standing, she showed a dystonic posture in which her left forearm took pronation and flexion at the elbow joint and her left lower extremity took extension in the knee joint and planter flexion in the ankle joint. Her dystonic posture increased during walking and disappeared in the supine position. She complained of severe spontaneous pain and tingling sensation in her left extremities. Position sense was diminished in her left leg. However other sensations were intact. She had slight ataxia on the left side. Deep tendon reflexes were symmetric, but the planter response was extensor on the left side. MRI revealed a small lacunar infarct involving the right posterolateral thalamic region. EMG with surface electrodes revealed non-reciprocal tonic discharges in the left biceps brachii and forearm flexor and extensor muscles. She responded poorly to various medications. Only trihexyphenidyl showed partial alleviation of her pain and dystonic posture. We thought her pain might be caused by dystonic contraction of the skeletal muscles, at least in part. We injected 25 IU of botulinus toxin as a total dose into her biceps brachii, triceps brachii, and wrist flexor muscles. A few days after the injection, her dystonic posture began to show marked improvement; as her dystonia improved, her pain also showed marked improvement. This patient appeared to represent a case of post-hemiplegic dystonia. Her pain was initially thought to be the thalamic pain. However, as her pain disappeared with improvement of her dystonia, her pain is most likely to have been caused by the dystonic muscle contraction. Botulinus toxin treatment appears to be useful for post-hemiplegic painful dystonia.
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PMID:[A case of post-hemiplegic painful dystonia following thalamic infarction with good response to botulinus toxin]. 949 Aug 97

Idiopathic cerebral calcification can be associated with a progressive neurologic disorder for which there is no known treatment. This report describes a patient with a familial form of this disorder presenting in middle age with progressive Parkinson-like features along with spasticity, dystonia, and ataxia. Disodium etidronate, a bisphosphonate, produced a two-fold improvement in the rate of his speech and gait, but did not affect his spasticity, dystonia, or ataxia. Quantitative analysis of cerebral calcification did not reveal any reduction in the amount of calcification, suggesting other possible mechanisms for this clinical improvement.
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PMID:Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. 953 53

A 15-year-old boy was suffering from splenomegaly and a 10-year history of a neurologic disorder that included mental retardation, vertical supranuclear gaze palsy, dysarthria, ataxia, and dystonia. Bone marrow aspirates revealed foamy cells with storage materials which were positive with filipin staining. Cultured skin fibroblasts derived from the patient showed moderate loss of sphingomyelinase activity and the impairment of cholesterol esterification. The characteristic clinical presentations and typical histochemical findings of this patient met the diagnostic criteria of Niemann-Pick disease type C (NPC). In the fibroblasts from the patient, there was an accumulation of GM2 ganglioside around their cytoplasms. Increased levels of glycolipids. including GM2 ganglioside are reported in the cerebral cortex of NPC, but not in the fibroblasts. The fibroblasts derived from NPC may reflect the abnormal metabolism of glycolipids in the central nervous system of NPC.
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PMID:Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann-Pick disease type C. 954 79

Paroxysmal tonic upgaze of childhood with ataxia is a rare form of age related dystonia. Out of 12 previously reported cases, three had a clinical history of similar symptoms occurring in at least one first degree relative belonging to the same or two consecutive generations. Autosomal dominant inheritance was therefore hypothesized. We report on a family in which the disorder appeared in three consecutive generations between ages 6 and 11 months, disappearing gradually and spontaneously between ages 18 to 24 months. All affected individuals had normal neurologic development. The pedigree analysis of previously reported cases and of the family reported herein provides strong evidence that the disorder may be inherited as an autosomal dominant trait and represents a form of transient paroxysmal dystonia with benign long-term prognosis.
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PMID:Paroxysmal tonic upgaze of childhood with ataxia: a benign transient dystonia with autosomal dominant inheritance. 954 83


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