Progressive Loss Of Motor Function Research Articles

Clenbuterol retards loss of motor function in motor neuron degeneration mice

Motor neuron degeneration (mnd) mice exhibit lysosomal accumulation of lipofuscin-like material that is associated with progressive loss of motor function and strength. Motor dysfunction scores at 8.5–9 months of age were highly correlated with the occurrence of abnormal spinal motor neurons with eccentric nuclei, although the total numbers of motor neurons were not significantly reduced. Nuclear eccentricity is a characteristic of the axon reaction that results from injury and subsequent compensatory axonal sprouting indicating axonal/synaptic dysfunction in mnd motor neurons. Treatment with clenbuterol, a β 2-adrenoceptor agonist that can enhance regeneration of motor neuron axons, opposed the development of motor deficits in parallel with a reduced proportion of motor neurons with eccentric nuclei consistent with improved synaptic function. Clenbuterol also opposed decreases in grip strength and muscle mass suggesting β 2-agonist treatment as a potential therapeutic modality for lipofuscinoses.

Muscular dystrophies and stem cells: a therapeutic challenge.

Correspondence to : E Gussoni, Division of Genetics, Children’s Hospital, 320 Longwood Ave, Boston, MA 02115, USA Introduction The muscular dystrophies are a diverse group of inherited disorders with common skeletal muscle pathological changes, characterized by progressive weakness and wasting due to muscle-cell necrosis [1,2]. Typical histological features include myofiber degeneration–regeneration, which lead to gradual destruction of skeletal muscle and replacement by connective tissue and fat. The X-linked Duchenne muscular dystrophy (DMD) represents the most frequent and severe form of muscular dystrophy, affecting 1 in 3500 live male births. Although the dystrophic process in DMD patients’ skeletal muscle is present at birth, the first motor difficulties do not appear until age 3–5 years. The disease leads to progressive loss of motor functions, wheelchair dependence by age 10–12 years and death in the third decade from respiratory and/or cardiac failures. In 1986–87, identification of the DMD gene and its encoded protein (dystrophin) opened new avenues of research [3–5]. Dystrophin is localized at the cytoplasmic side of the sarcolemma of skeletal and cardiac muscle [6], and is associated with a protein complex composed of trans-membrane (sarcoglycans, dystroglycans) and intracellular (dystrobrevins, syntrophins) proteins [7–10]. This dystrophin-associated protein complex (DAPC) provides a physical link between the actin cytoskeleton and the extracellular matrix, and one of its presumed functions is to stabilize the muscle-cell membrane during contraction– relaxation [7–10]. Since the discovery of the dystrophin gene, nearly 30 other forms of muscular dystrophy have been identified, many of them caused by mutations in members of the DAPC. For example, the limb-girdle muscular dystrophies (LGMD) LGMD2C-F result from mutations in one of four sarcoglycans [11,12]. Many of the histopathological changes observed in DMD are also seen in other forms of muscular dystrophy, implying that there are common pathways of muscle breakdown and regeneration among the different forms of dystrophy. Slowing or repairing these pathways may lead to effective disease treatment. In recent years, new mouse models have been generated for several forms of muscular dystrophy, including LGMDs [13]. These models not only have been very useful for the identification of common mechanisms underlying muscular dystrophy, but are also great tools for testing therapeutic approaches. In addition to these models, the naturally occurring muscular dystrophy models mdx (with a stop codon mutation in dystrophin exon 23) [14,15] and dy (with laminin a 2 chain deficiency) [16] are some of the most widely used models. Despite the progress made in understanding the molecular basis of muscular dystrophies, no efficient treatment is yet available for these devastating diseases [9,17,18]. Promising progress has been made in gene replacement [19,20] and pharmacological-based therapies, including utrophin up-regulation [21–23], corticosteroids [24–30] and aminoglycoside antibiotics [31,32]. However, this review will focus on recent efforts in the field of cell-based therapy.

Effects of assisted feeding on Wobbler mouse motoneuron disease and on serotonergic and peptidergic sprouting in the cervical spinal ventral horn

The Wobbler mouse is used as a model of human motoneuron disease (MND). During the disease progress, the significant loss of motoneurons in cervical spinal cord and cranial motor nuclei leads to the progressive loss of motor function in the forelimb, head, and neck regions. The loss of cutting and chewing ability that results in the inability to feed properly might lead to a lower mean body weight (b. wt.) that is generally one-half that of the normal phenotype littermate controls. Nutritional deficit might also influence neuronal processes sprouting in the cervical spinal ventral horn. To determine whether nutritional deficits contribute to the wt. loss, and influence the progress of MND as well as its sprouting phenomenon, Wobbler and normal phenotype control littermates were dropper-fed three times daily on a regular laboratory diet of Rat Chow. Weight measurements and behavioral tests were taken to monitor the disease. Immunocytochemisty of serotonin, substance P, and leucine enkephalin were conducted in the cervical spinal cord to investigate if any alteration occurred on the previously reported values in ad lib-fed animals. Organ wts. were measured to determine where nutritional benefit was incurred. Although mean wt. loss in Wobblers was reduced, wt. differed significantly from the control values after dropper feeding. However, the progress of the disease or alteration of neurotransmitters containing neuronal processes were not affected by nutritional factors. Therefore, nutritional intake affects wt. gain, but is not a primary consideration in the progress of MND. Behavioral deficits and neurotransmitter alterations are probably directly caused by motoneuron losses.

Diagnosis and progression of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons, leading to progressive loss of motor function. The disease is almost always fatal, and approximately 50% of patients die within 3 to 4 years after onset of symptoms. [1,2] ALS is more common in men than in women (until age 70, when the rate becomes equal) and, although the average age of onset is in the mid-fifties, the disease can occur at anytime after the teen years. [2-4] The disease is a distinct syndrome characterized by a combination of upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction and by generalized distribution and relentless progression. No specific blood test is available to provide an unequivocal diagnosis of ALS, and the clinical diagnosis is usually based on results of physical and neurologic examinations that identify the signs and symptoms of the disease. Because UMN and LMN symptoms associated with a variety of other disorders mimic those seen in ALS patients, an integral part of diagnosing ALS involves excluding other possible causes of the signs and symptoms exhibited by the patients. Diagnostic tests, such as electromyography (EMG), neuroimaging, blood and urine tests and, if indicated, muscle and nerve biopsy, are therefore used in this process. Although ALS was first described more than 120 years ago by Charcot, [5] it has remained an enigmatic disease. Recently, however, as the result of intense research during the past decade, significant advances have been made in understanding the pathogenesis and etiology of ALS and in identifying potential management strategies for the disease. More than 90% of ALS cases are classified as classical, a type of sporadic ALS, and are characterized by a combination of UMN and LMN involvement. [2] Among classical ALS patients, more than two-thirds present with …

The natural history of untreated phenylketonuria over 20 years

Fifty-one adults with untreated phenylketonuria (PKU), have been reviewed after a 20 year interval, at ages ranging from 28.8 to 71.8 years. Five died of causes unrelated to PKU. Three severely affected individuals had shown a progressive loss of motor function and three had developed epilepsy, bringing the total with this problem to 12. No loss of abilities was apparent in 41 patients. Other health problems, including cataracts, were not frequent. Serum phenylalanine levels had decreased over the 20 year period. Untreated PKU does not generally cause progressive loss of abilities during adult life.

Familial motor neuron disease. Evidence for at least three different types.

Based on a clinical, pathologic, and genetic study of 14 families, at least three types of familial motor neuron disease can be distinguished, all apparently of autosomal dominant transmission. The first is characterized by rapid, progressive loss of motor function with predominantly lower motor neuron manifestations and a course lasting less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second type is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke's column, and spinocerebellar tracts. The third type is characterized by a much longer survival usually beyond 10 and after more than 20 years in affected family members but is otherwise similar to the second type.

Hallervorden-spatz disease and infantile neuroaxonal dystrophy: Clinical characteristics and nosological considerations

Two patients with the infantile onset of a non-familial neuroaxonal dystrophy are presented. One patient developed a gait disorder from 1 1 2 years of age, followed by deterioration of speech, severe torsion dystonia with opisthotonos, choreoathetosis of the limbs, and death at age 14. The neuropathology showed findings typical of Hallervorden-Spatz disease; spheroids and abnormal excessive pigment were confined to the basal ganglia. The second patient also developed a gait disorder at 1 1 2 years of age, followed by seizures, progressive spasticity with equinovarus deformities, and signs of cerebellar disorder, but without torsion dystonia or opisthotonos. Death occurred at 17 years. The neuropathology showed features characteristic of both Hallervorden-Spatz disease and of infantile neuroaxonal dystrophy; spheroids and excessive abnormal pigment in the basal ganglia were accompanied by widespread collections of spheroids throughout the gray matter, loss of cortical neurons, degeneration of the caudate nuclei, atrophy of elements in the cerebellar cortex, and degeneration of the posterior and lateral columns of the spinal cord and of the optic nerves. The first patient is discussed as an example of infantile Hallervorden-Spatz disease, the second as an example of a disease process intermediate between infantile Hallervorden-Spatz disease and infantile neuroaxonal dystrophy. The literature relating to infantile Hallervorden-Spatz disease and infantile neuroaxonal dystrophy is reviewed and the reported cases separated into three categories on the basis of the neuropathology. The findings which emerge from this review suggest that the entities previously described as infantile Hallervorden-Spatz disease and infantile neuroaxonal dystrophy are related disease processes which present a spectrum of clinical abnormalities and corresponding neuropathology. At one extreme (Category I) there are cases showing progressive loss of motor function, severe rigidity, torsion spasm with opisthotonos, athetosis, deterioration of mental and speech functions, and death at a mean age of 16 years. It is unusual for these patients to have seizures, hypotonia of the limbs, reduced vision, or siblings affected by a similar disease process. The neuropathology consists of spheroids and excessive abnormal pigment confined to the basal ganglia and thalamus. At the other extreme (Category III) there are cases showing progressive loss of motor functions with hypotonia of the limbs early in the evolution of the disease process, seizures, reduced vision, failure of speech and mental function, and death at a mean age of 4 years. These patients frequently have siblings affected by a similar disease process. Although some patients develop rigidity or spasticity of the limbs, it is rare to have torsion spasms, opisthotonos, or athetosis. The corresponding neuropathology consists of widespread spheroid collections in the nervous system without excessive pigment accumulation in the basal ganglia. In addition, there are variable degenerative changes in many central nuclei, generalized atrophy of the cerebellar cortex, and degeneration of the optic pathways, pyramidal and spinocerebellar tracts, and posterior columns. Between these extremes there are cases (Category II) showing progressive loss of motor functions with rigidity, spasticity, occasional hypotonia of the limbs, seizures, reduced vision, failure of speech and mental function and death at a mean age of 10 years. Equinovarus deformities and flexion contractures occur frequently and athetosis occurs in a few cases, but it is rare for these patients to have torsion spasm or opisthotonos. There are a few instances in which siblings are affected with a similar disease process. The neuropathology of these cases consists of a combination of the abnormalities described for Category I and those described for Category III. The disorders in all three groups present early psychomotor retardation, arrest of motor and speech development in the infantile or late-infantile period, a gait disorder in the late-infantile period, or with seizures. None of the cases has a history of a similar disease affecting antecedent generations. The etiology of the disorder is unknown.

MYOTONIC DYSTROPHY IN INFANCY AND CHILDHOOD

Myotonic dystrophy is more often symptomatic in infancy and early childhood than previously supposed, seven definite and two possible cases having come to our attention during a single year. In all but one case the disease was present, though unrecognized, in one or more members of preceding generations. At least three patterns of expression of the disease are suggested. (1) The most common clinical syndrome (five cases) begins at birth or in early infancy with difficulty in nursing, attributable to bilateral facial weakness. Generalized myopathic weakness and hypotonia and variable degrees of retarded motor development are encountered during infancy. In one case there was no difficulty with bulbar musculature and only the limb muscles were involved. No evidence of a progressive loss of motor function has been observed during early childhood, but the pattern of greater proximal than distal weakness of extremities appears to become reversed gradually until the tyical adult distribution of weakness and atrophy is seen. The less common clinical syndromes, which include the two possible cases of myotonic dystrophy, are: (2) almost pure myotonia, symptomatic from early infancy (one case) or evident only on electromyography (one case) and (3) isolated congenital ptosis (one case). Percussion myotonia or myotonia of grasp or both is usually present if looked for. Electromyographic evidence of myotonia has been found in every case and was of great help in establishing the diagnosis. Myopathic changes were identified in three of the five available muscle biopsies. Mental defect was an associated finding in onethird of the cases in the present series.