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PubMed1976

Muscle nuclear size in neuromuscular disease.

Nuclear size has been estimated in muscle biopsy specimens from seven healthy individuals, eight patients with infantile spinal muscular atrophy (types I and II), and eight patients with Duchenne muscular dystrophy. The results indicate a great increase in nuclear size in Duchenne muscular dystrophy but not in spinal muscular atrophy when compared with controls. The reasons for this finding are discussed in relation to the pathogenesis of these two groups of diseases.

Cell Nucleus↗
PubMed2002

Hereditary motor neuropathies and motor neuron diseases: which is which.

When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Immunohistochemical analysis of the distribution of MyoD1 in muscle biopsies of primary myopathies and neurogenic atrophy.

The expression of the myogenic determination gene MyoD1 plays a primary role in the commitment of primitive mesenchymal cells to a striated muscle lineage and is down-regulated during later stages of differentiation. To determine the potential role of this gene in myopathic conditions, we examined its expression by means of immunohistochemical analysis, using a series of muscle biopsies from 14 patients with a variety of primary myopathies and neurogenic disorders. Utilizing the avidin-biotin-complex technique, cryostat sections were stained with monoclonal antibody 5.8 A, which we have previously described as having a high level of specificity for tumors with rhabdomyoblastic differentiation. Of special interest was the observation in 4 of 8 cases of neurogenic atrophy of varying levels of cytoplasmic positivity of muscle fibers, appearing to correlate with their degree of atrophy, in addition to weak nuclear staining. Muscle biopsies from 2 patients with Duchenne's muscular dystrophy and 2 patients with autoimmune inflammatory myopathies demonstrated various levels of nuclear positivity in scattered foci that appeared to correlate with areas of regeneration. A biopsy from a single case of neurogenic atrophy secondary to infantile spinal muscular atrophy (Werdnig-Hoffmann's disease) demonstrated diffuse but relatively weak staining of myofiber nuclei, in contrast to sections of normal striated muscle and muscle biopsies from patients with unexplained myoglobinuria, which exhibited only minimal amounts of staining. These data are compatible with observations that MyoD1 expression is related to electrical activity and muscle regeneration.

Adult↗
PubMed2003

The genetics of motor neuron diseases.

Motor neuron diseases may be divided into three categories: those with lower motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA or Kennedy's disease); those with upper motor neuron involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and those with combined upper and lower motor neuron involvement--amyotrophic lateral sclerosis (ALS). Other familial motor neuron disorders include hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome of Guam. The contribution of genetics to the etiopathogenesis of motor neuron considerably, accounting for a high percentage of spinal muscular atrophies, but only a small fraction of cases of ALS. The mode of inheritance also varies, with examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked kindreds. (Tables 1 and 2).

Amyotrophic Lateral Sclerosis↗
PubMed1997

Ultrasonographic assessment of the prevalence of fasciculations in lesions of the peripheral nervous system.

In previous studies, ultrasonography was a very sensitive method in detecting fasciculations. The present study was intended to examine the prevalence of ultrasonographically visible fasciculations in patients with neuromuscular diseases affecting the lower extremities. Ultrasonography of 9 muscles (rectus femoris, vastus lateralis, vastus intermedius, vastus medialis, sartorius, semitendinosus, tibialis anterior, gastrocnemius, and soleus muscles) was performed bilaterally in 70 adult healthy subjects and 172 patients with various neuromuscular diseases. Fasciculations were detected in 109 (63%) of 172 patients. The median value of affected muscles was 10 (range 1-18). Patients with spinal muscular atrophy (37/38, p < 0.001), hereditary motor and sensory neuropathy (24/25, p < 0.001), and lumbosacral radiculopathy with motor deficits (24/29, p < 0.001) exhibited fasciculations more frequently than did healthy volunteers. Radiculopathy with sensory deficits, lesions of either plexus or peripheral nerves, compartment syndrome, and myopathy were not associated with a significantly enhanced prevalence of fasciculations in the patient group compared to the control group. In summary, fasciculations are a frequent ultrasonographic sign in neuromuscular diseases. They are almost regularly found in patients with spinal muscular atrophy and those with hereditary motor and sensory neuropathy. Thus, the absence of fasciculations in ultrasonographic assessment should give cause for reconsidering these diagnoses.

Adolescent↗
PubMed2005

Quantitative analysis of SMN1 and SMN2 genes based on DHPLC: a highly efficient and reliable carrier-screening test.

Autosomal recessive spinal muscular atrophy (SMA) is a common, fatal neuromuscular disease caused by homozygous absence of the SMN1 gene in approximately 94% of patients. However, a highly homologous SMN2 gene exists in the same chromosome interval, centromeric to SMN1, and hampers detection of SMN1. We present a new, rapid, simple, and highly reliable method for detecting the SMN1 deletion/conversion and for determining the copy numbers of the SMN1 and SMN2 genes by DHPLC. We analyzed SMN1/SMN2 gene exon 7 deletion/conversion by DHPLC. A total of 25 patients with spinal muscular atrophy lacking the SMN1 gene as well as 309 control individuals from the general population and the family members of patients with SMA were analyzed. By DHPLC analysis, we could detect the SMA-affected cases efficiently just by recognizing an SMN2-only peak. Furthermore, after specific primer amplification and adjustment of the oven temperature, all of the SMA carriers with an SMN1/SMN2 ratio not equal to 1 could be identified unambiguously by this simple and efficient detection system. To calculate the total SMN1/SMN2 gene dosages further, we developed a specific multiplex competitive PCR protocol by simultaneously amplifying the CYBB gene (X-linked), the KRIT1 gene (on chromosome arm 7q), and the SMN1/SMN2 gene ratio by DHPLC. By applying this technique, we could successfully designate all of the genotypes with different SMN1/SMN2 gene copy numbers, including equal and unequal amounts of SMN1 and SMN2. We demonstrated that DHPLC is a fast and reliable tool for detection of carriers of SMA.

Chromatography, High Pressure Liquid↗
PubMed2004

Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA exclusively affects males, while females are usually asymptomatic. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the first exon of the androgen receptor (AR) gene. The histopathological hallmark is the presence of nuclear inclusions containing mutant truncated ARs with expanded polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as well as in some other visceral organs. The AR ligand, testosterone, accelerates AR dissociation from heat shock proteins and thus its nuclear translocation. Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their SBMA-like phenotypes are rescued by castration, and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as well as main therapeutic target of this disease.

Animals↗
PubMed2006

SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials.

BACKGROUND: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy. OBJECTIVE: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment. METHODS: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein. RESULTS: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity. CONCLUSION: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

Biomarkers↗
PubMed2000

A cell system with targeted disruption of the SMN gene: functional conservation of the SMN protein and dependence of Gemin2 on SMN.

The motor neuron degenerative disease spinal muscular atrophy is caused by reduced expression of the survival motor neuron (SMN) protein. Here we report a genetic system developed in the chicken pre-B cell line DT40, in which the endogenous SMN gene is disrupted by homologous recombination, and SMN protein is expressed from a chicken SMN cDNA under control of a tetracycline (tet)-repressible promoter. Addition of tet results in depletion of SMN protein and consequent cell death, which directly demonstrates that SMN is required for cell viability. The tet-induced lethality can be rescued by expression of human SMN, indicating that the function of SMN is highly conserved between the two species. Cells expressing low levels of SMN display slow growth proportional to the amount of SMN they contain. Interestingly, the level of the SMN-interacting protein Gemin2 decreases significantly following depletion of SMN, supporting the conclusion that SMN and Gemin2 form a stable complex in vivo. This system provides a powerful setting for studying the function of SMN in vivo and for screening for potential therapeutics for spinal muscular atrophy.

Amino Acid Sequence↗
PubMed1993

Features of motor control in patients with proximal childhood spinal muscle atrophy (pilot study).

The differences in the motor performance during different tasks between 19 subjects suffering from SMA and 10 healthy controls were observed. The simultaneous EMG activity of twelve lower limbs and lower trunk muscles was recorded with surface electrodes. EMG data were automatically reduced and compared with data evaluated from performed by physiotherapist manual testing of muscle strength. Results showed characteristic differences between healthy and spinal muscular atrophy (SMA) subjects: 1. SMA patients display generally more activity occurring in numerous muscle groups and more spinal levels are activated. 2. SMA patients reveal a disturbed functional relation between the posterior and anterior compartments of muscles. 3. EMG activity in SMA patients is spreading out also to the contralateral muscle groups even during slight, unilateral singlejoint movements. Oligosegmental, plurisegmental and brain sources are probably responsible for mentioned phenomena. The reciprocal influences between reduced number of motoneurons (in SMA) and function of central movement generators results in different mode of movement execution in SMA patients.

Adolescent↗
PubMed1984

Carnitine and acyltransferase in experimental neurogenic atrophies: changes with treatment.

Carnitine level and carnitine palmityl transferase (CPT) activity were investigated in muscles of patients with infantile and juvenile spinal muscular atrophy and polyneuropathies. A significant decrease of both carnitine and CPT was found in the infantile spinal muscular atrophy, but not in the other neurogenic muscle atrophies. These findings were compared with the experimental effect of denervation and reinnervation upon the lipid metabolism in soleus and extensor digitorum longus (EDL) of adult and newborn rats. Twenty-one days after denervation free and total carnitine decreased significantly in both EDL (P less than 0.001) and soleus (P less than 0.05) of adult animals. CPT activity was significantly decreased in the soleus 50 days after denervation (P less than 0.005). Long-term reinnervation restored the level of carnitine fraction and CPT activity. L-carnitine treatment for 21 days restored the level of free carnitine to normal in the soleus of denervated adult animals. Denervation in newborn rats influenced carnitine concentration in soleus and EDL to a lesser extent; the treatment with L-carnitine raised short-chain acylcarnitines in denervated muscles, while reinnervation restored carnitine level within 50 days.

Acyltransferases↗
PubMed2003

Reduction of the size of the Golgi apparatus of spinal anterior horn cells in patients with X-linked spinal and bulbar muscular atrophy.

The Golgi apparatus (GA) of spinal anterior horn cells was examined immunohistochemically in five patients with X-linked spinal and bulbar muscular atrophy (SBMA), in five patients with sporadic amyotrophic lateral sclerosis (ALS) and in five patients without neurodegenerative diseases. In SBMA cases, reduction of the size of the GA was observed in numerous anterior horn cells; however, fragmentation of the GA, previously described in sporadic and familial ALS with SOD1 mutations, was observed only in a few neurons. In addition, motor neurons bearing an intranuclear inclusion showed a normal network of elements of the GA. The frequencies of fragmented GA in counted motor neurons were 0-2.4 % in SBMA cases, 0-3.0 % in normal control cases and 15.7-55.3 % in ALS cases. The different frequency of fragmented GA between SBMA and ALS adds another finding of pathogenetic difference of neurodegeneration in these two motor neuron diseases.

Aged↗
PubMed1996

Prenatal diagnosis of X-linked spinal and bulbar muscular atrophy in a Greek family.

X-linked spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disorder which is caused by an expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene. Two cases of prenatal testing for the disease in a Greek family are reported. An affected male died in his late 50s of this disorder and his 30-year-old daughter (an obligate carrier) asked for prenatal testing for SBMA. DNA analysis revealed that she indeed carried an expanded allele of 40 repeats, as well as a normal size allele of 24 repeats. Prenatal diagnosis of SBMA was performed when, on two successive pregnancies, two male fetuses with the expanded (CAG)n allele were found.

Adult↗
PubMed1995

Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the androgen-receptor gene. The length of this repeat varies as it is passed down through SBMA families, and correlates inversely with the age of onset of the disease. The motor-neuron degeneration that occurs in this disease is probably caused by a toxic gain of function in the androgen-receptor protein. Subsequent to the identification of the mutation in SBMA, other inherited neurodegenerative diseases have been found to be caused by the expansion of CAG repeats in the coding regions of other genes. Because these diseases probably share a common pathogenesis, investigation of SBMA might help to determine a general mechanism of neuronal degeneration.

Humans↗
PubMed2006

Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.

Activities of Daily Living↗
PubMed2004

Congenital club foot with survival of motor neuron 1, telomeric (SMN1) gene deletion.

A boy with nonreducible bilateral congenital talipes equinovarus had delayed milestones with early-onset generalized hypotonia and muscular weakness. The condition remained stable until he was 8 years old. A slow worsening of motor abilities, with myopathic signs, was observed thereafter. A homozygous deletion of exons 7 and 8 of the survival of motor neuron 1, telomeric (SMN1) gene was found, without neuronal apoptosis inhibitory protein (NAIP) gene deletion, leading to the diagnosis of spinal muscular atrophy. Independent ambulation was lost when he was 13 years old. The occurrence of congenital clubfoot with early onset of neurologic signs, but with a very slowly progressive course, has not been reported in spinal muscular atrophy until now.

Adolescent↗