Progressive Motor Impairment Research Articles

The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. SCA1 belongs to a growing group of neurodegenerative disorders caused by expansion of CAG repeats, which encode glutamine. Although the proteins containing these repeats are widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involves a few neuronal subtypes. The mechanism(s) underlying this neuronal specificity is unknown. Here we show that the cerebellar leucine-rich acidic nuclear protein (LANP) interacts with ataxin-1, the SCA1 gene product. LANP is expressed predominantly in Purkinje cells, the primary site of pathology in SCA1. The interaction between LANP and ataxin-1 is significantly stronger when the number of glutamines is increased. Immunofluorescence studies demonstrate that both LANP and ataxin-1 colocalize in nuclear matrix-associated subnuclear structures. The features of the interaction between ataxin-1 and LANP, their spatial and temporal patterns of expression, and the colocalization studies indicate that cerebellar LANP is involved in the pathogenesis of SCA1.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm structure, before the onset of ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.

Transgenic animal models of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) occurs in both sporadic and familial forms, which have very similar clinical presentation and course. Approximately 20% of the familial cases of ALS are caused by mutation of the SODI gene encoding Cu, Zn superoxide dismutase (SOD). Over 30 different SODI gene mutations have been found in patients. Most are missense mutations that cause the substitution of one amino acid for another. The failure to find deletions in familial ALS suggests that the mutant protein is required for pathogenesis. Studies in transgenic mice indicate that familial ALS is caused by gain-of-function mutations in the SODI gene. These enhance formation of free radicals by the mutant enzyme. When expressed at high levels in transgenic mice, mutant human Cu,Zn SOD causes a clinical disease that resembles human ALS. Selective degeneration of motor neurones in the spinal cord and brainstem is accompanied by progressive motor impairment. Pathogenesis in the transgenic model of familial ALS is a sequential, two-step process in which damage mediated by free radicals accumulates to a threshold that triggers catastrophic motor neurone loss through glutamate-mediated, excitotoxic mechanisms. Evidence in support of this hypothesis comes from therapeutic studies with antioxidants and inhibitors of glutamatergic neurotransmission.

Recurrent Ischemic Events and Diffuse White Matter Disease in Patients with Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder of elastic tissue with prominent dermatologic, ocular, and vascular manifestations. Although PXE has been associated with ischemic stroke, the clinical and radiologic features have not been fully characterized. We describe two women with PXE, hypertension, and progressive motor and intellectual deterioration related to multiple strokes and transient ischemic attacks beginning at ages 50 and 56. Magnetic resonance imaging in both patients showed widespread and multiple punctate ischemic vascular lesions with diffuse white matter involvement. Although brain infarction in PXE may result from a variety of mechanisms, our patients show the association of this disorder with severe, predominantly small-vessel occlusive disease.

Cerebrospinal fluid proteins in patients with leucoaraiosis: Possible abnormalities in blood-brain barrier function

Some CSF protein abnormalities have been proposed as a possible marker for vascular dementia. We studied the CSF protein levels and albumin ratio in 21 patients (mean age 64.04 ± 7.5) with progressive bilateral motor impairment, and a CT picture of leucoaraiosis. Seven of these patients also presented with dementia. Twenty-seven Alzheimer's disease patients (mean age 59.59 ± 5.30) without leucoaraiosis were taken as controls. We also evaluated the correlations of the albumin ratio values with the diagnosis of dementia, the severity of cognitive impairment, the degree of cerebral atrophy and presence of infarcts on CT, and the abnormalities in CSF circulation, found on isotopic cisternography, in the leucoaraiosis group. After controlling for age and sex, the patients with leucoaraiosis showed greater CSF albumin levels (0.27 mg/l ± 0.11 vs. 0.21 mg/l ± 0.06; covariance analysis P = 0.066), CSF IgG values ( 4.68 mg 100 ml ± 1.45 vs. 2.85 mg 100 ml ± 1.03 ; covariance analysis P < 0.001), and a higher albumin ratio (0.0078 ± 0.0027 vs. 0.0058 ± 0.0019; covariance analysis P = 0.013) than those with Alzheimer's disease. The variations of these parameters were not apparently related to the presence of dementia in the leucoaraiosis group. A significantly higher albumin ratio was observed in patients with a slowed CSF circulation compared to those with normal CSF circulation (0.0086 ± 0.0028 vs. 0.0059 ± 0.0019; covariance analysis P = 0.05). We conclude that, independently from the presence of dementia, patients with leucoaraiosis have CSF abnormalities consistent with functional blood-brain barrier alterations.

Clinical and Genetic Analysis of Progressive Dystonia With Diurnal Variation

We examined 17 patients with progressive dystonia with diurnal variation, a dominantly inherited, generalized dystonia that begins in childhood. Dystonia was typically least severe in the morning, increased as the day continued, and markedly improved with low doses of carbidopa-levodopa. We also studied the patient's parents, children, and siblings from seven families. We observed a spectrum of neurologic involvement, phenotypic variability among siblings, and incomplete genetic penetrance. Progression of motor impairment over several years, which reaches a plateau during late adolescence, is useful in distinguishing progressive dystonia with diurnal variation from cerebral palsy and degenerative disorders. It is important to recognize the subtle, as well the extreme, manifestations of progressive dystonia with diurnal variation because it is treatable. Genetic counseling must consider that mildly affected parents with little or no disability may have profoundly affected children. Appreciation of the phenotypic variability and degree of genetic penetrance will permit detailed genetic and biochemical analyses.

Infantile neuroaxonal dystrophy: Diagnosis by skin biopsy

A child who shows progressive motor and mental deterioration after the first year of life, who has pyramidal signs, marked muscle hypotonia, but no seizures, suggests to have infantile neuroaxonal dystrophy (INAD). Beyond the age of two years, the EEG also entails characteristic findings. Diagnosis may be obtained by an ultrastructural examination of biopsied skin. The respective clinical and morphological findings are recorded and illustrated from four patients in this report.

Central Nervous System Involvement of Children with Hiv Nfection

The neurological findings in 41 HIV-seropositive children are described. 23 children were symptomatic, eight seropositive but without symptoms and 10 seropositive children less than 15 months of age had no other evidence of immunodeficiency. Acquired microcephaly, developmental regression and progressive motor deterioration indicated HIV encephalopathy, as did developmental delay, mental retardation, cerebellar symptoms and behavioural changes. Three children with progressive encephalopathy improved after treatment with azidothymidine (AZT). In eight children treated with prophylactic intravenous immunoglobulin therapy (IVIG) and seven treated with both IVIG and AZT, no mental deterioration has been observed since the beginning of therapy. One child with advanced encephalopathy and severe pyramidal tract involvement did not improve.

Fucosidosis revisited: A review of 77 patients

Fucosidosis is a rare, autosomal recessive, lysosomal storage disorder caused by a severe deficiency of alpha-L-fucosidase in all tissues. We have conducted a review of fucosidosis, compiling data from published reports and an international questionnaire survey. Seventy-seven patients affected with fucosidosis of which 19 had not been reported before have been identified. A major aim of the present study was to define the natural history of fucosidosis. The clinical picture of fucosidosis consists of progressive mental (95%) and motor (87%) deterioration, coarse facies (79%), growth retardation (78%), recurrent infections (78%), dysostosis multiplex (58%), angiokeratoma corporis diffusum (52%), visceromegaly (44%), and seizures (38%). Whereas the original fucosidosis patients described by Durand et al. (J. Pediatr 75:665-674, 1969) were decerebrate and died before age 5 years, most fucosidosis patients have a slower course of degeneration. Mortality before age 5 years was observed in only 7 patients (9%), whereas 36 patients (64%) reached the second decade. We did not find evidence for the existence of clinical heterogeneity with a rapidly progressive type I and a slowly progressive type II fucosidosis as suggested in the literature. Instead, there seems to exist a wide continuous clinical spectrum. At the biochemical level no heterogeneity in residual fucosidase enzyme activity or cross-reacting immunoreactive fucosidase protein was observed. At the DNA level at least 4 different mutations must be responsible for fucosidosis. These genotypic differences however do not explain the observed phenotypic differences.

Symptomatology of Late Onset Krabbe's Leukodystrophy: The European Experience

The authors present a study of 50 patients with late onset Krabbe's leukodystrophy (LOKL), including 27 from a pooled European Series collected in 1987, and 23 published between 1906 and 1987. In Europe, the disease appears to be relatively frequent in Sicily and exceedingly rare in Sweden. Most cases started before the age of 5 years. The initial signs consisted mainly of progressive motor impairment, although, characteristically, visual failure was the initial manifestation in 25% of patients. Low nerve conduction velocities and a high protein content in the CSF were only present in 50%. There was no age-linked symptomatic predominance. The pace and length of the disease was very variable, but in one-third of the children before the age of 3 the course was remarkably rapid. There was no difference in the residual activity of galactosylceramide galactosidase in LOKL compared to the early infantile form.

Developmental Abnormalities of Dendrites of the Cerebral Cortical Neurons in Mental Retardation*

Abstract This paper of Golgi studies describes abnormal dendritic structure and development assessed by camera lucida representation, quantitation of dendritic spines, and dendritic branch measurement in metabolic and chromosomal diseases with mental retardation, reviewing the literatures of Golgi study.Neuronal lipid storage diseases with progressive mental and motor deterioration show characteristic meganeurites between the soma and origin of the axon, and all dendrites have fewer number of branches, shorter total basal dendritic length and marked reduction of spines. Phenylketonuria and Lesch‐Nyhan syndrome also present decreased number of spines.On the other hand, children and adults with Down's syndrome show poor dendritic spine density and dendritic branchings as well as structural irregularity of spines. This poor' development of dendrites suggesting postnatal poor synaptogenesis may be related to mental retardation in children. These postnatal dendritic abnormalities may be based on genetic factors such as diminished number of cortical granular cells and extrinsic factors which include poor perception of external stimuli as noted in sensory deprivation.Thus, dendritic spine abnormalities may be correlated with mental retardation. However, we need better staining method and more sytemic study.

Canine fucosidosis: clinical findings

ABSTRACTThe clinical course of canine fucosidosis, a neurovisceral lysosomal storage disease, is described from observations of 31 affected English Springer Spaniels. The diagnosis of fucosidosis was suggested by the development of multifocal neurological signs in the second year of life and confirmed by a deficiency of alpha‐L‐fucosidase activity in plasma and leucocytes. The progressive motor and mental deterioration was similar in all dogs and no affected animal survived to four years of age. Alpha‐L‐fucosidase activity in plasma was &lt;0·05 μ/1 in all cases. The activity in leucocytes and other tissues was &lt; 5 per cent of that of normal dogs.Vacuolated leucocytes occurred in cerebrospinal fluid, blood and bone marrow. The enlargement of peripheral nerves which is observed at autopsy could be detected by palpation of the ulnar nerve in advanced disease, however the results of electrodiagnostic studies were within normal limits.The clinical signs and pathological changes were found to be remarkably consistent from case to case making it an excellent model for investigating therapeutic strategies in human lysosomal storage disorders.

Ocular Features of the Hagberg-Santavuori Syndrome

The Hagberg-Santavuori syndrome, the infantile form of the lipopigment storage disorders (so-called neuronal ceroid-lipofuscinoses), is a rare autosomal recessive disease characterized by progressive mental and motor deterioration with an onset between 1 and 1 1/2 years of age. Visual impairment is usually evident early in the disease and hypopigmented retinal degeneration has been described. We studied two unrelated patients with the infantile Hagberg-Santavuori form and found stellate posterior polar cataracts and retinal degeneration with hyperpigmented "bone spicules" in both.

INFANTILE NEUROAXONAL DYSTROPHY

Eight cases of late infantile neuroaxonal dystrophy are reported. In all cases, the diagnosis was made during life on the basis of the clinical picture and course, the results of neurophysiological studies and the finding of typical spheroids in cortical or peripheral (skin and conjunctival) biopsies. A review of 76 previously published cases revealed that 42 displayed a stereotyped clinical picture identical to that exhibited by our 8 patients. The most important clinical features, as they emerge from the study of these 50 cases, are those of a progressive disorder starting at the end of the first or beginning of the second year of life, progressive motor and mental deterioration bilateral pyramidal tract signs, marked hypotonia and early visual disturbances without epileptic seizures. The presence of high voltage, fast rhythms in the EEG and signs of denervation of an anterior horn-cell type at EMG, with normal nerve conduction velocities, is frequent additional evidence in favour of infantile neuroaxonal dystrophy. The finding of spheroid bodies in axonal endings seems to be constant and is necessary for an in vivo diagnosis. Spheroids can be found in peripheral tissues, for example, skin and conjunctiva, and cortical biopsy is no longer required. The spheroids, however, are not specific and both clinical and pathological features are necessary to establish a firm diagnosis. Since infantile neuroaxonal dystrophy is a recessively inherited disorder its recognition is imperative even though the nosology of the disease remains uncertain.

Congenital lactic acidosis due to pyruvate carboxylase deficiency: Absence of an inhibitor of TPP-ATP phosphoryl transferase

Two children are described who suffered from episodes of metabolic acidosis and progressive mental and motor deterioration. The patients showed periodic elevation of blood lactate, pyruvate and alanine, which was accompanied by vomiting, hypotonia or convulsions. The concentrations of lactate and pyruvate in cerebrospinal fluid were found to be increased. Liver biopsies revealed a decrease in pyruvate carboxylase activity and normal pyruvate decarboxylase activity. No inhibitor of TPP-ATP phosphoryl transferase was detected in urine from the patients. These findings suggest that congenital lactic acidosis due to pyruvate carboxylase deficiency is probably a different disease entity from Leigh's encephalomyelopathy. A possible mechanism of brain damage caused by a defect in pyruvate carboxylase is postulated.

Isolation of rubella virus from brain in chronic progressive panencephalitis.

Rubella virus was isolated from the brain of a congenitally-infected, 12-year-old child in whom progressive mental and motor deterioration became evident at age 8 and 11 years respectively. The virus was initially isolated in a co-culture of CV-I cells with the trypsinized brain tissue; subsequently the culture of the brain tissue also showed evidence of rubella virus infection recognized by indirect fluorescent antibody technique (IFA) using anti-rubella virus antibody prepared in rabbits as intermediate serum. Both isolates interfered with infection of BSC-I cell lines by echovirus type II. The interfering virus was identified as rubella virus by IFA with the specific antiserum, and it is designated as the NTr strain of rubella virus. The complement fixing antibody titre to rubella virus in serum was I:256. The spinal fluid was anticomplementary. Rubella virus haemagglutinating antibody titre (HI) in serum was I:8196 and in the spinal fluid I:128. The HI antibody was of the IgG class. The corresponding HI titres to rubeola virus in serum and spinal fluid were I:8 and less than I:2 respectively.

Progressive degeneration of the cerebral cortex in infancy. Report of a case.

The clinical and pathological features of a case with primary progressive degeneration of the cerebral cortex are presented. Two siblings had nearly identical clinical histories. All three children were born microcephalic and they died at the age of 7, 10 and 18 months, respectively. All showed progressive mental and motor deterioration. Myoclonus and attacks of opisthotonus were prominent features. Postmortem examination was performed in the third child, who died at the age of 10 months. The brain weight was 310 g. The cerebral cortex was severely atrophic, with extensive laminar neuronal loss. The cerebellum was normal. The optic tracts were atrophic. Neuronal loss was observed also in a few other systems but their relation to the primary disease is uncertain. The basal ganglia were normal and the hippocampus showed only slight nerve cell loss.

Subacute encephalitis and hypogammaglobulinemia.

A 5-year-old white boy with X-linked hypogammaglobulinemia and subacute encephalitis developed paresis of the right upper and lower extremities, symmetrical polyarthritis, and bilateral basal bronchiectasis at 1 year of age. At 5 years, he was exposed to rubeola and received a preventive dose of γ-globulin. During the next six months he developed progressive mental and motor deterioration. Electroencephalographic pattern was consistent with subacute sclerosing panencephalitis. Brain biopsy revealed extensive inflammatory infiltrates but neither inclusion bodies nor viral particles could be demonstrated by electron microscopy. Immunofluorescence studies of the biopsy specimen and the ethanol fixed monolayer cell cultures revealed intracellular fluorescence specific for measles antigen. As expected, serologic studies for measles antibodies were negative. On the basis of clinical, EEG, and histopathologic studies, in the absence of measles antibodies in serum and cerebrospinal fluid, we chose the term subacute encephalitis rather than subacute sclerosing panencephalitis.

Progressive motor disabilities of the mouth.

Some entities of progressive motor impairment are most clearly identified in the oral area, and most of them are characterized by critical disabilities in the oral and pharyngeal areas. The continued muscular fasciculation in amyotrophic lateral sclerosis, for example, is readily visible at the surface of the tongue. Simple manual tests are useful in evaluating the muscles of the mandible, hyoid and tongue.

METACHROMATIC LEUKO-ENCEPHALOPATHY

Metachromatic leuko-encephalopathy is a familial degenerative disease of the central nervous system included with Schilder's disease as a type of diffuse cerebral sclerosis. The disease usually has its onset early in childhood and is characteried by progressive motor and mental deterioration with ataxia, muscular weakness, spasticity, optic atrophy, convulsions and finally dementia. The concentration of protein of the cerebrospinal fluid is frequently elevated. The pathologic findings consist of demyelination, destruction of axons, gliosis and the accumulation of metachromatic granules in the brain and other organs. The metachromasia can be demonstrated in formalin-fixed frozen sections with a toluidine blue stain. It is not demonstrable in paraffin sections. Histochemical studies indicate this abnormal material is probably a complex of glycolipids and protein. It has been reported elsewhere that early diagnosis can be established by demonstrating the metachromatic materials in urinary sediment or in a real biopsy. An illustrative case has been presented.