Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe 3-year clinical course of a 54-year-old Japanese man who presented with action myoclonus, parkinsonism and epilepsy. There was no family history or consanguinity. The patient was well until the age of 51 years (in 1986), when he noted slow movements, memory disturbance and left hand tremor. He was treated with anti-Parkinson drugs without any improvements. Soon thereafter, he developed a gait disturbance and generalized tonic clonic seizures. He was admitted to our service at the age of 53 years. General physical examination revealed no hepatosplenomegaly. Neurological examination showed mild dementia. Neither retinal pigmentation nor cherry red spot was noted. He was unable to walk due to marked frozen gait. His upward gaze was limited and saccadic eye movement was slow. He had action myoclonus in both upper extremities and resting tremor on the left side. He showed mild left hemiparesis. Deep tendon reflex was hyperactive in both side with extensor plantar responses. MRI demonstrated cortical atrophy, especially marked at the bilateral temporal lobes with a right side predominance. Leukocyte lysosomal enzyme activities of beta-hexosaminidase, beta-galactosidase and sialidase were within normal limits. The patient died of pneumonia on April 25, 1989. At the time of a neurological CPC, neurologists reached the clinical diagnosis of adult-type neuronal ceroid-lipofuscinosis. Postmortem examination revealed bilateral bronchopneumonia. The brain weighed 1,219 g and showed atrophy of the temporal lobes. Histological examination showed neuronal cells with swollen cytoplasm and lipofuscin-like granules throughout the CNS, including the cerebral cortex, thalamus, substantia nigra, motor nuclei of the brain stem, dentate nuclei, inferior olivary nuclei. Clarke's nuclei and anterior horn cells. Marked neuronal loss was noted in the right temporal lobe and substantia nigra. Electron micrographs of the frontal cortex revealed "fingerprint profiles" in the cytoplasm of neuronal and glial cells. Pathological findings were consistent with the diagnosis of adult-type neuronal ceroid-lipofuscinosis (Kufs' disease).
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PMID:[A 54-year-old man with action myoclonus, parkinsonism and epilepsy]. 1058 20

Clinical picture of neuronal ceroid lipofuscinosis with late infantile onset (LINCL) is characterized by myoclonic seizures and psychomotor regression. We present a case of classic LINCL and reduced cerebrospinal fluid (CSF) pterins in a girl of normal psychomotor development and born to non-consanguineous parents. She first presented with febrile seizures at the age of four. At that time, brain computed tomography finding was normal, but electroencephalogram showed hypsarrhythmia. At the age of five, tremor, generalized ataxia, and motor and mental regression appeared. Brain magnetic resonance imaging showed cerebellar atrophy. Electron microscopy examination showed storage of intracytoplasmic curvilinear inclusions in neurons, fibroblasts, and secretory cells of the skin and rectal mucosa. Tripeptidyl peptidase I (TPP-I) activity in leukocytes was very low (5.4 nmol/h/mg protein; range in homozygote cases of LINCL, 0.4-26.0). Molecular genetic studies showed a homozygous mutation, R208X, in exon 6 of CLN2 gene. CSF analysis revealed very low neopterin (7.3 nmol/L; normal range, 9-30) and biopterin (4.1 nmol/L; normal range, 10-30), reduced homovanillic acid (266 nmol/L; normal range, 211-871), and low homovanillic acid/5-hydroxyindoleacetic acid ratio (1.21; normal ratio, 1.5-3.5). Treatment with L-Dopa/Carbidopa (4 mg/kg) and antiepileptics was introduced, but without significant effect. It seems that low CSF pterins and impaired dopamine turnover are secondary manifestations of classical LINCL caused by homozygous inheritance of the R208X mutation in CLN2 gene.
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PMID:R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis. 1295 Jan 56

Mutations in the CLN2 gene, which encodes a lysosomal serine protease, tripeptidyl-peptidase I (TPP I), result in an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL). cLINCL is inevitably fatal, and there currently exists no cure or effective treatment. In this report, we provide the characterization of the first CLN2-targeted mouse model for cLINCL. CLN2-targeted mice were fertile and apparently healthy at birth despite an absence of detectable TPP I activity. At approximately 7 weeks of age, neurological deficiencies became evident with the onset of a tremor that became progressively more severe and was eventually accompanied by ataxia. Lifespan of the affected mice was greatly reduced (median survival, 138 d), and extensive neuronal pathology was observed including a prominent accumulation of cytoplasmic storage material within the lysosomal-endosomal compartment, a loss of cerebellar Purkinje cells, and widespread axonal degeneration. The CLN2-targeted mouse therefore recapitulates much of the pathology and clinical features of cLINCL and represents an animal model that should provide clues to the normal cellular function of TPP I and the pathogenic processes that underlie neuronal death in its absence. In addition, the CLN2-targeted mouse also represents a valuable model for the evaluation of different therapeutic strategies.
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PMID:A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. 1548 30

A female Japanese domestic shorthair cat showed gait abnormality at 5 months of age, and head shaking and tremor became apparent from 6 months of age. Serum biochemistry at 13 months of age revealed markedly elevated ALT and ALP. The cat died at 16 months of age. Histopathologic examination revealed prominent cytoplasmic swelling of neurons with accumulation of yellowish pigments. The storage pigments stained positively with periodic acid Schiff reaction, Schmorl method, and Oil red O stain. Ultrastructurally, the neuronal storage consisted of aggregates of dense materials, similar to the granular osmiophilic deposits in infantile ceroid-lipofuscinosis in humans. Hepatocytes were markedly swollen and contained faintly eosinophilic inclusion. To our knowledge this case is the sixth case of feline ceroid-lipofuscinosis, which is characterized by granular osmiophilic dense bodies in the neurons and prominent involvement of hepatocytes.
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PMID:Neuronal ceroid-lipofuscinosis in a Japanese domestic shorthair cat. 1949 97

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.
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PMID:Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). 2911

Disorders affecting the control of saccadic eye movements result in involuntary saccadic oscillations and are widely reported in human medicine. Information regarding the occurrence and potential importance of saccadic oscillations in veterinary medicine is currently limited. The clinical histories of three dogs and one cat displaying involuntary eye movements consistent with opsoclonus are presented, with final diagnoses including idiopathic generalized tremor syndrome and neuronal ceroid lipofuscinosis (NCL). A dog with eye movements closely resembling macrosaccadic oscillations is also presented, for which a final diagnosis of NCL was made. All animals had clinical signs of cerebellar disease. As in human medicine, recognition of these forms of involuntary eye movement might suggest a cerebellar neuroanatomic localization. Opsoclonus and macrosaccadic oscillations are forms of involuntary saccadic eye movement that are both unrecognized and under-reported in veterinary medicine.
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PMID:Saccadic oscillations in 4 dogs and 1 cat. 2970 74

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7-/-). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7-/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7-/- macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease.
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PMID:Discovery of a CLN7 model of Batten disease in non-human primates. 3004 4